Clinical Oncology News - April 2010 - Digital Edition

McMahon Publishing

Advances in Cancer Care CLINICALONCOLOGY.COM • April 2010 • Vol. 5, No. 4

SOLID TUMORS

7

Large trial correlates rectal cancer TN staging with outcome.

9 30

Genetic markers identified for poor outcomes in gastric cancer.

Challenges in advancing antiangiogenic cancer therapy.

FDA NEWS

13

News on Trelstar, bisphosphonates and new dosing regimen for Dacogen.

POLICY & MANAGEMENT

15

Recession-proof investment alternatives for doctors.

SUPPORTIVE CARE

24

Treating the side effects of aromatase inhibitor therapy.

HEMATOLOGIC DISEASE

31

Alemtuzumab effective for relapsed CLL patients.

EDUCATIONAL REVIEW

Management of EGFR InhibitorInduced Dermatologic Toxicity After page 22.

WWW.CMEZONE.COM

Breakthrough Pain Significant for Many Cancer Patients

Prostate Cancer Drug Promising for Unmet Need

B

San Francisco—A drug that few oncologists have even heard of may soon provide an option for men with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel-based chemotherapy. Cabazitaxel (Sanofi-aventis) improved median overall survival by roughly 2.4 months compared with standard therapy in this patient population, according to a study presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCOGCS) held in March (abstract 9).

“Cabazitaxel demonstrated a statistically and clinically significant overall s u r v i va l improvement compared with

reakthrough pain (BTP) inflicts a heavy toll on the quality of life of cancer patients and cancer survivors, according to a survey commissioned by the American Pain Foundation.

The survey did not aim to provide rigorous epidemiological data, but it does offer a “snapshot of the adverse consequences that occur in a subset of patients with cancer and significant BTP,” according to one of its designers, Russell Portenoy, MD, chairman of the Department of Pain Medicine and Palliative Care at Beth Israel Medical Center, New York City. The burden these patients report may encourage physicians to ask about the phenomenon in cancer patients and survivors, he added.

The survey was administered online to 545 individuals with cancer see SURVEY, page 23

Court Battle Fought Over BRCA Patents

Credit: Steve Gschmeissner/ Photo Researchers, Inc.

mitoxantrone.

T h e ove ra l l survival benefit was consistent across subgroups.

The safety profile was predictable and manageable,” said Oliver Sartor, MD, Plitz Professor for Cancer Research at Tulane Cancer Center, New Orleans, who led the study. “We believe that cabazitaxel is a potential new therapeutic option for the treatment of patients with metastatic castration-resistant see CABAZITAXEL, page 8

POLICY & MANAGEMENT

I

s it legal to patent a gene? A lawsuit winding its way through the courts argues that it is not. On March 29, 2010, a judge in a New York federal court

agreed and ruled that patents on BRCA1 and BRCA2 are invalid because genes are products of nature. The lawsuit filed last May against Myriad, the maker of the BRCA gene test, and the United States Patent and Trademark Office, see BRCA, page 40

Colored scanning electron micrograph of a moving prostate cancer cell on a filter (green).

Cytotoxic Drug Residues Still Lurking in Hospitals Las Vegas—Despite decades of regulation and policies in health care institutions, workplace contamination from cytotoxic agents is still widespread, even in facilities that have made concerted efforts to foster workplace safety, according to studies presented at the American Society of Health-System Pharmacists Midyear Clinical Meeting.

Computer keyboards, elevator buttons and flooring were just a few of the areas found to be contaminated with cytotoxic agents—often several hundred feet beyond

prep areas that are supposedly designed to prevent the spread of these potentially harmful substances. The findings led one safe-handling expert to warn against continued complacency.

“I want to demythologize the idea that we have taken care of this problem,” stressed presenter Melissa McDiarmid, MD, MPH, DABT, professor of medicine and director of the University of Maryland School of Medicine’s Occupational Health Program, in Baltimore. Some see CYTOTOXIC, page 10

Imatinib Dose Escalation in the Management of Recurrent Gastrointestinal Stromal Tumors: A Case Study See page 32

Indications and Important Safety Information for ALIMTA Indications ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Important Safety Information Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Contraindication: ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

Warnings and Precautions: Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities.

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA® is a registered trademark of Eli Lilly and Company.

PM58001 0709 PRINTED IN USA © 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drugrelated toxicity following administration of ALIMTA alone.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

Drug Interactions: Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration.

Histology Matters with ALIMTA because

EXTENDED SURVIVAL MATTERS. Approved for the 1st-line treatment of advanced nonsquamous NSCLC and now approved for the maintenance treatment of advanced nonsquamous NSCLC. ALIMTA is not indicated for the treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Within the ALIMTA maintenance trial design, ALIMTA/cisplatin was not included as an induction therapy.

For more information, visit www.ALIMTA.com Use in SpeciďŹ c Patient Populations: It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

The safety and effectiveness of ALIMTA in pediatric patients have not been established.

Dose adjustments may be necessary in patients with hepatic insufďŹ ciency.

Dosage and Administration Guidelines: Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence) for NSCLC 1st-line: The most severe adverse reactions (Grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1).

Common adverse reactions (all Grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6).

Abbreviated Adverse Reactions (% incidence) for NSCLC Maintenance: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NSCLC) were anemia (3 vs 1); neutropenia (3 vs 0); leukopenia (2 vs 1); fatigue (5 vs 1); nausea (1 vs 1); anorexia (2 vs 0); mucositis/ stomatitis (1 vs 0); diarrhea (1 vs 0); infection (2 vs 0); neuropathy-sensory (1 vs 0). Common adverse reactions (all Grades) with ALIMTA as a single agent versus placebo, respectively, were anemia (15 vs 6); neutropenia (6 vs 0); leukopenia (6 vs 1); increased ALT (10 vs 4); increased AST (8 vs 4); fatigue (25 vs 11); nausea (19 vs 6); anorexia (19 vs 5); vomiting (9 vs 1); mucositis/stomatitis (7 vs 2); diarrhea (5 vs 3); infection (5 vs 2); neuropathy-sensory (9 vs 4); and rash/desquamation (10 vs 3).

Abbreviated Adverse Reactions (% incidence) for NSCLC 2nd-line: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus docetaxel, respectively, for the 2nd-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (5 vs 40); leukopenia (4 vs 27); thrombocytopenia (2 vs 0); anemia (4 vs 4); fatigue (5 vs 5); nausea (3 vs 2); anorexia (2 vs 3); vomiting (2 vs 1); increased ALT (2 vs 0); increased AST (1 vs 0); and stomatitis/pharyngitis (1 vs 1). Common adverse reactions (all Grades) with ALIMTA as a single agent versus docetaxel, respectively, were fatigue (34 vs 36); nausea (31 vs 17); anorexia (22 vs 24); anemia (19 vs 22); vomiting (16 vs 12); stomatitis/pharyngitis (15 vs 17); rash (14 vs 6); diarrhea (13 vs 24); leukopenia (12 vs 34); and neutropenia (11 vs 45).

For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

5 5.1

CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

WARNINGS AND PRECAUTIONS Premedication Regimen Need for Folate and Vitamin B12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.

Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)].

5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)].

5.5 Required Laboratory Monitoring Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. [see Use in Specific Populations (8.1)] 5.7 Third Space Fluid The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC)—Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa ALIMTA/cisplatin Gemcitabine/cisplatin Reaction b (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Leukopenia 18 5 21 8 Thrombocytopenia 10 4 27 13 Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/Pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/Heartburn 5 0 6 0 Neurology Neuropathy-sensory 9 0 12 1 Taste disturbance 8 0c 9 0c Dermatology/Skin Alopecia 12 0c 21 1c Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.

In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Whole—febrile neutropenia, infection, pyrexia General Disorders—dehydration Metabolism and Nutrition—increased AST, increased ALT Renal—creatinine clearance decrease, renal failure Special Senses—conjunctivitis

ALIMTA姞 (pemetrexed for injection)

ALIMTA姞 (pemetrexed for injection)

ALIMTA姞 (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1

INDICATIONS AND USAGE

1.1

Nonsquamous Non-Small Cell Lung Cancer—Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2

Nonsquamous Non-Small Cell Lung Cancer—Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.3

Nonsquamous Non-Small Cell Lung Cancer—After Prior Chemotherapy ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

1.4

Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

1.5

Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, and 14.3)] 2

DOSAGE AND ADMINISTRATION

2.1

Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.

See cisplatin package insert for more information.

2.2

Single-Agent Use Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3

Premedication Regimen Vitamin Supplementation To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)].

Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4

Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/ mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery.

Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3 75% of previous dose (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC 75% of previous dose (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 with bleeding a, regardless of nadir ANC 50% of previous dose (pemetrexed and cisplatin) a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Nonhematologic Toxicities a,b Dose of ALIMTA Dose of Cisplatin (mg/m 2) (mg/m 2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea 75% of previous dose 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose a NCI Common Toxicity Criteria (CTC). b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3.

Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Neurotoxicity Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information].

3

DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4

PV 5206 AMP

PV 5206 AMP

Incidence Less than 1% Cardiovascular—arrhythmia General Disorders—chest pain Metabolism and Nutrition—increased GGT Neurology—motor neuropathy Non-Small Cell Lung Cancer (NSCLC) - Maintenance Table 5 provides the frequency and severity of adverse reactions that have been reported in >5% of 438 patients with NSCLC who received ALIMTA and 218 patients with NSCLC who received placebo. All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa ALIMTA Placebo (N=438) (N=218) Reaction b All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Leukopenia 6 2 1 1 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional Symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Infection 5 2 2 0 Neurology Neuropathy-sensory 9 1 4 0 Dermatology/Skin Rash/Desquamation 10 0 3 0 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.

No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.

Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA. Incidence 1% to 5% Dermatology/Skin—alopecia, pruritis/itching Gastrointestinal—constipation General Disorders—edema, fever (in the absence of neutropenia) Hematologic—thrombocytopenia Renal—decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate Special Senses—ocular surface disease (including conjunctivitis), increased lacrimation Incidence Less than 1% Cardiovascular—supraventricular arrhythmia Dermatology/Skin—erythema multiforme General Disorders—febrile neutropenia, allergic reaction/hypersensitivity Neurology—motor neuropathy Renal—renal failure Non-Small Cell Lung Cancer (NSCLC)—After Prior Chemotherapy Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy.

Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa ALIMTA Docetaxel Reaction b (N=265) (N=276) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Anemia 19 4 22 4 Leukopenia 12 4 34 27 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Hepatic Increased ALT 8 2 1 0 Increased AST 7 1 1 0 Clinical Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/Pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Constitutional Symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Dermatology/Skin Rash/Desquamation 14 0 6 0 Pruritis 7 0 2 0 c 38 2c Alopecia 6 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0). c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

ALIMTA姞 (pemetrexed for injection) PV 5206 AMP

No clinically relevant differences in adverse reactions were seen in patients based on histology.

Clinically relevant adverse reactions occurring in <5% of patients that received ALIMTA treatment but >5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel).

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA. Incidence 1% to 5% Body as a Whole—abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin—erythema multiforme Neurology—motor neuropathy, sensory neuropathy Renal—increased creatinine Incidence Less than 1% Cardiovascular—supraventricular arrhythmias Malignant Pleural Mesothelioma (MPM) Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12.

Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa ALIMTA/cisplatin Cisplatin (N=168) (N=163) Reaction b All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Neutropenia 56 23 13 3 Leukopenia 53 15 17 1 Anemia 26 4 10 0 Thrombocytopenia 23 5 9 0 Renal Creatinine elevation 11 1 10 1 Creatinine clearance decreased 16 1 18 2 Clinical Eye Disorder Conjunctivitis 5 0 1 0 Gastrointestinal Nausea 82 12 77 6 Vomiting 57 11 50 4 Stomatitis/Pharyngitis 23 3 6 0 Anorexia 20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Constitutional Symptoms Fatigue 48 10 42 9 Metabolism and Nutrition Dehydration 7 4 1 1 Neurology Neuropathy-sensory 10 0 10 1 Taste Disturbance 8 0c 6 0c Dermatology/Skin Rash 16 1 5 0 Alopecia 11 0c 6 0c a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity except the term “creatinine clearance decreased” which is derived from the CTC term “renal/genitourinary-other”. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Whole—febrile neutropenia, infection, pyrexia Dermatology/Skin—urticaria General Disorders—chest pain Metabolism and Nutrition—increased AST, increased ALT, increased GGT Renal—renal failure Incidence Less than 1% Cardiovascular—arrhythmia Neurology—motor neuropathy Effects of Vitamin Supplementations Table 8 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.

Table 8: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence) Fully Supplemented Never Supplemented Patients Patients a Adverse Event (%) (N=168) (N=32) Neutropenia/granulocytopenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).

The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).

Subpopulations No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinal—colitis General Disorders and Administration Site Conditions—edema Injury, poisoning, and procedural complications—Radiation recall has been reported in patients who have previously received radiotherapy Respiratory—interstitial pneumonitis ALIMTA姞 (pemetrexed for injection)

PV 5206 AMP

7

DRUG INTERACTIONS

7.1

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration.

If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

7.2

Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy Teratogenic Effects—Pregnancy Category D [see Warnings and Precautions (5.6)] Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3

Nursing Mothers It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17

PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling.

Patients should be instructed to read the patient package insert carefully.

17.1 Need for Folic Acid and Vitamin B12 Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)].

17.2 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur.

17.3 Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.

17.4 Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

17.5 FDA-Approved Patient Labeling Patients should be instructed to read the patient package insert carefully.

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

Pediatric Use The safety and effectiveness of ALIMTA in pediatric patients have not been established.

8.5

Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 33.3% of patients treated with ALIMTA were ≥65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.74 (95% CI: 0.58, 0.93) and for patients ≥65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were ≥65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients ≥65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent-to-treat population.

The mesothelioma trial included 36.7% patients treated with ALIMTA plus cisplatin that were ≥65 years, and Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.71 (95% CI: 0.53, 0.96) and for patients ≥65 years, the HR was 0.85 (95% CI: 0.59, 1.22) in the intent-to-treat population.

8.6

Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)].

8.7

Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8

Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent-totreat population.

In the mesothelioma trial, 82% of patients were males and 18% females. For males the HR for overall survival was 0.85 (95% CI: 0.66, 1.09) and for females the HR was 0.48 (95% CI: 0.27, 0.85) in the intent-to-treat population.

8.9

Race In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others.

For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent-to-treat population.

In the mesothelioma trial, 92% of patients were Caucasians and 8% others. For Caucasians, the HR for overall survival was 0.77 (95% CI: 0.61, 0.97) and for others the HR was 0.86 (95% CI: 0.39, 1.90) in the intent-to-treat population.

Literature revised July 2, 2009

Eli Lilly and Company Indianapolis, IN 46285, USA

10

OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • APRIL 2010

Anal

Large Trial Correlates Anal Cancer TN Staging With Outcome

TM

ADVISORY BOARD Bioethics Joseph P. DeMarco, PhD Paul J. Ford, PhD

Community Oncology Michael J. Fisch, MD, MPH John W. Finnie, MD

Oncology Nursing

Polly E. Kintzel, PharmD Melvin E. Liter, MS, PharmD

Policy and Management Mary Lou Bowers, MBA Barbara Constable, RN, MBA Rhonda M. Gold, RN, MSN

75

60

59

Solid Tumors

Infection Control

Bone Metastases

Susan K. Seo, MD

Allan Lipton, MD

Symptom Control and Palliative Care

Breast Cancer

William S. Breitbart, MD Steven D. Passik, PhD Joseph V. Pergolizzi Jr., MD Russell K. Portenoy, MD Charles F. von Gunten, MD

Andrew Seidman, MD Maura N. Dickler, MD

Gastrointestinal Cancer Edward Chu, MD Cathy Eng, MD Leonard Saltz, MD

Gastrointestinal Cancer and Sarcoma

40 20 0

Figure 1. Five-year survival in node-negative anal cancer patients.

80 66 60 44 40 20 0

Figure 2. Five-year survival in node-positive anal cancer patients.

‘Because anal cancer is uncommon, statistics on survival are not exact. They depend on reporting from centers that only see a small number of patients.’

— Wasif Saif, MD, MBBS

EDITORIAL STAFF Kate O’Rourke, Editor korourke@mcmahonmed.com

Ephraim Casper, MD

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

Genitourinary Cancer

James Prudden, Group Editorial Director

Ronald M. Bukowski, MD

David Bronstein, Editorial Director, Hospital Group

Gynecologic Cancer

T3N1-3

81 80

The findings clearly support TN categorization of anal cancer, Dr. Gunderson said. “Patients with two high-risk categories have lower survival and higher relapse rates than patients with only one risk factor.” According to Dr. Saif, “once a diagnosis of anal cancer is made, additional tests should be performed to determine the exact stage of the disease.”

Investigators say the results call for increased study on ways to best treat patients and suggest that patients at greater risk may be candidates for dose escalation with intensity-modulated irradiation and targeted chemotherapy

Betty Ferrell, RN, PhD

Pharmacy

T2N1-3

100

T4N0

groups of patients and three groups of patients. The first set comprised patients with T2-3N0 versus T4N0/TanyN+ and the second included T2-3N0, T2N+/T4N0 and T3-4N+, Dr. Gunderson explained.

When researchers looked at overall survival (OS), increased tumor invasiveness was associated with decreased survival among node-negative patients; at five years, 81% of patients with T2N0 disease were alive, 75% of patients with T3N0 disease were alive, and 59% who had T4N0 were alive (P=0.0001) (Figure 1). Survival rates were lower among node-positive compared with node-negative patients of the same tumor stage; however, TN stage remained a significant factor, as five-year survival among T2N13 patients was 22% higher than T3N1-3, at 66% versus 44% (P=0.0001) (Figure 2).

Researchers also looked at whether TN categorization could be used to predict distant metastasis, and found that distant metastasis was “significantly higher” in node-positive T2N1-3 and T3N1-3 than in node-negative T2N0 and T3N0.

However, researchers found a decrease in distant metastasis in T4N1-3 patients compared with T2-3N1-3.

“This may have been due to patients dying of local-regional relapse before they could manifest distant disease,” Dr. Gunderson said. Additionally, the study found an almost inverse relationship between OS and local-regional relapse.

Hematologic Malignancies Jennifer R. Brown, MD, PhD Agnes Y.Y. Lee, MSc, MD Richard Stone, MD

T3N0

100

Patients Alive, %

Results from the U.S. Gastrointestinal Intergroup RTOG 98-11 trial were presented at the recent Gastrointestinal Cancers Symposium (GCS; abstract 285)

by Leonard L. Gunderson, MD, MS, president-elect of the American Society for Radiation Oncology.

According to Wasif Saif, MD, MBBS, associate professor and co-director of the gastrointestinal cancers program at the Yale Cancer Center, Yale School of Medicine, in New Haven, Conn., the study is important because it is the first to correlate TNM staging with outcome in anal cancer. “Because anal cancer is uncommon, statistics on survival are not exact. They depend on reporting from centers that only see a small number of patients. The highest number of patients is collected by the SEER [Surveillance, Epidemiology, and End Results] database of the National Cancer Institute,” said Dr. Saif, who was not involved with the study. The SEER, however, does not report survival of patients with anal cancer by TNM stage, but instead divides them into three groups: localized, regional and distant.

In the study presented at GCS, investigators analyzed data from 615 patients.

Initially, patients were separated into six groups based on the pathologic stage of the cancer: T2N0, T3N0, T4N0, T2N+, T3N+ and T4N+. After initial analyses, however, patients were split into two

T2N0

Patients Alive, %

Orlando, Fla.—Categorizations of anal carcinoma based on primary tumor extension and the extent of lymph node spread can accurately predict patient survival, disease relapse and colostomy failure, according to a Phase III trial.

agents like cetuximab. Additionally, Dr. Gunderson said, aggressive surgery should not be overlooked as a key tool in fighting anal cancer. “We have left that on the shelf too long,” he asserted.

Dr. Gunderson urged that the findings should not lead providers to ease up on treating patients determined to be in lower-risk groups. “Significant challenges remain for patients with T4N0 and T3-4N+ categories of disease, but there are still challenges for patients with T2-3N0 and T2N1-3 disease.”

—David Jakubiak

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ART AND PRODUCTION STAFF Michele McMahon Velle, Creative Director, MAX Graphics Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics Dan Radebaugh, Director of Production and Technical Operations Diane Nielebock, Circulation Coordinator Mark Neufeld, Associate Director, Project Management

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7

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • APRIL 2010

Prostate

CABAZITAXEL continued from page 1

prostate cancer after failure of docetaxel-based therapy.”

The news created quite a buzz at the ASCO-GCS meeting. “This came out of nowhere,” said Philip W. Kantoff, MD, director of the Lank Center for Genitourinary Oncology at Dana- Farber Cancer Institute, and a professor in the Department of Medicine at Harvard Medical School, both in Boston. “Very few people had heard about this drug, so there is a lot of excitement about this.” Dr. Kantoff was not involved with the study.

Limited Options The standard of care for first-line therapy of mCRPC is docetaxel (Taxotere, Sanofi-aventis), but there is currently no approved standard second-line therapy. Treatment options include supportive care or investigational drugs. According to Dr. Kantoff, the standard default is to treat these patients with prednisone and mitoxantrone. In the international Phase III TROPIC trial, investigators tested cabazitaxel, a novel taxane that has been shown to be active in docetaxel-resistant tumor cells. The drug is a microtubule stabilizer.

The TROPIC trial, which involved 132 centers in 26 countries, enrolled 755 men with mCRPC with Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function who had progressed during or after therapy with docetaxel (cumulative dose ≥225 mg/m2). Study participants were randomized in a 1-to-1 fashion to receive 10 mg per day of prednisone with either 12 mg/m2 mitoxantrone every three weeks (MP) for 10 cycles or prednisone

‘If it gets approved, it will likely be used in the post-Taxotere setting, but the question is—is this a newer, better version of Taxotere?’

—Philip W. Kantoff, MD

in the same dose with cabazitaxel 25 mg/m2 for 10 cycles. The median number of cycles given during the trial was four in patients receiving mitoxantrone and six in patients receiving cabazitaxel. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate, pain measures and safety.

The median age of patients was 68 years and 84% were white; patient characteristics were well balanced. Dr. Sartor said the extent of disease in many of the subjects distinguished this trial from previous studies. “More than half the patients in the trial had measurable disease [54.1% in the MP arm and 53.2% in the cabazitaxel arm],” he pointed out. “This is quite a large number compared to other trials with castrate-refractory prostate cancer, and I think it reflects this [is an] advanced patient population.” Additionally, “almost 25% of the patients had visceral disease,” further demonstrating advanced disease.

He also pointed out that the patients had received a fair amount of docetaxel therapy. The median total prior dose of docetaxel was 529 mg/m2 in the MP group and 576.5 mg/m2 in the cabazitaxel arm.

The investigators found that patients receiving cabazitaxel demonstrated a statistically significant longer median OS compared with MP, 15.1 versus 12.7 months, respectively (hazard ratio, 0.70; 95% confidence interval, 0.590.83; P<0.0001) (Figure 1). PFS (composite of tumor, prostate-specific antigen [PSA] or pain progression; or death)

and response rates for tumor assessments by RECIST (Response Evaluation Criteria In Solid Tumors), PSA response and PSA progression also favored cabazitaxel (Figures 2 and 3). The median number of treatment cycles was six for patients receiving cabazitaxel and four for patients receiving MP. The most frequent grade 3/4 toxicity was neutropenia, which was observed in 81.7% of patients treated with cabazitaxel and 58% treated with MP. Grade 3/4 febrile neutropenia was also more common in patients receiving cabazitaxel at 7.5% and 1.3%, respectively (Figure 4), reported Dr. Sartor, who disclosed that he had been a consultant and received honoraria and research support from Sanofi-aventis.

Optimism About Approval Three additional experts not involved with the TROPIC study say the results from the trial may be practice-changing in a year or two. “It looks like it might be a game-changing drug in the future,” said Scott Williams, MD, a consultant radiation oncologist with the Peter MacCallum Cancer Centre Uro-Oncology service in Melbourne, Australia. Nicholas Vogelzang, MD, chair and medical director, Developmental Therapeutics Committee, US Oncology Research, and a medical oncologist at the Comprehensive Cancer Centers of Nevada, in Las Vegas, agreed. “We believe that this will be an FDA-approvable drug in the near term. It’s a very powerful study,”

Dr. Vogelzang said. “It’s the first positive study of its kind, and it should clearly be considered now as an alternative for men who have failed docetaxel therapy.”

Dr. Kantoff is also optimistic about a drug approval, but pondered whether the drug may have an even brighter future. “If it gets approved, it will likely be used in the post-Taxotere setting, but the question is—is this a newer, better version of Taxotere? That is a question that has to be raised,” Dr. Kantoff said.

He pointed out that the TROPIC study does not address this question, but is something that has weighed on his mind since he heard the TROPIC data.

William D. Figg Sr., PharmD, head of the Molecular Pharmacology Section and senior scientist at the National Cancer Institute in Bethesda, Md., said that the higher rates of neutropenia seen in the cabazitaxel-treated patients is a cause for concern. “I don’t think it will preclude anyone from using this drug, if approved, but it’s something that [clinicians] will have to monitor more carefully, and potentially recommend other agents to reverse the side effect.”

Dr. Figg also put the OS data in perspective. “Just over two months of increased survival may not seem like a significant number, in terms of a person’s overall lifespan,” he said. “But it’s huge in cancer research, where advances are sometimes measured in weeks, not months.” Dr. Figg added that for some of the patients in the trial, the survival benefits were even more pronounced. “At 24 months, there were 28 patients who were still alive in the cabazitaxel arm, versus only 11 patients in the mitoxantrone/prednisone arm,” he said. Thus, for some patients, the new taxane “can really make a huge difference in survival.”

—Kate O’Rourke

Cabazitaxel + prednisone

Cabazitaxel + prednisone

Cabazitaxel + prednisone

Cabazitaxel + prednisone

Mitoxantrone + prednisone

Mitoxantrone + prednisone

Mitoxantrone + prednisone

Mitoxantrone + prednisone

P=0.0005

P=0.0005

P=0.0005

P=0.0005

20

15

10

14.4

100 8.8 81.7

12

15.1

8

80

10

9

6 4.4

6

5.4

4

Neutropenia, %

12.7

Median TTP, mo

15

Response Rate, %

Median Overall Survival, mo

8

60

58

40

5

0

Figure 1. Comparison of median overall survival.

3

2

20

0

0

0

Figure 2. Tumor assessment by response rate.

Figure 3. Tumor assessment by median time to progression.

Figure 4. Comparison of grade 3/4 neutropenia.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • APRIL 2010

Stomach

Genetic Markers Identified for Poor Outcome in Gastric Cancer Orlando, Fla.—Patients with gastric cancer who have variants in the CD44 gene have a significantly shorter time to disease recurrence than those without the polymorphisms, according to a recent study.

Patients who had a CD44 variation had a mean time to recurrence of approximately two years, compared with seven years for those without the genetic variation. “For the first time, we have identified germline polymorphisms in the CD44 gene which are associated with clinical outcomes in patients with localized gastric adenocarcinoma,” said lead author Thomas Winder, MD, a postdoctoral research fellow at the University of Southern California, Los Angeles. He presented the study at the 2010 Gastrointestinal Cancers Symposium (abstract 3).

Previous studies have only shown that high CD44 levels are associated with poor prognosis.

“CD44 germline variations may identify patients at high risk for tumor recurrence or metastasis, and if our findings are confirmed in larger, prospective clinical trials, testing for the CD44 variations could help us identify patients who may benefit from more aggressive treatment,” Dr. Winder said. “They could also facilitate the development of therapies targeting this variation.”

In the new study, investigators analyzed the association between the presence of the CD44 variations and the time to cancer recurrence in 137 patients with localized gastric cancer. Investigators isolated DNA from peripheral blood samples of patients between 1992 and 2008.

They analyzed four cell adhesion-related, potentially functional polymorphisms within the CD44 gene. Genetic variations at the CD44 +4883G>A or CD44 +779G>A gene loci were associated with worse outcomes, Dr. Winder reported.

For the first polymorphism, time to recurrence was just 2.1 years for patients with the A/G or G/G phenotype (n=94), compared with seven years for those with the A/A genotype (n=30), which was statistically significant (P=0.022). A trend in decreased overall survival for patients with the genetic mutations was also seen, 4.1 versus seven years respectively (P=0.079).

For the second polymorphism, patients with the A/G or A/A genotype recurred at a mean time of 2.2 years compared with seven years for those with the G/G genotype (P=0.045). Overall survival was significantly different at 3.8 versus 7.3 years, respectively (P=0.018). The differences held true after adjusting for covariates, including chemotherapy, nodal category and race.

The loss of cell adhesion is a significant event in human cancer

development. The CD44 glycoprotein serves as the principal transmembrane hyaluronate receptor and is associated with adhesion and metastasis in gastrointestinal carcinomas, according to Dr. Winder. Moreover, a gastric cancer stem cell population with CD44 as their

defined surface marker has been identified as having increased resistance to chemotherapy- or radiation-induced cell death. “[The investigators] present very interesting data that goes along with the trend in oncology, which is to tailor therapies to the individual, and one that uses a genetic blueprint to help accomplish that,” said Robert Sticca, MD, chairman, program director and director of surgical oncology at the University of North Dakota School of Medicine

and Health Sciences of Fargo. Because gastric cancer is highly lethal, he said, the ability to genetically tailor therapies would be especially beneficial.

According to Ed Chu, MD, chief of the Section of Medical Oncology and deputy director of clinical research at the Yale Cancer Center, Yale School of Medicine, New Haven, Conn., the study shows that the CD44 polymorphism is an important prognostic biomarker that can identify individuals with early-stage see MARKERS, page 30

9

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Worker Safety

CYTOTOXIC continued from page 1

of these drugs, she noted, “came out of chemical/ biological warfare from World War I. If that doesn’t get our respect, I don’t know what does.”

The studies—one a National Institute for Occupational Safety and Health (NIOSH) investigation conducted at three facilities, another done at Massachusetts General Hospital (MGH) in Boston and the third, a subanalysis of the main NIOSH study—underscore the need for stepped-up efforts to address contamination and better protect workers. The studies provide an extensive amount of new data about problem areas, particularly surface contamination, that are leading to biologically important exposures for health care workers.

Comprehensive Study According to Thomas H. Connor, PhD, a research biologist at NIOSH and lead author of the NIOSH study, other studies have examined cytotoxic contamination, but none have looked at the issue in such a comprehensive manner. “We had about 10,000 handling events, which really helps our power,” said Dr. McDiarmid, co-investigator on the trial.

The NIOSH-led team evaluated three sites—University of Maryland Medical Center, in Baltimore; University of North Carolina Memorial Hospitals, in Chapel Hill; and the University of Texas M.D. Anderson Cancer Center, in Houston—and looked for contamination from five commonly used chemotherapeutic agents—cyclophosphamide, cytarabine, 5-fluorouracil (5-FU), ifosfamide and paclitaxel.

To determine exposure, the investigators had exposed workers at the sites (pharmacists, pharmacy technicians, nurses and nursing aides) complete a six-week drug-handling diary listing all the drugs handled and the specific tasks performed. They performed wipe samples of surfaces, took air samples and collected urine samples from the workers, comparing them with a matched control population. The samples were taken from biological safety cabinets, counter tops, waste containers, drug trays, passthrough windows, floors, patient rooms, nursing stations, IV bags and other areas.

In addition to taking air samples from pharmacy areas, the investigators outfitted health care workers with air-collection devices to obtain personal air samples that would assess the air the worker was inhaling for a given period.

They also performed single-cell gel electrophoresis tests (also known as comet assays) to measure DNA damage.

For each worker, they evaluated variables including exposure, the number of handling events for all five agents

combined and separately, the mutagenicity of the drugs handled, the use of personal protective equipment (PPE), and the use of closed-system transfer devices (CSTDs). Liquid chromatography-tandem mass spectroscopy (LC/ MS/MS) techniques was used to analyze the samples.

Substantial Contamination Found The NIOSH results show that “surface contamination is still an issue in pharmacy and nursing areas,” with pharmacy areas generally having “more positive samples and higher values than

nursing [areas].” Defining the limit of detection (LOD) as 1 ng/cm2 for cyclophosphamide, cytarabine and ifosfamide, and 0.7 for 5-FU and paclitaxel, they found that of the 80 wipe samples taken from pharmacy areas, 75% had values above the LOD for at least one of the five drugs.

Of the 65 nursing samples, 42% had values above the LOD for at least one drug.

In addition to a high number of contaminated samples, the degree of contamination from some of the wipe samples was significant (Table). Dr. Connor noted that at one of the sites, there was “some contamination uncovered in an adjoining office area.” Additionally, two

pharmacists at that site were found to have “measurable levels of cyclophosphamide in their urine.” Dr. Connor said that this site did have some flaws in its design, in that the drug preparation area was open to an office area and it had no clean-room design with an anteroom or pass-through windows. The design of the site has since been rectified and a clean room has been added.

At another of the sites, the highest contamination found—910 ng/cm2 of 5-FU—came from a waste container lid in a nursing station. Noting that they also detected a high level of ifosfamide on that waste container (19.8 ng/

In EGFR-Expressing Metastatic Colorectal Cancer . . .

Consider ERBITUX in an Appropriate Patient Population ERBITUX Is the Only MAb With: EFFICACY IN COMBINATION With Irinotecan After Irinotecan Failure

SINGLE AGENT OVERALL SURVIVAL After Irinotecan and Oxaliplatin Failure

ERBITUX® (cetuximab), in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of ERBITUX in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma.1

ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens.1

K-ras STATUS Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13.

Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations.1

ERBITUX + BSC Significantly Increased Overall Survival by 34%vs BSC Alone (P=0.0046) Overall Survival, All Patients (N=572)*1

Safety Limitation Based on K-ras Mutational Status

Incidence of K-ras Mutations Among K-ras Evaluable Patients in NCIC CTG CO.17 Trial1

Mutant 41.6%

OS=overall survival; CI=confidence interval.

Wild Type 58.4%

■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1 ■ The overall survival data presented here include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ In a retrospective analysis of the NCIC CTG CO.17 data shown at left, ERBITUX was not effective in patients with K-ras mutated tumors1 — In this analysis, investigational tests were used to detect K-ras mutations in codon 12 or 13 — 68.9% (394/572) of the patients in the original trial were evaluable for K-ras status — Of those patients, 41.6% (164/394) had tumors containing K-ras mutations

*NCIC CTG CO.17 was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFR-expressing, previously treated, recurrent metastatic colorectal cancer. Patients were randomized (1:1) to receive either ERBITUX plus BSC or BSC alone. ERBITUX was administered as a 400-mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. Of the 572 randomized patients, the median age was 63 years, 64% were male, 89% were Caucasian, and 77% had baseline ECOG performance status of 0-1. All patients were to have received and progressed on prior therapy, including an irinotecan-containing regimen and an oxaliplatin-containing regimen. The main outcome measure of the study was overall survival.

The data shown here are for patients in whom K-ras status was not a predetermined eligibility criterion.1 EGFR=epidermal growth factor receptor; MAb=monoclonal antibody; BSC=best supportive care.

Please see Important Safety Information including Boxed WARNINGS on adjacent page.

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • APRIL 2010

Worker Safety

cm2), Dr. Connor speculated that there was “probably some breakdown of work practice at this nursing station.” Their findings indicated that some of these agents could linger for prolonged periods of time. In one spot, they detected cyclophosphamide in floor tiles six months after a spill.

Results from this study indicate that such spills might be prevented with CSTDs. At sites 1 and 2 (Maryland and North Carolina), where CSTDs were not used, 108 spills were reported during the 4,422 handling events that occurred. In contrast, at site 3 (Texas), where CSTDs were used, no spills were reported during

the 5,223 handling events.

Dr. Connor acknowledged that the investigators only sampled five drugs, so they don’t know for sure what’s going on with the other 100 or so other antineoplastic agents “that are out there,” but he said he assumes the study findings hold for the drugs that were not sampled.

Massachusetts Study The MGH study was prompted by a need for information on the relative value of CSTDs in reducing environmental contamination and employee risk of exposure. An MGH task force was formed in mid-2007 to explore

the merits of the closed-system devices. Speaking on behalf of the task force, Sami Ahmed, PharmD, clinical lead oncology pharmacist at MGH, said his colleagues looked at the problem of contamination “from loading dock to loading dock” to assess the “global exposure and the risk to all employees.” They wanted to determine how the contamination moves from place to place within the institution.

The investigators took hundreds of environmental samples, evaluating for the presence of 10 drugs: cyclophosphamide, docetaxel, doxorubicin, etoposide, 5-FU, gemcitabine, ifosfamide,

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials.

Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials.

Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary Pregnancy ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus Adverse Events ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%) Reference: 1. ERBITUX® (cetuximab) [package insert]. New York, NY and Princeton, NJ: ImClone Systems Incorporated and Bristol-Myers Squibb Company; July 2009.

Please see brief summary of Full Prescribing Information including Boxed WARNINGS on adjacent pages.

Weigh the Evidence That Supports

© 2009, ImClone LLC, New York, New York 10014, U.S.A. and Bristol-Myers Squibb Company, Princeton, New Jersey 08543, U.S.A. All rights reserved.

ERBITUX is a registered trademark of ImClone LLC.

693US09AB17908

1/10

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

irinotecan, methotrexate and paclitaxel.

Using LC/MS and flame-atomic absorption spectrometry, they found widespread, low-level contamination from all 10 agents.

The MGH team found “low levels of contamination across the entire chain of custody,” said Dr. Ahmed. As in the NIOSH study, contaminated residues migrated from preparation and administration areas. Dr. Ahmed noted that keyboards 50 feet away from hazardous drug preparation and administration areas, elevator buttons 200 to 300 feet away from such areas and pumps sent home with see CYTOTOXIC, page 12

11

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Worker Safety

CYTOTOXIC continued from page 11

patients were found to be contaminated.

“This was truly a global problem within our institution,” he said.

At their first sampling, in June 2007, the investigators took 148 samples of final IV products and found 104 (70%) to be positive for contamination. They also found significant cross contamination; 47 of the 104 contaminated samples (45%) were positive for drugs not inside the container. In a later test of 45 samples done in June 2009, contamination was found on

80% of final product containers and 14% of transport containers.

The findings suggested two possible methods of contamination—active transfer “related to a breach in technique or protocol,” and passive transfer “related to proper handling of assumed clean but contaminated products.” There are numerous points where contamination occurs throughout the chain of custody (Figure), said Dr. Ahmed. “The major source of contamination,” he added, “was employee’s hands.” Pointing to workers’ overreliance on gloves, he said that gloves “do not have magical powers.” If not used properly, gloves may

help to transmit contamination.

Contaminated Containers MGH investigators also sampled the outside of manufacturers’ vials of all 10 agents to assess contamination. Of the 79 samples, 77% were contaminated on the exterior of the vial; for all 10 agents, at least some and in some cases all of the vials sampled tested positive. “If the vial is contaminated, then whatever the technician touches becomes contaminated,” cautioned Dr. Ahmed, noting that the FDA does not require that the outside of the vials be clean.

So, are there any initiatives to pressure

ERBITUX® (cetuximab) Solution for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.]

INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.]

Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients.

Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]

Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

the FDA to tighten regulations? Dr. Connor noted that he had presented the results of three studies assessing surface contamination of drug vials in 2005 (Am J Health Syst Pharm 62:475484). The results of the studies clearly showed that surface contamination exists on commercially available vials of cyclophosphamide, ifosfamide, fluorouracil and cisplatin available in the United States and Europe. The investigators suggested, “contamination can be reduced by using decontamination equipment and protective sleeves during the manufacturing process.” see CYTOTOXIC, page 14

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Infusion reactions [See Boxed Warning and Warnings and Precautions.]

Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]

Pulmonary toxicity [See Warnings and Precautions.]

Dermatologic toxicity [See Warnings and Precautions.]

Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 1:

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 Infusion Reaction2 15 3 2 0 Infection 13 1 9 1 Chills1 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 Alanine Transaminase, high3 43 2 21 1 Aspartate Transaminase, high3 38 1 24 1 Alkaline Phosphatase, high3 33 <1 24 0 Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 4 Acneform Rash 87 17 10 1 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3

4

Includes cases also reported as infusion reaction.

Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

FDA NEWS

CLINICAL ONCOLOGY NEWS • APRIL 2010

Dosing Regimen Approved for Dacogen

per cycle. The cycle is repeated every four weeks.

The previously approved decitabine three-day regimen is administered in an inpatient setting at a dose of 15 mg/ m2 continuous intravenous infusion over three hours repeated every eight hours for three days per cycle and repeated every six weeks.

Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of decitabine in MDS patients with any of the FrenchAmerican-British (FAB) subtypes. In one study, 99 patients with International Prognostic Scoring System (IPSS) Intermediate-1, Intermediate-2 or high-

T

he FDA has approved a five-day dosing regimen for decitabine (Dacogen, Eisai) for injection to treat patients with myelodysplastic syndromes (MDS). The new outpatient dosing option provides physicians and patients with the flexibility of a dosing regimen that has a reduced infusion time.

Decitabine is the only hypomethylating agent approved for a five-day dosing regimen. The new regimen involves administration at a dose of 20 mg/m2 continuous intravenous infusion over one hour repeated daily for five days

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2: Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Body System Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation Dry Skin Pruritus Other-Dermatology Nail Changes Body as a Whole Fatigue Fever Infusion Reactions3 Rigors, Chills Pain Abdominal Pain Pain-Other Headache Bone Pain Pulmonary Dyspnea Cough Gastrointestinal Constipation Diarrhea Vomiting Stomatitis Other-Gastrointestinal Mouth Dryness Infection Infection without neutropenia Neurology Insomnia Confusion Anxiety Depression

89 49 40 27 21

12 0 2 1 0

16 11 8 6 4

<1 0 0 1 0

89 30 20 13

33 1 5 <1

76 18

26 <1

4

0

59 51 33 15

14 16 4 3

52 34 11 7

16 7 0 2

48 29

16 2

43 19

12 1

46 39 37 25 23 11

4 2 6 1 10 0

38 20 29 10 18 4

5 2 6 <1 8 0

35

13

17

6

30 15 14 13

1 6 2 1

15 9 8 6

1 2 1 <1

1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.

2 Adverse events were graded using the NCI CTC, V 2.0.

3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated.

BSC = best supportive care The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%).

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading.

Postmarketing Experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

Aseptic meningitis

risk prognostic scores received decitabine by intravenous infusion at a dose of 20 mg/m2 continuous infusion over one hour repeated daily for five days per cycle. The cycle is repeated every four weeks. If myelosuppression is present, subsequent treatment cycles of decitabine should be delayed until there is a hematologic recovery.

New Formulation of Trelstar Approved

T

he FDA has approved triptorelin pamoate 22.5 mg injectable suspension (Trelstar, Watson Pharmaceuticals), a new twice-yearly formulation

DRUG INTERACTIONS A drug interaction study was performed in which Erbitux (cetuximab) was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations.

Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.

OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).

Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIENT COUNSELING INFORMATION Advise patients: To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Erbitux® is a registered trademark of ImClone Systems Incorporated.

Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876 Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543

Copyright ©2010 ImClone Systems Incorporated and Bristol-Myers Squibb Company. All rights reserved.

1236886A6 ER-B0001A-03-10

Rev March 2010

of Trelstar, an effective palliative treatment for advanced prostate cancer. The company says the product, which does not require refrigeration, should be available in May. Trelstar 22.5 mg is the only six-month intramuscular gonadotropin-releasing hormone (GnRH) agonist available for the palliative treatment of advanced prostate cancer.

Until now, the product was available only in one-month (3.75 mg) and threemonth (11.25 mg) forms. The new, longeracting six-month formulation is designed to provide a more convenient therapeutic option. Trelstar 22.5 mg releases triptorelin pamoate, GnRH, over a prolonged period, and in turn, suppresses testosterone production for six months.

Approval of the new formulation is based on a Phase III study evaluating the efficacy, pharmacokinetics and safety of the drug administered every six months in patients with advanced prostate cancer. During the study, the drug produced a mean testosterone serum level of 12.8 ng/dL from the second through the 12th month, well below castration levels associated with androgen deprivation therapy. By day 29, 97.5% of the clinical trial patients achieved castrate level, and more than 98% of all patients were below castrate level at the sixth and 12th months.

Median prostate-specific antigen level was also reduced by 96.4% at the end of the study. The most commonly reported adverse events associated with the drug were hot flushes (71.7%), erectile dysfunction (10%) and testicular atrophy (7.5%).

Oral Bisphosphonates and Thigh Bone Fractures

R

ecently, two studies presented at the American Academy of Orthopaedic Surgeons associated the longterm use of oral bisphosphonates with unusual fractures of the thigh bone. The FDA has notified health care professionals and patients that at this point, the data the agency has reviewed have not shown a clear connection between bisphosphonate use and a risk for atypical subtrochanteric femur fractures. The FDA is working with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather more information and evaluate the issue further.

The FDA states that health care professionals should follow the recommendations on the drug label when prescribing oral bisphosphonates. Patients should continue taking oral bisphosphonates unless told to stop by their health care provider. Patients should talk to their health care provider if they develop new hip or thigh pain or have any concerns about their medications.

13

14

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • APRIL 2010

Worker Safety

CYTOTOXIC continued from page 12

Thus, the data are there, Dr. Connor said. “We’ve shown it, Mass General has shown it, other studies have shown it.

It’s a problem that’s not going away.” Dr. Connor said a study conducted by Rudolf Schierl, PhD, of the University of Munich, is going to provide further evidence (Am J Health Syst Pharm 2010;67:428-429, PMID: 20208047).

According to Luci Power, MS, RPh, senior pharmacy consultant at Power Enterprises, pharmacists must pressure manufacturers to clean up the outside of containers. “We must use our collective influence to pressure manufacturers to address and correct this problem,” she wrote in an editorial that accompanied Dr. Connor’s earlier study (Am J Health Syst Pharm 2005;62:471, PMID: 15745909), urging, “Changes in drug manufacturing processes are not inexpensive, and manufacturers are unlikely to undertake the needed changes without this pressure.”

According to Burkhard Wichert, MD, vice president of manufacturing oncology at Baxter Healthcare Corp., several decades ago, Baxter was the first company to initiate outside cleaning of vials to reduce contamination prior to delivery to health care facilities. Currently, the company is investigating the addition of a protective cover that may be applied to the vials once they have been cleaned to further reduce outside residue. Dr. Connor said that such protective sleeves are “probably a good approach to help reduce contamination,” but he added that the contamination “should not be there in the first place.”

Dr. Wichert maintained that it is difficult to ensure that there is no contamination on the vials. “While we work hard to minimize contamination in our manufacturing process and continually implement new cleaning strategies, we cannot guarantee that cytotoxic drug vials will be completely clear of residue. … There are myriad points of contact with these vials before they reach the hospitals and pharmacies, and once they leave our facilities, we are unable to control all potential contaminating factors.”

Biological Effects of Exposure Although the NIOSH and MGH studies highlight how extensive contamination from hazardous drugs is, they leave open the question of what it means to the exposed workers. To examine this, Dr. McDiarmid and her colleagues conducted a subanalysis of the NIOSH study at the Maryland site on the chromosomal effects of the five agents they studied.

They used fluorescence in situ hybridization to evaluate the DNA from the exposed workers, looking for abnormalities in chromosomes 5, 7 and 11, the most

common abnormalities found in patients with therapy-mediated MDS or AML. The exposed workers had between one and 918 handling events (mean, 153 events). Comparing those with low levels of exposure (one to 153 handling events) to those with high levels of exposure (>153 handling events), they found that some differences in DNA damage “are starting to show up,” said Dr. McDiarmid. Although the results were not significant, “it looks like there’s a potential dose response,” she said.

When the Maryland investigators assessed the contribution of drughandling frequency to chromosomal abnormalities, they found that for each handling event, there was a statistically significant increased frequency of damage to chromosome 5 or 7 (P=0.01) and an increased frequency of damage to chromosome 5 alone (P=0.01).

When they looked specifically at handling events with alkylating agents (cyclophosphamide and ifosfamide), they also found a statistically significant increased frequency of damage to chromosome 5 or 7 (P=0.001) and to chromosome 5 alone (P=0.01). In fact, said Dr. McDiarmid, they observed a “fivefold increase in the absolute value of the effect estimate” (the estimate of the insult to chromosomes 5 or 7) for each handling event with alkylating agents compared with all agents.

She concluded, “We are seeing specific types of lesions that … are the signature lesions seen in therapy-related myelodysplastic syndrome and therapy-related AML, and we’re clearly seeing a dose response, [with] this additional spike in the effect estimate when we look at alkylating agent handling alone.”

The data from these studies show that “biologically important exposure to

genotoxic drugs is occurring in oncology work settings despite hospital endorsement of safe handling,” concluded Dr. McDiarmid. The bottom line, she said, is that “there is exposure taking place and [these drugs] are getting into people’s bodies. We have this biological progression of evidence here.”

Dr. Connors recently reviewed studies conducted worldwide between 1990 and 2009 looking at genetic damage in pharmacists and nurses, and said that “about two-thirds of those show a significant increase in whatever marker they were using for genetic damage in those workers.”

Steps To Address the Problem Although they acknowledged that improvements have been made since problems with cytotoxic drugs were revealed in the 1970s, the recent findings show clearly that more needs to be done. In Dr. Connor’s view, “we need good training, retraining, administrative controls, better work practices, in addition to better engineering controls, PPE and the like.”

One recommendation he made related to the importance of proper design. “You really need some type of clean-room technology with an anteroom, with the correct amount of air exchanges, the right level of air quality, pass-through windows and so forth because, in general, those help reduce the contamination.” Additionally, although Dr. Ahmed found that “at best, CSTDs could only attenuate the active transfer process, but not passive transfer, which may be more important,” Dr. Connor referred back to the NIOSH study findings as indicating the value of CSTDs. Reiterating that no spills occurred at the site that used CSTDs, he said that some of these devices “have shown they reduce

Table. Results of Surface Wipe Samples Pharmacy Drug

Concentration Maximum/Mean, ng/cm2 Site 2

Site 3

Cyclophosphamide 7.95/0.70

Site 1

143/16

9.52/0.47

Cytarabine

20.6/1.33

9.18/0.53

0

5-fluorouracil

2.05/0.19

1.95/0.13

3.47/0.53

Ifosfamide

1.41/0.09

6.03/0.65

2.41/0.08

Paclitaxel

0

1.28/0.15

0.43/0.08

Nursing Drug

Concentration Maximum/Mean, ng/cm2 Site 1

Site 2

Site 3

Cyclophosphamide

0.11/0.01

1.42/0.12

0.45/0.07

Cytarabine

0

0

0

5-fluorouracil

1.90/0.08

0

910/35.4

Ifosfamide

1.36/0.05

0.19/0.01

19.8/0.85

Paclitaxel

0

0

0.23/0.01

contamination. I think they do contribute to reducing contamination.”

Based on their findings, the team at MGH recommended against the purchase of CSTDs and is working on major revisions to their policies and procedures to prevent contamination due to active transfer as well as passive transfer. They are planning to change their storage procedures so that chemotherapy drugs are stored in isolation from other agents, and they are exploring the use of protective sleeves and other options. They plan to conduct biologic sampling of workers to ensure that their new approaches are working.

Dr. Ahmed said there has to be a cultural change in that PPE is viewed as community protective equipment.

“What is good for me should be good for all,” he said. “All persons handling hazardous drugs have a responsibility to understand the guiding principles of safe handling.” He stressed that transparency and staff participation are critical and that the sponsorship of senior leadership also is important.

So, what about specific recommendations for cleaning biological safety cabinets and other work surfaces? “After all these years, we don’t have any really good recommendations,” Dr. Connor said.

“There are more than 100 different antineoplastic agents, all with different chemical structures … there’s really no universal method.” A good approach is to use a detergent followed by a water rinse, then another detergent and water rinse, followed by alcohol. Further recommendations can be found in the 2006 ASHP guidelines (Am J Health Syst Pharm; 63:1172-1191).

Ms. Power also stressed the need to get with the program. “I don’t think exposure is linear. I think you need to put money where you can identify your highest exposure.” She said health care workers are “in jeopardy” if they handle hazardous drug vials and other packaging without gloves and other PPE and if they do not decontaminate vials and surface areas in the primary engineering control.

She stressed the importance of double gloving, and she suggested that two shoe covers could be beneficial in areas where hazardous drugs are compounded. Another suggestion Ms. Power made was to use two technicians, “one preparing and one serving. It doesn’t necessarily change what’s happening in the hood, but it changes what’s happening after.”

She noted that this work practice is done in Denmark.

For her part, Dr. McDiarmid said that the extent of the problem could not be denied. “As a minimum, everybody has to get on point here on what we’re supposed to be doing because we can tell you from the walkthroughs we did, that’s not even happening, so it’s probably not happening at your place either.”

—Sarah Tilyou

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • APRIL 2010

Finance

Getting off the Roller Coaster Recession-Proof Investment Alternatives for Doctors Like most Americans, you probably are confused, if not outright frightened, by investment choices you have today.

You may have seen your stock market portfolio fall more than 40% or suffered from real estate woes. Smaller investment options have become scary, too, thanks to scandals like Madoff and Stanford. Bailouts in the billions were handed out to banks, financial firms and selected industries. So, what can one do today to wisely invest their money?

Investment Theory for Doctors Most savvy doctor investors understand that portfolio diversification is key to reducing some of the risk for loss in a portfolio. In historically volatile markets, mitigation of loss is not a luxury—it is a necessity. Although savvy investors who thought they were “adequately diversified” also lost almost half of their portfolio, on average, over the last two years, there is an explanation for this. Many of them were diversified “within” the stock market with holdings in various sectors. What these investors suffered was “market risk.” As the entire market came crashing down, so did all investors within the market.

What even experienced investors often don’t understand is that diversification need not be limited to securities like traditional stock and bond investments or bank deposits. Proper diversification, especially in a highly volatile market like the one we are currently experiencing, must also be across investment classes and not just within a class (like securities or real estate).

A balanced combination of domestic and foreign securities, real estate, small businesses, commodities and other investments would prove to be much less risky than holding the majority of your investments in real estate and securities (which is what most doctors do). It may not come as a surprise that many physicians have taken a more active interest in the investment opportunities of surgery centers, medical office buildings and other health care–related real estate.

This strategy apparently contradicts the idea of achieving portfolio diversification by avoiding any investments within the health care arena. One strategy of portfolio diversification for doctors is to avoid all health care–related investments. The theory behind this is that doctors already have so much of their income related to health care that they

should not invest in health care–related investments. Unless a doctor has a very good reason to think that a particular company will excel in its market, this theory suggests they should avoid health care stocks. On the other hand, for doctors who have the ability to personally influence the success of a surgery center or MediSpa, this is obviously an attractive investment.

Alternative Investments For those doctors who can’t build or participate in surgery centers or other profitable health care investments, a popular investment strategy is to take advantage of different investment programs that are not traded on a public exchange like the New York Stock Exchange. Non-traded real estate investment trusts, leasing funds, and oil and gas drilling programs are a few examples. As with any investment, each type of offering has its pros and cons.

Given recent market conditions, many physician investors have been attracted to non-traded programs because they offer a certain level of stability. Most of these programs are sold to investors at a flat price, for example $10 per share, during the offering period. Because the offerings are not traded in a public market, share values do not fluctuate with daily trading activity. So in a market where many investors are experiencing portfolio losses of up to 50%, many alternative investments suffered no drop at all. This is a nice hedge against a recession. In addition, these investments have cash flows (dividends) that are reasonably predictable. Another advantage of these programs is that their performance is not correlated with any particular market or index, making them an additional form of diversification. Because non-traded offerings are not tied to any particular index, they will not ride the “volatility roller coaster” that the rest of a traditional portfolio will. They should be an additional allocation in your portfolio, not a substitute for proper allocation.

Another significant benefit for physicians in higher income tax brackets (which are sure to increase to pay for government bailouts and other federal expenditures) is the potential tax benefit that an alternative program can offer.

Some programs offer tax deductions on the initial investment. Others pay taxefficient dividends. Some programs offer both advantages. For example, some drilling programs offer tax deductions on the initial investment related to intangible drilling costs as well as tax deductions on the program’s cash flow covering allowances for depreciation

Given recent market conditions, many physician investors have been attracted to non-traded programs because they offer a certain level of stability.

and depletion. Dividends paid by real estate investment trusts and leasing funds often are only partly taxable to the investor. By reducing taxes within a portfolio, you can offset some of the losses during a recession. Although these tax efficiencies vary by program and from year to year, every investor is looking for reduced taxes anywhere possible.

A Caution It is important to note that one of the advantages of a non-traded offering is also a disadvantage. There is typically no market for shares of these programs. As an investor, you are expected to hang onto the security for the life of the investment—which can be as long as 10 years. Although the long-term nature of the investment makes it appealing as a hedge against a recession, it also puts your money in a relatively illiquid vehicle. If you need it, you might not be able to get it quickly. In addition, these programs are not without risk. You could invest in an oil and gas drilling program that does not find oil. Sure, you will get a deduction, but you may not get back much of the initial money. Like any other investment class, some offerings are more aggressive than others, and none make any guarantee about future performance.

Conclusion For doctors who began investing in earnest in the 1990s, today’s economic climate is truly different. Many economists are predicting three to six years or longer for the current recession to pass. There has never been a better time to focus on investment risk management and tax reduction planning. For physician investors seeking ways to diversify traditional stock and bond portfolios and reduce portfolio volatility, while possibly reducing unnecessary taxes, non-traded investments are an attractive alternative.

—Jason M. O’Dell, CWM, R. Paul Wilson, and Kim Renners, CPA, MBA

Jason O’Dell is a founder of O’Dell Jarvis Mandell and author of Investing Secrets for Physicians. R. Paul Wilson is region manager of private client services for the Cincinnati office of O’Dell Jarvis Mandell.

Kim Renners is director of wealth management for OJM Group. The authors are offering a free e-newsletter on investment strategies, tax reduction and asset protection to all McMahon Publishing readers. Register at www.ojmgroup.com to receive this e-newsletter.

15

Help Deliver

in Chronic Phase Ph+ CML After Gleevec

®

(imatinib mesylate) tablets

WARNING: QT PROLONGATION AND SUDDEN DEATHS TASIGNA prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

ADVERSE REACTIONS: Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. In CML-CP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, and vomiting.

TASIGNA (nilotinib) capsules is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of TASIGNA is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

Please see Important Safety Information, including Boxed WARNING, and brief summary of Prescribing Information on following pages.

TASIGNA delivers cytogenetic response in the chronic phase after Gleevec1 40% of patients achieved an unconfirmed major cytogenetic response (MCyR) (95% CI: 33-46)1 28% of patients achieved an unconfirmed complete cytogenetic response (CCyR) (95% CI: 22-34)1 12% of patients achieved an unconfirmed partial cytogenetic response (PCyR) (95% CI: 8-16)1 Rapid responses: 2.8 months median time to MCyR2

Important study design information1 A single, open-label, multicenter study was conducted to evaluate efficacy and safety in patients with Ph+ CML in the chronic phase with resistance or intolerance to Gleevec. At the time of data cutoff, 280 patients with a minimum follow-up of 6 months were enrolled Of the 280 patients, 232 were evaluable for efficacy. The efficacy end point was unconfirmed MCyR, which included CCyR and PCyR CyR criteria: CCyR (0% Ph+ metaphases) or PCyR (1%-35%). Cytogenetic responses were based on the percentage of Ph+ metaphases among ≥20 metaphase cells in each bone marrow sample

Prescribe TASIGNA for your patients in the chronic phase who are no longer responding or are intolerant to Gleevec1 Patients who are not meeting minimum treatment goals: Complete hematologic response (CHR) at 3 months, CyR at 6 months, or MCyR at 12 months Patients who lose HR or CyR at any time Patients who cannot tolerate Gleevec

References: 1. TASIGNA® (nilotinib) capsules prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Aug 2009.

2. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance.

Blood. 2007;110(10):3540-3546.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936

©2009 Novartis

10/09

C-AM7-100019

TASIGNA® (NILOTINIB) CAPSULES IMPORTANT SAFETY INFORMATION INDICATIONS AND USAGE TASIGNA (nilotinib) is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

The effectiveness of TASIGNA is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

WARNING: QT PROLONGATION AND SUDDEN DEATHS TASIGNA prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment.

ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.

WARNINGS AND PRECAUTIONS Myelosuppression Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding TASIGNA temporarily or dose reduction.

QT Prolongation TASIGNA prolongs the QT interval. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated, and following dose adjustments. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically.

Significant prolongation of the QT interval may occur when TASIGNA is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.

Sudden Deaths There were sudden deaths reported in the safety population and in the expanded access program. Ventricular repolarization abnormalities may have contributed to their occurrence.

Elevated Serum Lipase Caution is recommended in patients with a history of pancreatitis.

Check serum lipase levels monthly or as clinically indicated.

Hepatotoxicity Serum bilirubin and hepatic transaminases The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.

Electrolyte Abnormalities TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating TASIGNA and monitor periodically during therapy.

Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment and QT interval should be monitored closely.

Drug Interactions The concomitant use of QT prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of TASIGNA. Concomitant strong CYP3A4 inhibitors The concomitant use of strong CYP3A4 inhibitors or antiarrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with TASIGNA be interrupted. If interruption of treatment with TASIGNA is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval, and a dose reduction to ½ the daily dose is recommended (400 mg once daily). If the strong inhibitor is discontinued, a washout period should be allowed before TASIGNA is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. Grapefruit products and other foods that are known to inhibit CYP3A4 should also be avoided.

Concomitant strong CYP3A4 inducers The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone,

phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St John’s Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of TASIGNA may need to be increased, depending on patient tolerability. If the strong inducer is discontinued, the TASIGNA dose should be reduced to the indicated TASIGNA dose. TASIGNA is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1.

In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8, and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes. Single-dose administration of TASIGNA to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of TASIGNA to induce metabolism has not been determined in vivo. Caution should be exercised when co-administering TASIGNA with substrates for these enzymes that have a narrow therapeutic index. TASIGNA inhibits human P-glycoprotein. If TASIGNA is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised.

Food Effects Food increases blood levels of TASIGNA. Patients should avoid food 2 hours before and at 1 hour after the dose is taken.

Lactose Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.

Use in Pregnancy There are no adequate and well controlled studies of TASIGNA in pregnant women. However, TASIGNA may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do.

ADVERSE REACTIONS In chronic phase patients, the most commonly reported adverse reactions (>10%) were rash (33%), pruritus (29%), nausea (31%), fatigue (28%), headache (31%), constipation (21%), diarrhea (22%), and vomiting (21%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (28%), neutropenia (28%), elevated lipase (15%), and hyperglycemia (11%). In accelerated phase patients, the most commonly reported adverse reactions (>10%) were rash (28%), pruritus (20%), and constipation (18%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (37%), neutropenia (37%), anemia (23%), and elevated lipase (17%). Other serious adverse reactions included pneumonia,

febrile neutropenia, leukopenia, intracranial hemorrhage, and pyrexia (Grade 3/4: 2%).

DOSE ADJUSTMENTS OR MODIFICATIONS TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematological toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors. With concomitant use of strong CYP3A4 inducers, the dose of TASIGNA may need to be increased, depending on patient tolerability.

For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. For Grade 3 to 4 bilirubin elevations, dosing should be withheld, and may be resumed at 400 mg once daily.

Hepatic impairment If possible, consider alternative therapies. If TASIGNA must be administered to patients with hepatic impairment, a lower starting dose is recommended in patients with hepatic impairment and QT interval should be monitored. The following dose reduction should be considered: For patients with mild (Child-Pugh Class A) or moderate (ChildPugh Class B) hepatic impairment, an initial dosing regimen of 400 mg in the morning and 200 mg in the evening (12 hours apart) per day followed by dose escalation to 400 mg twice daily based on patient tolerability should be considered.

For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 400 mg in the morning and 200 mg in the evening (12 hours apart) per day and then to 400 mg twice daily based on patient tolerability should be considered.

OTHER PATIENTS IN WHOM TASIGNA SHOULD BE USED WITH CAUTION TASIGNA should not be used during pregnancy. Sexually active female patients should use effective contraception during treatment. Women should not breast feed while taking TASIGNA. The safety and effectiveness of TASIGNA in pediatric patients have not been established.

Tasigna® (nilotinib) Capsules Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information.

WARNING: QT PROLONGATION AND SUDDEN DEATHS Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided (5.7). Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). A dose reduction is recommended in patients with hepatic impairment (5.9).

ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. (5.2, 5.3, 5.6, 5.12) 1 INDICATIONS AND USAGE Tasigna (nilotinib) is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates. [See Clinical Studies (14) in the full prescribing information]. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily. [See Clinical Pharmacology (12.3) in the full prescribing information]. Treatment should continue as long as the patient does not show evidence of progression or unacceptable toxicity.

Tasigna should be taken twice daily at approximately 12 hour intervals and must not be taken with food.

The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken.

[See Boxed Warning, Warnings and Precautions (5.8), Clinical Pharmacology (12.3) and Clinical Studies (14) in the full prescribing information].

If a dose is missed, the patient should not take a make-up dose, but should resume taking the next prescribed daily dose.

Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.

2.2 Dose Adjustments or Modifications QT interval prolongation: Table 1. Dose Adjustments for QT Prolongation ECGs with a QTc >480 msec 1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed.

2. Resume within 2 weeks at prior dose if QTcF returns to <450 msec and to within 20 msec of baseline.

3. If QTcF is between 450 msec and 480 msec after 2 weeks reduce the dose to 400 mg once daily.

4. If, following dose-reduction to 400 mg once daily, QTcF returns to >480 msec, Tasigna should be discontinued.

5. An ECG should be repeated approximately 7 days after any dose adjustment.

Myelosuppression: Tasigna may need to be withheld and/or dose reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2).

Table 2. Dose Adjustments for Neutropenia and Thrombocytopenia 1. Stop Tasigna, and monitor blood counts Chronic Phase or ANC* <1.0 x 109/L Accelerated Phase and/or platelet counts 2.

Resume within 2 weeks at prior dose if ANC >1.0 x 109/L CML at 400 mg <50 x 109/L and platelets >50 x 109/L twice daily 3. If blood counts remain low for >2 weeks, reduce the dose to 400 mg once daily *ANC = absolute neutrophil count See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases. [See Adverse Reactions (6.1)].

Table 3. Dose Adjustments for Selected Non-hematologic Laboratory Abnormalities Elevated serum lipase 1. Withhold Tasigna, and monitor serum lipase or amylase or amylase ≥Grade 3 2. Resume treatment at 400 mg once daily if serum lipase or amylase return to ≤Grade 1 Elevated bilirubin 1. Withhold Tasigna, and monitor bilirubin ≥Grade 3 2. Resume treatment at 400 mg once daily if bilirubin return to ≤Grade 1 Elevated hepatic transaminases ≥Grade 3

1. Withhold Tasigna, and monitor hepatic transaminases 2. Resume treatment at 400 mg once daily if hepatic transaminases return to ≤Grade 1

Other Non-hematologic Toxicities: If other clinically significant moderate or severe non-hematologic toxicity develops, dosing should be withheld, and may be resumed at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 400 mg twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Serum lipase levels should be tested monthly or as clinically indicated. For Grade 3 to 4 bilirubin elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Bilirubin and hepatic transaminases levels should be tested monthly or as clinically indicated. [See Warnings and Precautions (5) and Use in Specific Populations (8) in the full prescribing information].

Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit products may also increase serum concentrations of nilotinib and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, 400 mg once daily (a dose reduction to 1/2 of the original daily dose) is predicted to adjust the nilotinib AUC to the AUC observed without inhibitors.

However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period should be allowed before the Tasigna dose is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. [See Boxed Warning, Warnings and Precautions (5.2 and 5.7) and Drug Interactions (7.2) in the full prescribing information].

Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital).

Patients should also refrain from taking St. John’s Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of Tasigna may need to be increased, depending on patient tolerability. If the strong inducer is discontinued the nilotinib dose should be reduced to the indicated dose. [See Drug Interactions (7.2) in the full prescribing information].

Hepatic Impairment: If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, the following dose reduction should be considered: For patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an initial dosing regimen of 400 mg in the morning and 200 mg in the evening (12 hours apart) per day followed by dose escalation to 400 mg twice daily based on patient tolerability should be considered. For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 400 mg in the morning and 200 mg in the evening (12 hours apart) per day and then to 400 mg twice daily based on patient tolerability should be considered. [See Boxed Warning, Warnings and Precautions (5.9) and Use in Specific Populations (8.7) in the full prescribing information].

3 DOSAGE FORMS AND STRENGTHS 200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI.” 4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. [See Boxed Warning].

5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna (nilotinib) can cause Grade 3/4 thrombocytopenia, neutropenia and anemia.

Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. [See Dosage and Administration (2)].

5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner. [See Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments.

Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome.

Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy.

Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. [See Drug Interactions (5.7) and Food Effects (5.8)]. The presence of hypokalaemia and hypomagnesaemia may further enhance this effect. [See Electrolyte Abnormalities (5.6), Monitoring Laboratory Tests (5.12), and Warnings and Precautions (5.8)].

5.3 Sudden Deaths There were five sudden deaths reported in patients receiving nilotinib in an on-going study (n=867; 0.6%).

A similar incidence was also reported in the expanded access program. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. Serum lipase levels should be tested monthly or as clinically indicated.

5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.

5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy.

5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted.

If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. [See Boxed Warning, Dosage and Administration (2), and Drug Interactions (7.2) in the full prescribing information].

5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided. [See Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information].

5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment and QT interval should be monitored closely. [See Boxed Warning, Dosage and Administration (2) and Use in Specific Populations (8.7) in the full prescribing information].

5.10 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactosecontaining products or of glucose-galactose malabsorption.

5.11 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in laboratory animals at maternal exposures that were lower than the expected human exposure at the recommended dose of 400 mg BID. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna and should be advised of the potential hazard to the fetus if they do. [See Use in Specific Populations (8.1) in the full prescribing information].

5.12 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments. [See Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion.

6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert. [See Boxed Warning and Warnings and Precautions (5)].

QT prolongation and Sudden Deaths [See Boxed Warning, Warnings and Precautions (5.2, 5.3)] Myelosuppression [See Warnings and Precautions (5.1)] Elevated serum lipase [See Warnings and Precautions (5.4)] Hepatotoxicity [See Warnings and Precautions (5.5)] Electrolyte abnormalities [See Boxed Warning and Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the single open-label multicenter clinical trial, a total of 438 patients were treated (CML-CP=318; CML-AP=120).

The median duration of exposure in days for CML-CP and CML-AP patients is 245 (range 1-502) and 138 (range 2-503), respectively. The median dose intensity of 797 mg/day (range 145-1149) was similar for both the chronic and accelerated phase patients and corresponded to the planned 400 mg twice daily dosing.

The median cumulative duration in days of dose interruptions for the CML-CP patients was 18 (range 1-185), and the median duration in days of dose interruptions for the CML-AP patients was 22 (range 1-163).

In CML-CP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritis, nausea, fatigue, headache, constipation, diarrhea and vomiting. The common serious drugrelated adverse reactions were thrombocytopenia and neutropenia.

In CML-AP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritus and constipation. The common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.

Sudden deaths and QT prolongation were reported. [See Boxed Warning and Warnings and Precautions (5.2 and 5.3)].

Discontinuation for drug-related adverse reactions was observed in 11% of CML-CP and 8% of CML-AP patients.

Table 4 shows the percentage of patients experiencing treatment-emergent adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in at least 10% of patients who received at least one dose of Tasigna are listed.

Table 4. Treatment-Emergent Adverse Reactions Reported in ≥10% of Patients in the Clinical Studya CML-CP CML-AP N=318 N=120 Body System and Preferred Term All Grades CTC Gradesb All Grades CTC Gradesb (%) 3/4 (%) (%) 3/4 (%) Skin and subcutaneous Rash 33 2 28 0 tissue disorders Pruritus 29 1 20 0 Gastrointestinal disorders Nausea 31 1 18 <1 Diarrhea 22 3 19 2 Constipation 21 <1 18 0 Vomiting 21 <1 10 0 Abdominal pain 11 1 13 3 Nervous system disorders Headache 31 3 21 2 General disorders and Fatigue 28 1 16 <1 administration site conditions Pyrexia 14 1 24 2 Asthenia 14 0 12 2 Edema, peripheral 11 0 11 0 Musculoskeletal and Arthralgia 18 2 16 0 connective tissue disorders Myalgia 14 2 14 <1 Pain in extremity 13 1 16 2 Bone pain 11 <1 13 <1 Muscle spasms 11 <1 14 0 Back pain 10 <1 12 <1 Respiratory, thoracic and Cough 17 <1 13 0 mediastinal disorders Dyspnea 11 1 8 3 Infections and infestations Nasopharyngitis 16 <1 11 0 a Excluding laboratory abnormalities b NCI Common Terminology Criteria for Adverse Events, Version 3.0 Table 5 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 5. Incidence of Clinically Relevant Grade 3/4 Laboratory Abnormalities CML-CP CML-AP N=318 N=120 Grades 3/4* Grades 3/4* Hematologic Parameters 37%2 Thrombocytopenia 28%1 Neutropenia2 28% 37%3 Anemia 8% 23% Biochemistry Parameters Elevated lipase 15% 17% Hyperglycemia 11% 4% Hypophosphatemia 10% 10% Elevated bilirubin (total) 9% 10% Elevated SGPT (ALT) 4% 2% Hyperkalemia 4% 3% Hyponatremia 3% 3% Hypokalemia 1% 5% Elevated SGOT (AST) 1% 1% Decreased albumin 1% 1% Hypocalcemia 1% 4% Elevated alkaline phosphatase 1% 3% Elevated creatinine <1% 0% *NCI Common Terminology Criteria for Adverse Events, version 3.0 1CML-CP: Thrombocytopenia: 11% were grade 3, 17% were grade 4 2CML-AP: Thrombocytopenia: 7% were grade 3, 30% were grade 4 3CML-AP: Neutropenia: 12% were grade 3, 25% were grade 4 6.2 Additional Data from Clinical Trials The following drug-related adverse reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1%-10%), and uncommon (0.1%-1%) adverse reactions single events are captured as unknown frequency. For laboratory abnormalities, very common events (≥1/10) not included in Table 4 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.

Infections and Infestations: Uncommon: pneumonia, urinary tract infection, gastroenteritis, pharyngitis.

Unknown frequency: sepsis, bronchitis, herpes simplex, candidiasis.

Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia.

Unknown frequency: thrombocytosis, leukocytosis.

Endocrine Disorders: Uncommon: hyperthyroidism.

Unknown frequency: hypothyroidism, thyroiditis.

Metabolism and Nutrition Disorders: Common: hypomagnesemia, hyperkalemia, hyperglycemia, anorexia.

Uncommon: hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, dehydration, decreased appetite, increased appetite.

Unknown frequency: diabetes mellitus, hypercalcemia, hyperphosphatemia.

Psychiatric Disorders: Common: Insomnia.

Uncommon: depression, anxiety.

Unknown frequency: disorientation, confusional state.

Nervous System Disorders: Common: dizziness, paresthesia.

Uncommon: intracranial hemorrhage, migraine, tremor, hypoesthesia, hyperesthesia.

Unknown frequency: brain edema, loss of consciousness, optic neuritis, peripheral neuropathy.

Eye Disorders: Uncommon: eye hemorrhage, visual acuity reduced, periorbital edema, conjunctivitis, eye irritation, dry eye.

Unknown frequency: papilloedema, diplopia, vision blurred, photophobia, eye swelling, blepharitis, eye pain.

Ear and Labyrinth Disorders: Common: vertigo.

Unknown frequency: hearing impaired, ear pain.

Cardiac Disorders: Common: palpitations, electrocardiogram QT prolonged.

Uncommon: cardiac failure, angina pectoris, atrial fibrillation, pericardial effusion, coronary artery disease, cardiomegaly, cardiac murmur, bradycardia.

Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, cardiac flutter, extrasysoles.

Vascular Disorders: Common: hypertension, flushing.

Uncommon: hypertensive crisis, hematoma.

Unknown frequency: shock hemorrhagic, hypotension, thrombosis.

Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, cough, dysphonia.

Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, epistaxis, pharyngolaryngeal pain, throat irritation.

Unknown frequency: pulmonary hypertension.

Gastrointestinal Disorders: Common: abdominal discomfort, dyspepsia, flatulence.

Uncommon: pancreatitis, gastrointestinal hemorrhage, melena, abdominal distension, mouth ulceration, gastroesophageal reflux, stomatitis, dry mouth.

Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus.

Hepatobiliary Disorders: Uncommon: hepatitis.

Unknown frequency: hepatotoxicity, hepatomegaly, jaundice.

Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, alopecia, erythema, hyperhidrosis, dry skin.

Uncommon: exfoliative rash, ecchymosis, swelling face.

Unknown frequency: erythema nodosum, skin ulcer, petechiae, photosensitivity.

Musculoskeletal and Connective Tissue Disorders: Common: musculoskeletal chest pain, musculoskeletal pain.

Uncommon: muscular weakness.

Unknown frequency: arthritis, joint swelling.

Renal and Urinary Disorders: Uncommon: dysuria, micturition urgency, nocturia, pollakiuria.

Unknown frequency: renal failure, hematuria, urinary incontinence.

Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction.

General Disorders and Administration Site Conditions: Common: pyrexia.

Uncommon: chest pain, face edema, gravitational edema, influenza-like illness, chills, malaise.

Investigations: Very common: lipase increased.

Common: blood amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood glucose increased, weight decreased, weight increased.

Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood creatinine increased, blood urea increased.

Unknown frequency: troponin increased, blood potassium decreased, blood bilirubin unconjugated increased.

10 OVERDOSAGE No cases of overdose have been reported. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

16 HOW SUPPLIED/STORAGE AND HANDLING Tasigna (nilotinib) capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs.

Carton of 4 blister packs of (4x28)...............................................................................NDC 0078-0526-87 Blisters of 28 capsules .................................................................................................NDC 0078-0526-51 Each blister pack contains one folded blister card of 28 capsules each, for dosing two in the morning and two in the evening at 12 hour intervals over a 7 day period.

Tasigna (nilotinib) Capsules, 200 mg, should be stored at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Rev: August 2009 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

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SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • APRIL 2010

Pain

Managing Cancer Pain, One Patient at a Time Recent studies reveal that nearly one-third of cancer patients nationwide—approximately 3 million to 5 million people—suffer moderate to severe pain, regardless of the stage of their disease. Those with advanced cancer experience severe pain 90% of the time—yet only about one-half of all cancer patients receive adequate pain management.

“In the past, cancer pain wasn’t recognized as a priority,” said Allen W. Burton, MD, clinical medical director of the Pain Management Center, University of Texas M.D. Anderson Cancer Center, Houston. “Killing or arresting the cancer, and treating the side effects of therapies, such as nausea and hair loss, took precedence. Pain was something patients had to live with.”

Dr. Burton and his team have worked hard for more than 25 years to change that erroneous perception. They believe that pain relief is an integral component of cancer treatment, and they continue to raise expectations for relieving cancer’s “hurt.” Clinicians and cancer centers looking to improve pain management of cancer patients can learn a thing or two from M.D. Anderson—their convictions have earned them the 2009 American Pain Society Center of Excellence Award, the first time a cancer pain management center has been chosen.

Complex and Challenging “Pain is an all-encompassing issue for cancer patients,” said Larry Driver, MD, vice chair of Anderson’s pain management center. “It is part of a complex constellation of symptoms that may include chronic fatigue, sleep disturbances, drowsiness, anxiety, depression, poor appetite and so on. All of them interact and often magnify each other. The pain makes the anxiety and depression worse; and the worse the anxiety and depression are, the worse the pain seems.”

According to Michael Erdek, MD, the emotional trauma of being diagnosed with cancer puts patients in a very fragile psychological state.

“The psychological issues with cancer pain are different,” said Dr. Erdek, assistant professor of anesthesiology, critical care medicine and oncology, Division of Pain Medicine, Johns Hopkins University School of Medicine, Baltimore. “A key one is that a patient may be dealing with impending death. That contributes to a certain duress that is unique to cancer.”

Diane M. Novy, PhD, professor of psychology at the Anderson Pain Management Center, believes the duress cancer patients are under often makes them more cognizant of pain.

“Any new pain might make them think the cancer has spread,” she said. “There

also are social issues with cancer pain.

Patients wonder what will happen to their jobs, will they be able to provide for their families, will they live to see their grandchildren. And even if they survive the disease, the

the Pain Management Center to departmental status. “I think it is an indication that pain medicine is maturing and standing on its own feet,” Dr. Burton said.

The Pain Management Center provides a full spectrum of care for both chronic and acute postoperative cancer pain, using a multidisciplinary team to deliver comprehensive evaluations, medical management, psychological therapies and more. The team consists of anesthesiologists, physical medicine and rehabilitation practitioners, neurologists, nurses, psychologists, social workers and even chaplains.

“We’re not only multidisciplinary, but multimodal,” Dr. Burton explained. “It’s where the rubber hits the road. While oncologists provide chemotherapy or radiation therapies, our pain specialists are talk-

‘In the past, cancer pain wasn’t recognized as a priority. … Pain was something patients had to live with.’

—Allen W. Burton, MD

pain reminds them of it on a daily basis.”

For clinicians, treating cancer pain is a challenge due to its dualedged nature—it can arise from the disease and also from treatments to cure it, especially chemotherapy and radiation.

“The chemotherapy agents in use today are more potent and powerful, and unfortunately can lead to pain, especially from nerve damage,” said Basem Hamid, MD, program director of Anderson’s pain management fellowship. “The damage is often irreversible, making it hard to treat.”

Taking Cancer Pain Seriously The M.D. Anderson Cancer Center takes its mission of treating cancer patients’ pain and improving their quality of life so seriously that this year it elevated

ing to patients about analgesic medicines or nerve blocks. Our psychologists work on behavioral issues and, if necessary, our palliative care specialists help patients deal with living wills and endof-life preferences.”

That is one aspect of the M.D. Anderson Pain Management Center that differentiates it from clinics treating ordinary chronic pain. All of its physicians have training and experience in palliative care, which the center believes gives them a better understanding of pain and makes them better pain clinicians.

“We provide a seamless transition for patients to palliative care treatments, resulting in a continuity of care,” said Dr. Driver.

Palliative care patients have full access to all modes of treatment available at the center—pharmacologic therapies, procedural interventions and psychological support. The palliative care team also works closely with patients’ families to deal with any ethical issues.

Dr. Driver, the center’s ethicist, said a common ethical concern involves the doctrine of “double effect.”

“When we prescribe an opioid to a patient nearing the end of life, we do it with the intention of relieving his or her pain,” he said. “But we also recognize that one of the side effects may be respiratory depression and sedation. This is sometimes called “palliative sedation” or “terminal sedation,” and it is sometimes perceived as hastening a patient’s death.

“That is never our intent. It is always the ethically supportable concept of relieving pain.”

Dual Services For patients without advanced-stage cancers or who are in remission, the Pain Management Center has two services—the Cancer Pain Service, which works with both inpatients and outpatients to manage pain, and the Postoperative Pain Service, which assists patients who have pain after surgery.

The Cancer Pain Service sees outpatients in an advanced care center, comprising more than 5,200 square feet of clinical space, including examination rooms, a procedure room for minor nerve blocks, ablations and injections under fluoroscopy, and a post-procedure room.

The service creates individual treatment plans, using a combination of pain management strategies, to meet each patient’s needs. Last year, it treated approximately 7,000 patients, and the number continues to grow.

The Postoperative Pain Service provides 24-hour care for inpatients after surgery. Its specialized therapies include thoracic epidurals, ultrasoundguided regional anesthesia, rescue blocks and home catheter care programs for acute pain. Daily managements have increased from approximately 7,000 per year in 2004 to more than 15,000 currently.

According to Dr. Burton, treating acute pain is critical to preventing chronic pain. “The more effectively you treat somebody’s acute pain, the less likely the odds they’re going to develop a longterm, chronic pain syndrome,” he said.

Lots of Tools in the Toolbox For chronic cancer pain, the Pain

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Management of

Epidermal Growth Factor Receptor Inhibitor-Induced Dermatologic Toxicity COURTNEY KRUEGER, PHARMD, BCPS University of Illinois at Chicago College of Pharmacy Chicago, Illinois Reviewed by:

EDITH MITCHELL, MD, FACP Clinical Professor of Medicine and Medical Oncology Program Leader, Gastrointestinal Oncology Department of Medical Oncology Kimmel Cancer Center at Jefferson Philadelphia, Pennsylvania

T

he epidermal growth factor receptor (EGFR) is 1 of 4 types of human epidermal receptors that are found primarily on cells of epithelial origin and have a vital role in cellular growth,

proliferation, and migration.1-3 Abnormal activity at the EGFR receptor

has been implicated in many types of solid tumors, including colorectal, non-small cell lung, head and neck, and pancreatic cancers.

Two distinct drug categories have been developed to inhibit tumor growth and proliferation that results from dysregulated EGFR activity. The small molecule inhibitors, also known as tyrosine kinase inhibitors (TKIs), enter the cell and inhibit signaling pathways by binding to the adenosine triphosphate binding site. The monoclonal antibodies do not enter the cell but rather bind to the extracellular receptor, resulting in inactivation of the receptor. Table 1 lists the FDA-approved EGFR inhibitors and their indications.4-9 Other TKIs and monoclonal antibodies that affect receptors other than EGFR are available but will

I N D E P E N D E N TLY DEVELOPED BY MCMAHON PUBLI SHING

not be discussed in this review.

One benefit of the EGFR inhibitors is that they are devoid of traditional systemic chemotherapeutic adverse effects. Their use, however, is associated with dermatologic toxicity.2,3,10,11 Skin rash is the most commonly reported dermatologic adverse effect, but other toxicities include pruritus and xerosis, as well as nail and hair changes. The mechanism of this toxicity appears to be related to the inhibition of EGFR in the skin. EGFR is highly expressed in keratinocytes, the major cellular component of epidermal tissue, in the basal layer of the epidermis. Keratinocytes undergo

C L INIC AL ONCOLOGY NE WS â&#x20AC;˘ AP RIL 2010

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Table 1. EGFR Inhibitors EGFR Inhibitor

Receptor(s)

Indications

Monoclonal Antibodies Cetuximab (Erbitux, ImClone/ Bristol-Myers Squibb)

EGFR

Colorectal cancer • As a single agent for the treatment of EGFR-expressing metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-based regimens or in patients who are intolerant of irinotecan regimens • In combination with irinotecan in patients with EGFR-expressing metastatic cancer who are refractory to irinotecan-based therapy Head and neck cancer • In combination with radiation therapy for locally or regionally advanced squamous cell carcinoma of the head and neck • As monotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy

Panitumumab (Vectibix, Amgen)

EGFR

Colorectal cancer • As a single agent for the treatment of EGFR-expressing metastatic colorectal cancer with disease progression on or following fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy regimens

Tyrosine Kinase Inhibitors Erlotinib (Tarceva, Genentech)

EGFR

Pancreatic cancer • First-line for patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine Non-small cell lung cancer • Treatment of locally advanced or metastatic disease after failure of 1 or more chemotherapy regimens

Gefitinib (Iressa, AstraZeneca)

EGFR

Non-small cell lung cancer • Monotherapy for patients with locally advanced or metastatic cancer after failure of both platinum-based and docetaxel chemotherapies

Lapatinib (Tykerb, GlaxoSmithKline)

EGFR, HER2

Breast cancer • In combination with capecitabine for patients with advanced or metastatic disease whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab • In combination with letrozole for treatment of postmenopausal women with hormone receptor-positive metastatic cancer who overexpress the HER2 receptor for whom hormonal therapy is indicated

EGFR, epidermal growth factor receptor; HER2, human epidermal receptor type 2 Based on references 4-9.

a highly regulated process of differentiation as they move from the basal layer of the epidermis to the skin surface. EGFR inhibitors interfere with this regulation, thus compromising the skin’s integrity.2,12-14

Dermatologic Toxicities Rash The rash that occurs with EGFR inhibitors often is described as papular, pustular, or papulopustular, with a follicular distribution; it most commonly occurs on the scalp, face, and upper trunk.14,15 The rash generally appears within 1 to 2 weeks of treatment and evolves from edema and erythema to pustular eruptions.2,14,16 Rash symptoms usually dissipate within 1 month of

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EGFR inhibitor discontinuation and often will improve even with continued EGFR inhibitor therapy. Some patients with rash will not require intervention, but others will be bothered by the skin dryness and itching and will need treatment.

Although the terms acne-like or acneiform frequently are used to describe the rash, this is discouraged because of the differences in the pathologic processes of acne and EGFR-inhibitor rash.17 The severity of the EGFR-induced rash has been graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), initially version 3.0 and more recently version 4.0 (Table 2).18,19 However, it has been suggested that NCI-CTCAE criteria do not

Table 2. NCI Grading Criteria for EGFR Inhibitor-Induced Rash Source

Adverse Event

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

NCICTCAE v3.0

Rash (acneiform)

Intervention not indicated

Intervention indicated

Associated with pain, disfigurement, ulceration, or desquamation

Not available

Death

NCICTCAE v4.0

Rash (acneiform)

Papules and/or pustules covering <10% BSA that may or may not be associated with symptoms of pruritus or tenderness

Papules and/or pustules covering 10% to 30% BSA that may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL

Papules and/or pustules covering >30% BSA that may or may not be associated with symptoms of pruritus or tenderness; limiting selfcare ADL; associated with local superinfection requiring oral antibiotics

Papules and/or pustules covering any percentage of BSA that may or may not be associated with symptoms of pruritus or tenderness and are associated with extensive superinfection requiring IV antibiotics; life-threatening consequences

Death

NCICTCAE v4.0

Rash (maculopapular)

Macules/ papules covering <10% BSA with or without symptoms (eg, pruritus, burning, tightness)

Macules/papules covering 10% to 30% BSA with or without symptoms (eg, pruritus, burning, tightness); limiting instrumental ADL

Macules/papules covering >30% BSA, with or without associated symptoms; limiting selfcare ADL

Not available

Not available

ADL, activities of daily living; BSA, body surface area; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events Based on references 18 and 19.

adequately address adverse events associated with the EGFR inhibitors, prompting a Multinational Association of Supportive Care in Cancer expert group to propose a new scale (Table 3).20 Rash has been reported to be more severe and to occur more frequently in patients treated with the monoclonal antibodies compared with those treated with TKIs.2,10,14 The reason for this is not fully described, and multiple theories have been proposed. Li and colleagues proposed that the monoclonal antibodies suppress EGFR signaling more, resulting in greater toxicity.2 Eaby and colleagues suggested that higher peak concentrations are reached with the monoclonal antibodies due to the intermittent administration of higher doses of these agents, which results in greater toxicity compared with that seen with the daily administration of lower doses of TKIs.10 The incidence of EGFR inhibitor-induced rash is difficult to determine due to differences in categorization and reporting.10 Jatoi and colleagues reviewed clinical trials of cetuximab (Erbitux, ImClone/Bristol Myers Squibb), panitumumab (Vectibix, Amgen), and erlotinib

(Tarceva, Genentech) and found that, in general, rash occurred in more than 50% of patients.21 A recent metaanalysis of patients receiving cetuximab revealed that the incidence of reported rash was 88.2% (81.6% follicular-pustular).22 A small number of patients (6.5%) had rash that was grade 3 or higher.

Xerosis Xerosis is dry, itchy skin that occurs in up to 35% of patients who receive EGFR inhibitors.14,23 Xerosis can occur in areas of the face and trunk but also frequently presents on the extremities after several weeks of EGFR inhibitor therapy. Patients who are older, have a history of atopic dermatitis, or have had previous cytotoxic chemotherapy are at greater risk for xerosis.24 Hyperpigmentation of the skin may occur in patients with rash or xerosis and may not reverse with treatment discontinuation.

Nail Changes Nail changes including cracking, discoloration, pitting, paronychia (inflammation of the lateral nail bed),

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Table 3. Suggested Grading Criteria for EGFR Inhibitor-Induced Rash Source Lacouture 2010

Adverse Event Papulopustular eruption

Grade 1A

Grade 1B

Grade 2A

Grade 2B

Grade 3A

Grade 3B

<5 papules or pustules OR 1 area of erythema or edema <1 cm

<5 papules or pustules OR 1 area of erythema or edema <1 cm AND pain or pruritus

6-20 papules or pustules; OR 2 to 5 areas of erythema or edema <1 cm

6-20 papules or pustules OR 2 to 5 areas of erythema or edema <1 cm AND pain, pruritus, or effect on emotions or functioning

>20 papules or pustules OR >5 areas of erythema or edema <1 cm

>20 papules or pustules OR >5 areas of erythema or edema <1 cm AND pain, pruritus, or effect on emotions or functioning

Based on reference 20.

and nail loss have been described.2,14,23,25 These changes are reported to occur in approximately 10% to 20% of patients. Paronychia is the most well-described nail change and is believed to result from skin thinning.14 Paronychia typically occurs on the thumbs and great toes, with a delayed onset of at least 1 month from the start of treatment and a duration that can persist months beyond discontinuation of EGFR inhibitor therapy.2,14 Patients with paronychia are predisposed to secondary infections.

Hair Changes Changes in hair growth, texture, or thickness have been reported in up to 15% of patients taking EGFR inhibitors.2,23,25 Infrequently, trichomegaly (excess

eyelash growth) has been reported. These alterations tend to be more delayed than other EGFR-related dermatologic adverse effects, generally occurring after 2 or more months of therapy. Hair changes typically resolve within weeks or months after therapy discontinuation.2

Rash and Survival The presence of rash from EGFR inhibitors has been correlated with increased response to EGFR inhibitor therapy and improved survival.26-28 It has been proposed that dermatologic toxicity may be a marker for full EGFR receptor inhibition. However, results from studies that dose EGFR inhibitors until the presence of rash occurs are preliminary and have been conflicting.29,30 Further research in this area is necessary.

Management

Table 4. Basic Measures To Prevent EGFR Inhibitor-Induced Toxicities Sun exposure

• Avoid the sun when possible • Use sunscreen (preferably containing zinc oxide or titanium dioxide)

Skin care

• Use alcohol-free emollients to prevent dry skin • Avoid dyes and perfumes • Use mild body wash • Take cool or lukewarm baths (rather than hot showers) • Apply hypoallergenic makeup for covering rash • Avoid over-the-counter acne products

Nail care

• Keep nails clean and trimmed • Avoid activities that could cause nail bed trauma (eg, wearing tight-fitting shoes)

There are no well-established guidelines for the prevention or treatment of EGFR inhibitor-induced dermatologic changes. Treatment is largely based on anecdotal data from case reports, cases series, and expert opinion.

Rash Prophylaxis

Based on references 2, 3, 10, 15, and 38.

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General nonpharmacologic prophylactic recommendations are shown in Table 4. In addition to these measures, the use of oral antibiotics for prophylaxis has been studied in 2 randomized controlled trials.31,32 Tetracycline and its derivatives have been the primary antibiotics studied because of their anti-inflammatory effects. Scope and colleagues randomly assigned 48 cetuximab-treated patients to receive 100 mg of minocycline or placebo daily.31 All patients also received topical tazarotene 0.05% (Tazorac, Allergan) to be applied to one side of the face twice daily. Prophylactic therapy was initiated on the same day as cetuximab therapy and continued for 8 weeks. Patients in the minocycline group had a significantly reduced log lesion count at 4 weeks compared with placebo (P=0.005); however, by 8 weeks there was no significant difference between

Table 5. Recommendations for the Treatment of EGFR Inhibitor-Induced Rash Expert Group

Recommendations

Erlotinib Expert Panel Recommendations17

Grade 1 • Treatment with topical agents is optional (topical antibiotics, 2% sulfosalicylic creams) • No dose reduction or treatment interruption Grade 2 • Topical treatment as in Grade 1, with controversial recommendation for topical corticosteroids; patients with more severe symptoms could add oral therapy with tetracyclines and corticosteroids; antihistamines for pruritus • No dose reduction or treatment interruption; for very distressing symptoms, erlotinib may be interrupted for 3 to 5 days (restart at full dose; if rash recurs within 15 days, a dose reduction to 100 mg can be considered) Grade 3 • Topical agents, tetracycline, and oral corticosteroids can be used; tetracycline may be considered for a short duration to prevent future episodes after resolution of event • EGFR therapy should be interrupted until rash improves to Grade 2; restart at 100 mg/day; discontinue therapy if rash recurs with the reduced dose Grade 4 • Refer to burn unit for intensive care • Discontinue therapy indefinitely

Canadian Panel Recommendations for Monoclonal Antibodies in Gastrointestinal Malignancies11

Mild (Grade 1) • Topical corticosteroid (hydrocortisone 1%) and clindamycin 2% twice daily until resolution Moderate (Grade 2) • Topical treatment as above until rash improves to Grade 1 plus oral antibiotics (minocycline 100 mg twice daily or doxycycline 100 mg once or twice daily) for at least 4 weeks and as long as symptoms of rash are present • For scalp lesions, use topical clindamycin plus triamcinolone acetonide 0.1% in equal parts propylene glycol and water until resolved Severe (Grade 3) • Panitumumab: hold treatment until toxicity is Grade 2 or less • Cetuximab: hold treatment for 1 week • THEN follow Grade 2 recommendations; treatment can be continued if symptoms improve (follow dose escalation as recommended by manufacturer); treatment should be discontinued if no improvement is seen

2006 EGFR Inhibitor Dermatologic Toxicity Forum3,10

Mild • No treatment OR topical hydrocortisone (1% or 2.5%) and/or clindamycin 1% gel for 2 weeks (no alteration in EGFR inhibitor regimen); proceed to moderate treatment if no improvement or worsening reaction Moderate • Either topical hydrocortisone 2.5% cream, clindamycin 1% gel, or pimecrolimus 1% cream AND doxycycline or minocycline 100 mg twice daily for 2 weeks (no alteration in EGFR inhibitor regimen); proceed to severe treatment if no improvement or worsening reaction Severe • Add oral corticosteroid to moderate regimen and reduce EGFR inhibitor dose for 2 weeks; EGFR inhibitor may be interrupted or discontinued if symptoms worsen

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the groups. The proportion of patients with moderate to severe rash and itching was somewhat improved with minocycline at 4 weeks, but again, the difference between the groups was minimal by 8 weeks. Almost one-third of patients discontinued tazarotene due to skin dryness or irritation, and there appeared to be little beneficial effect with this treatment. In a second study, tetracycline (500 mg twice daily) was compared with placebo for rash prevention in patients receiving EGFR inhibitors.32 Tetracycline was initiated within 14 days of EGFR initiation and continued for 4 weeks. Although there was little difference in overall rash incidence, the tetracycline-treated patients had a lower incidence of physician-reported grade 2 or higher skin toxicity at week 4 (17% vs 55%; P=0.04). At week 8, the incidence of moderate to severe skin toxicity remained lower in the tetracycline group (27% vs 47%), but it was not significantly different.

Rash Prophylaxis Versus Treatment Recently, Lacouture et al published the first trial comparing preemptive therapy (given at the start of EGFR inhibitor therapy) with reactive therapy (treatment after the development of a rash).33 All 95 patients were being treated with panitumumab for colorectal cancer. Preemptive therapy consisted of a morning application of moisturizer, sunscreen prior to going outdoors, 1% hydrocortisone cream at bedtime, and 100 mg of doxycycline twice daily. Reactive treatment was at the discretion of the investigator and was prescribed at any point during weeks 1 to 6 of the study.

Patients in the preemptive therapy group had fewer grade 2 or higher skin toxicities (29% vs 62%) during the 6-week treatment period. Based on these results, it appears that preventive therapies for rash should be further studied; however, the presence of rash has been correlated with survival, and there is concern that preventive therapy reduces the appearance of this marker of efficacy.14 Rash Treatment Table 5 summarizes several expert recommendations for the treatment of EGFR inhibitor-induced rash.10,11,17 A number of authors also have published recommendations based on their personal practice.15,34 Treatment recommendations typically include topical therapy for mild symptoms with progression to systemic antibiotics and corticosteroids for more severe rashes.

Topical agents. Topical corticosteroids, antibiotics, and immunosuppressants frequently are recommended. Use of topical antiseptics, fusidic acid, econazole, and benzoyl peroxide also have been reported without obvious benefit.35

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Pimecrolimus (Elidel, Novartis), a topical immunosuppressant, was evaluated in a small trial (N=24) of patients receiving cetuximab.36 Pimecrolimus applied to one side of the face for 5 weeks reduced the lesion count on the treated side at both 2 and 5 weeks compared with the nontreated side. Additionally, patients reported decreases in burning, itching, dryness, and redness. However, the authors reported that the results did not show a clinically significant benefit, and thus they call into question the role of pimecrolimus.

The use of topical corticosteroids is also controversial. Li and colleagues reported that corticosteroids may potentiate EGFR toxicity and recommend that these agents be avoided.2 Lynch and colleagues recommend topical steroids be applied for 7 days beyond resolution of symptoms but not for more than 14 consecutive days.3 One author recommends use of topical corticosteroids for a maculopapular rash but recommends clindamycin gel if the rash has pustular characteristics.15 It is possible that topical steroids are most effective early in rash treatment.26 In addition to clindamycin, other topical antibiotics that have been used include erythromycin, fusidic acid, and metronidazole. Topical clindamycin appears most frequently in the literature and seems effective, particularly for pustular rash.15,37 Topical retinoids have been recommended by some authors, but many reports suggest they should be avoided because of their drying effects.38 In the prevention study by Scope and colleagues, tazarotene cream resulted in significant skin irritation.31 The Erlotinib Expert Panel suggests that further study of topical retinoids is necessary because one case report suggests positive results.17 Regenecare, a wound gel with lidocaine, aloe vera, collagen, and sodium alginate, is being evaluated for its efficacy in improving itching and pain in patients receiving EGFR inhibitors.2 A pilot study revealed that a small number of patients with grade 2 rash applying the gel to affected areas had less itching and pain.39 Menadione (vitamin K3), has been shown to reverse the effects of EGFR inhibitors in the skin and is the first proposed treatment to reverse the EGFR inhibition process.40 A topical formulation is in Phase I clinical trials.

Oral agents. The mechanism of oral antibiotics has been reported to be primarily anti-inflammatory rather than antibacterial; thus, tetracycline and its derivatives are the most widely recommended agents.17 Although minocycline and tetracycline were not dramatically successful when given as preventive agents, their use did improve rash severity.31,32 These data combined with success in case reports make them a reasonable option for rash treatment. Oral corticosteroids also are frequently

recommended. Oishi suggests that corticosteroids are a good option for a rash that has progressed but is not pustular.15 Several authors recommend the use of antihistamines for itching.10,15,38

for EGFR inhibitor-induced dermatologic toxicities, and multidisciplinary care should be instituted for patients who develop these toxicities.

References Xerosis Management Little information has been published on the management of xerosis associated with EGFR inhibitors.

Emollient use is generally recommended.37 The emollient for the face and upper trunk should be an oil-inwaterâ&#x20AC;&#x201C;based cream because greasy ointments could worsen the papulopustular rash; however, if the limbs are affected, a water-in-oil cream or ointment may be used.24 Low-dose corticosteroids can be used if eczema develops. Secondary infections should be treated appropriately.

Treatment of Nail and Hair Changes Li and colleagues recommend the use of topical steroids and antiseptic soaks for paronychia.2 Segaert and colleagues suggest that a potent topical steroid applied to the nail bed at symptom onset may prevent worsening of the paronychia.24 Suh and colleagues reported a case of paronychia that failed to respond to oral cephalexin and topical mupirocin but did respond to doxycycline 100 mg twice daily. Therapy was continued for 6 weeks, with full symptom resolution.41 The hair changes that can occur in patients treated with EGFR inhibitors often do not require intervention,2 but if trichomegaly occurs, an ophthalmologic examination may be indicated and the patientâ&#x20AC;&#x2122;s eyelashes may need to be cut.

Conclusion Although dermatologic reactions are common with EGFR inhibitors, treatments for these reactions have not been fully evaluated in clinical trials. Recent data suggest that preventive regimens may be valuable, but further research in this area is necessary before widespread use is recommended. Rash management will be necessary for some patients. Patients with mild to moderate symptoms may improve with topical therapy; however, patients with more severe rash will likely require oral therapy with antibiotics or possibly systemic corticosteroids. Typically, discontinuing or reducing doses of EGFR inhibitors is avoided unless a severe reaction occurs.

Patients undergoing treatment with EGFR inhibitors should be educated about the common dermatologic toxicities, especially skin rash. Techniques for skin care, rash prevention, and potential management strategies should be thoroughly discussed. Oncologists, dermatologists, nurses, and pharmacists should remain vigilant

1.

Zahorowska B, Crowe PJ, Yang JL. Combined therapies for cancer: a review of EGFR-targeted monotherapy and combination treatment with other drugs. J Cancer Res Clin Oncol. 2009;135(9):1137-1148, PMID: 19533170.

2. Li T, Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol. 2009; 4(2):107-119, PMID: 19452131.

3. Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacouture ME. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621, PMID: 17522250.

4. Wickersham RN, ed. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2010. http://online.factsandcomparisons. com/searchresults.aspx?search=30946%7c24. Accessed February 10, 2010.

5. Iressa [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2005.

6. Tykerb [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010.

7. Tarceva [package insert]. Seymour, IN: Schwarz Pharma; 2009.

8. Vectibix [package insert]. Thousand Oaks, CA: Amgen; 2008.

9. Erbitux [package insert]. Branchburg, NJ: ImClone; 2009.

10. Eaby B, Culkin A, Lacouture ME. An interdisciplinary consensus on managing skin reactions associated with human epidermal growth factor receptor inhibitors. Clin J Oncol Nurs.

2008;12(2):283-290, PMID: 18390464.

11. Melosky B, Burkes R, Rayson D, Alcindor T, Shear N, Lacouture M. Management of skin rash during EGFR-targeted monoclonal antibody treatment for gastrointestinal malignancies: Canadian recommendations. Curr Oncol. 2009;16(1):16-26, PMID: 19229368.

12. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803-812, PMID: 16990857.

13. Chou LS, Garey J, Oishi K, Kim E. Managing dermatologic toxicities of epidermal growth factor receptor inhibitors.

Clin Lung Cancer. 2006;8(suppl 1):S15-S22, PMID: 17239286.

14. Hu JC, Sadeghi P, Pinter-Brown LC, Yashar S, Chiu MW. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management.

J Am Acad Dermatol. 2007;56(2):317-326, PMID: 17141360.

15. Oishi K. Clinical approaches to minimize rash associated with EGFR inhibitors. Oncol Nurs Forum. 2008;35(1):103-111, PMID: 18192159.

16. Solomon BM, Jatoi A. Rash from EGFR inhibitors: opportunities and challenges for palliation. Curr Oncol Rep. 2008;10(4):304-308, PMID: 18778556.

17. Gridelli C, Maione P, Amoroso D, et al. Clinical significance and treatment of skin rash from erlotinib in non-small cell lung cancer patients: results of an Experts Panel Meeting. Crit Rev Oncol Hematol. 2008;66(2):155-162, PMID: 18083041.

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18. National Cancer Institute. Common terminology criteria for adverse events (Version 3.0); 2003. http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3. pdf. Accessed February 9, 2010.

19. National Cancer Institute. Common terminology criteria for adverse events (Version 4.0); 2009. http://evs.nci.nih.gov/ftp1/ CTCAE/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf.

Accessed February 11, 2010.

20. Lacouture ME, Maitland ML, Segaert S, et al. A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group. Support Care Cancer.

2010;18(4):509-522, PMID: 20145956.

21. Jatoi A, Nguyen PL. Do patients die from rashes from epidermal growth factor receptor inhibitors? A systematic review to help counsel patients about holding therapy. Oncologist.

2008;13(11):1201-1204, PMID: 18988655.

22. Su X, Lacouture ME, Jia Y, Wu S. Risk of high-grade skin rash in cancer patients treated with cetuximabâ&#x20AC;&#x201D;an antibody against epidermal growth factor receptor: systemic review and metaanalysis. Oncology. 2009;77(2):124-133, PMID: 19622903.

23. Galimont-Collen AF, Vos LE, Lavrijsen AP, Ouwerkerk J, Gelderblom H. Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer. 2007;43(5):845-851, PMID: 17289377.

24. Segaert S, Chiritescu G, Lemmens L, Dumon K, Van Cutsem E, Tejpar S. Skin toxicities of targeted therapies. Eur J Cancer.

2009;45(suppl 1):295-308.

25. Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006;55(4):657-670, PMID: 17010747.

26. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptors. J Clin Oncol. 2004;22(7): 1201-1208, PMID: 14993230.

27. Mohamed MK, Ramalingam S, Lin Y, Gooding W, Belani CP. Skin rash and good performance status predict improved survival with gefitinib in patients with advanced non-small cell lung cancer. Ann Oncol. 2005;16(5):780-785, PMID: 15728108.

28. Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies.

Clin Cancer Res. 2007;13(13):3913-3921, PMID: 17606725.

29. Tejpar S, Peeters M, Humblet Y, et al. Phase I/II study of cetuximab dose-escalation in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic (PK), pharmacodynamic (PD) and efficacy data. J Clin Oncol.

2007;25(18 suppl):abstract 4037.

30. Sangha RS, Ho C, Beckett L, et al. Rash severity and dose in

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Phase I dose escalation cetuximab (c225) trial. J Clin Oncol.

2008;26:abstract 14573.

31. Scope A, Agero AL, Dusza SW, et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol.

2007;25(34):5390-5396, PMID: 18048820.

32. Jatoi A, Rowland K, Sloan JA, et al. Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer.

2008;113(4):847-853, PMID: 18543329.

33. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a Phase II, open-label, randomized trial evaluating the impact of a preemptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol.

2010;28(8):1351-1357, PMID: 20142600.

34. Lacouture ME, Basti S, Patel J, Benson A. The SERIES Clinic: an interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol. 2006;4(5):236-238, PMID: 16724647.

35. Jacot W, Bessis D, Jorda E, et al. Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumours. Br J Dermatol. 2004;151(1):238-241, PMID: 15270903.

36. Scope A, Lieb JA, Dusza SW, et al. A prospective randomized trial of topical pimecrolimus for cetuximab-associated acne-like eruption. J Am Acad Dermatol. 2009;61(4):614-620, PMID: 19646778.

37. Tan EH, Chan A. Evidence-based treatment options for the management of skin toxicities associated with epidermal growth factor receptor inhibitors. Ann Pharmacother.

2009;43(10):1658-1666, PMID: 19755624.

38. Perez-Soler R, Delord JP, Halpern A, et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist. 2005;10(5):345-356, PMID: 15851793.

39. Wong S, Osann K, Lindgren A, Byun T, Mummaneni M. Pilot cross-over study to evaluate Regenecare topical gel in patients with epidermal growth factor receptor (HER1/EGFR) inhibitorsinduced skin toxicity: the final analysis. J Clin Oncol. 2008; 26(15 suppl):abstract 20507.

40. Perez-Soler R, Zou Y, Li T, Tornos C, Ling T. Steroids and immunosuppressive agents potentiate the cytotoxicity of the EGFR inhibitor erlotinib (E) in human skin keratinocytes whereas Vit K3 exerts a protective effect: implications for the management of the skin rash. J Clin Oncol. 2006; 24(18 suppl):abstract 3036.

41. Suh KY, Kindler HL, Medenica M, Lacouture M. Doxycycline for the treatment of paronychia induced by the epidermal growth factor receptor inhibitor cetuximab. Br J Dermatol.

2006;154(1):191-192, PMID: 16403122.

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CLINICAL ONCOLOGY NEWS • APRIL 2010

Pain

Management Center employs a threepronged treatment algorithm—medication and procedural interventions, physical rehabilitation to improve function, and psychological counseling. Medications can include acetaminophen, nonsteroidal anti-inflammatories, opioids, antidepressants, antiepileptic drugs and steroids.

procedure, called the “spine wand,” for vertebral compression fractures. Pain specialists thread the wand into spinal tumors, where it uses electrical energy in a conductive medium—e.g., saline solution—to create a highly localized plasma cloud that dissolves cancerous tissue without damaging surrounding structures. The void created is then

and group therapy, biofeedback, relaxation techniques or meditation. Integrative therapies, such as acupuncture and massage therapy, also are used and have proven effective in treating cancer pain.

“We take care of the whole patient,” said Dr. Novy, “even encouraging them to be proactive in other parts of their lives, such as good nutrition.”

Why Pain Happens

—Larry Driver, MD

If they don’t work, procedural interventions can include neural blocks, such as injections, radiofrequency ablation and the chemical destruction of nerves, called neurolysis; minimally invasive, image-guided pain relieving procedures, such as vertebroplasty and kyphoplasty, which repair vertebral fractures caused by tumors; or implanted devices, such as neurostimulators and intrathecal analgesic pumps.

One of the newest interventional techniques the center is using is a state-of-the-art, minimally invasive

filled with a medical-grade cement to stabilize the spinal cord. Patients have reported significant pain relief with this technique.

On the rehabilitation front, the center’s physical rehab specialists work with patients to help them regain functionality and return to normal activities, while its psychologists teach patients how to cope and work through their pain. “For the psychological impact of cancer pain, we provide whatever a patient needs to cope,” said Dr. Novy.

That can include individual, family

SURVEY continued from page 1

related pain who were taking pain medications and had experienced BTP. Their chronic pain conditions stemmed from the cancer itself, the treatment or post-treatment conditions. Although the online survey’s results could be affected by response bias, the results, Dr. Portenoy explained, offer insight into how BTP affects aspects of daily life and medical care for affected patients.

The overwhelming majority of survey participants reported that spikes in pain significantly impacted their quality of life. More than nine out of 10 respondents (91%) reported that better control of BTP would improve their quality of life, and 75% cited it as one of the most challenging aspects of having cancer. Similarly, more than four in five (82%) respondents said BTP caused hardship in their lives. The same percentage reported negative effects on emotional health, and more than three out of four (76%) said it made doing chores more difficult.

Most participants reported BTP as severe and frequent—measuring, on average, 7.4 on a 10-point scale—with more than half (53%) rating the typical spike in pain at 8 to 10 out of 10. Furthermore, 71% of respondents experienced BTP once per week or more frequently, 22% experienced BTP several times per day, and nearly three-fourths (74%) indicated that it occurred without warning.

Almost nine out of 10 (87%) respondents said that BTP also impacted medical treatment in various ways. It required additional medication (66%) and necessitated more frequent visits to health care

M.D. Anderson’s efforts to help cancer patients in pain include an annual $4 million commitment to clinical and basic research. It has more than 8,700 square feet of research space in close proximity to main operating rooms, post-anesthesia care units and intensive care units, allowing for collaboration between scientists and clinicians.

“Cancer and cancer treatment-related pain significantly reduces the quality of everyday life in many patients, as well as the return to productivity for cancer survivors,” said Chris Rubio, director of clinical research. “Our pain research program seeks to reduce those burdens through combined basic science and clinical investigations that clarify underlying mechanisms of pain, better define and lower the side effects of current pain treatments, and discover novel analgesics and pain treatments.”

providers for over half (51%). Use of hospitals may also be greater in patients with BTP—18% reported being hospitalized more frequently during episodes of BTP and 14% had gone to the emergency room more often because of it.

In financial terms, nearly three-fourths (73%) of patients said that BTP increased their daily medical expenses. “Medical-related financial issues as a result of BTP” was a problem for 67%, with 37% reporting more medical care–related debt. More than half (54%) said their out-of-pocket expenses had increased because of BTP, whereas one-fourth (25%) said they were unable to pay for prescribed treatments for BTP. Most patients (95%) had discussed their symptoms with physicians, mostly with their primary care provider (69%) or oncologist (65%). Strikingly, more than one in four patients (28%) reported that their health care providers seemed uninterested in addressing problems associated with BTP. Only 32% of the respondents had seen pain physicians for BTP, and only 20% were currently seeing a pain physician.

For pain specialists, the impact of BTP on patients’ lives simply underscores the importance of interrogating and treating patients as necessary, Dr. Portenoy said.

“Cancer pain management is a partnership” between the oncologist, the pain physician and other medical staff, said Amy Abernethy, MD, program director of the Duke University Cancer Care Research Center, Durham, N.C. Because oncologists “may be limited in their knowledge” of treatments for pain, the role of the pain physician is to help develop a suitable regimen.

She also noted that treating pain is especially

—Thomas McDonough

Causes hardship in my life Negatively affects my emotional health

100

Is one of the most challenging aspects of having cancer

82

82

80

Patients, %

‘We’re not only multidisciplinary, but multimodal. Our pain specialists are talking to patients about analgesic medicines or nerve blocks. If necessary, our palliative care specialists help patients deal with living wills and end-of-life preferences.’

To move its basic and clinical research from the bench to the bedside, the pain center founded a start-up biotech company two years ag o, called Vapogenix, Inc., to develop any new analgesic agents discovered. One such finding is a cannabinoid medicine for neuropathic pain.

“Vapogenix also is working on an early-stage trial of a new pain pump, used to treat refractory pain conditions,” said Dr. Burton.

According to Oscar de Leon Casasola, MD, the entire landscape has changed regarding cancer pain. “Today, 95% of cancer patients can achieve pain relief through medication,” said Dr. de Leon Casasola, chief of pain medicine, Department of Anesthesiology and Pain Medicine, Roswell Park Cancer Institute, Buffalo, N.Y. “With interventional techniques, that goes up to 99%. That is the good news.”

“Our message is that cancer pain is treatable,” said Dr. Burton. “Maybe we can’t take the pain away, but we can control it and improve a patient’s quality of life. The depth and breadth of our experience, combined with our multidisciplinary/multimodal approach and dedicated staff, offer cancer patients real hope in relieving their pain.”

75

60

40

20

0

Figure. Impacts of breakthrough pain.

difficult in cancer survivors because there are few data on managing BTP in this population. Whereas for people with active cancer, a long-acting opioid coupled with a short-acting or immediate-release opioid is often considered the standard of care, abuse risk may be higher in cancer survivors, thus potentially limiting treatment options.

The survey was funded by an unrestricted educational grant from Meda Pharmaceuticals and was conducted by Harris Interactive.

—Clayton Simmons

23

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CLINICAL ONCOLOGY NEWS • APRIL 2010

AI Side Effects

Treating the Side Effects of AI Therapy San Antonio—Vitamin D and testosterone may help ameliorate muscle and joint pain associated with aromatase inhibitor (AI) use.

These are the findings from two small studies presented at the San Antonio Breast Cancer Symposium (SABCS). If larger studies corroborate these results, doctors may have a way to improve adherence to AI therapy, a significant problem among women with postmenopausal, hormone receptor–positive breast cancer.

Although the reasons for nonadherence to any therapy are complex, muscle and joint pain account for a sizeable proportion of AI treatment discontinuations.

The magnitude of the nonadherence problem is illustrated by a study presented by Canadian researchers at the SABCS (abstract 36) that analyzed adherence to adjuvant hormonal therapies in 2,403 women with postmenopausal hormone receptor–positive early breast cancer. Within the first two years of AI use, 40% of the women became nonadherent; nonadherence to aromatase inhibitors was 37% and nonadherence to tamoxifen was 42% (Figure).

“This problem is significant,” said Stephen K. Chia, MD, a staff oncologist at the British Columbia Cancer Agency in Vancouver, Canada, who was involved with the study.

Other studies have shown rates of nonadherence to AI therapy ranging from 25% to about 50% over four years.

The study presented by Dr. Chia was not designed to explore reasons for nonadherence, but the researchers found that nonadherent patients were more likely to have lower-risk cancers, while adhering patients tended to have poor prognostic factors.

Vitamin D and Musculoskeletal Pain In a small, randomized clinical trial, high-dose vitamin D (ergocalciferol) significantly reduced muscle and joint pain in breast cancer patients treated with anastrozole (Arimidex, AstraZeneca) (abstract 803). Two months of weekly high-dose vitamin D treatment significantly improved pain and mobility, but this benefit was lost four to six months after patients were switched to monthly high-dose vitamin D supplementation. Pain was measured by validated questionnaires. At two months, the high-dose vitamin D group reported lower scores on pain-related questions— Brief Pain Inventory question 3 (P=0.01) and Fibromyalgia Impact Questionnaire question 15 (P=0.02).

According to lead author Antonella Rastelli, MD, an instructor in the Department of Medicine, Oncology Division, Washington University in St. Louis, the pilot study suggests that weekly, rather than monthly, treatment with high-dose vitamin D can improve anastrozole-induced muscle and joint tenderness. Larger studies are needed to confirm the potential benefit, and future studies should evaluate the effect of continuing weekly supplementation for a longer period of time.

Although the high-dose vitamin D was well tolerated, Dr. Rastelli said that some of the patients treated with it had a tendency toward higher urinary calcium excretion, which could lead to kidney stones. Patients included in the trial had been taking anastrozole for at least eight weeks before enrollment and had a history of generalized musculoskeletal pain that started or worsened on initiation of AI treatment.

All patients (N=60) were treated with 1,000 mg calcium and 400 IU vitamin D3 per day. Those randomized to highdose supplementation (n=30) received 50,000 IU per week for eight or 16 weeks, depending on baseline vitamin D levels; then they were switched to vitamin D 50,000 IU per month. Patients in the control arm (n=30) received matching placebo supplementation.

Patients included in the trial had marginal vitamin D levels (10-29 ng/nL). Dr. Rastelli suggested that future trials should include women with normal vitamin D levels and also evaluate other forms of

Nonadherence to aromatase inhibitors Nonadherence to tamoxifen

50 N= 2,403

42

40

Patients, %

24

37

30

20

10

0

Figure. Adherence to adjuvant hormonal therapies within the first two years.a a

Adherence measured in 2,403 women with postmenopausal hormone receptor–positive early breast cancer.

vitamin D, such as cholecalciferol, which achieves more stable vitamin D levels than the preparation used in the study.

The study was supported by AstraZeneca Pharmaceuticals.

Testosterone for AI-Induced Arthralgia In a second study presented at SABCS, a Phase II, doubleblind randomized trial of 90 women on adjuvant anastrozole revealed that testosterone reduced pain and stiffness (abstract 804). “AIinduced arthralgia causes significant morbidity, and also may be affecting compliance,” said lead author Steve N. Birrell, MD, Chavah Pty Ltd., Adelaide, South Australia.

Dr. Birrell’s research demonstrated that AI-induced arthralgia results from altered metabolism of testosterone. The recent observations of a high level of Sjögren’s syndrome in women on AIs and the strong association of this syndrome with low levels of activated testosterone support the hypothesis that the etiology of AI-induced joint pain is the reduced conversion of testosterone to its potent active metabolite dihydrotestosterone, Dr. Birrell explained.

“This situation results from ultralow levels of estrogen, leading to a futile attempt by the body to maintain high levels of testosterone at the expense of metabolizing testosterone,” he said. “We propose that by maintaining testosterone levels during long-term AI therapy, quality of life, compliance, and efficacy may be improved by forcing testosterone metabolism to the metabolite known to be antiinflammatory in the joint and antiproliferative to breast carcinoma. Due to the power of AIs to prevent the conversion of testosterone to estrogen, we saw no increase in serum estrogen in women on testosterone supplementation.”

The study included 90 women on adjuvant anastrozole randomized in a 1-to1-to-1 fashion: placebo, testosterone 40 mg per day or testosterone 80 mg per day. The median age was 61 years (range, 41-84); median time on anastrozole was 15.5 months (range, two to 66); and 40% had prior chemotherapy.

At three months, a significant reduction from baseline visual analog scale (VAS) score for pain and VAS stiffness score was observed in the group on the higher dose of testosterone (80 mg) compared

with placebo (P=0.04 and P=0.06, respectively, for pain and stiffness scores).

No changes in lipid profile were seen at either dose of testosterone. No significant reduction in bone absorption was seen at three months with either dose of testosterone, but a trend was observed toward reduced absorption with the higher dose.

The study was supported by AstraZeneca Pharmaceuticals.

Viewpoint According to most oncologists, musculoskeletal complaints and arthralgias are a significant problem for breast cancer survivors taking AIs. “Improved prediction and assessment of this problem, understanding the mechanism of these side effects and how they affect adherence and patient quality of life, as well as interventions to ameliorate it are clearly warranted,” said Ann H. Partridge, MD, MPH, an oncologist based at Dana-Farber Cancer Institute, in Boston.

Turning to vitamin D deficiency, Dr. Partridge said that this problem is being increasingly recognized in breast cancer survivors. “The idea that [vitamin D] supplementation may mitigate musculoskeletal side effects in patients on AIs is very exciting and should be studied further beyond this small provocative study,” she said.

According to Dr. Partridge, the role of androgens, specifically testosterone, is also an interesting approach and may address the mechanism underlying musculoskeletal complaints and arthralgias. “Some evidence suggests that increased androgen levels may be associated with increased risk of developing breast cancer, so the safety of using testosterone to treat this side effect would have to be considered and thoroughly tested before this could become a standard option,” she cautioned.

—Alice Goodman

APPROVED in combination with paclitaxel first line

First and only biologic for HER2-negative metastatic breast cancer Indication Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in metastatic breast cancer is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

Please see the next page and following brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Avastin plus paclitaxel in first-line HER2-negative MBC*

Provide more timewithout progression Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls.

The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions Grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E2100 increased by 20.5% in the Avastin plus paclitaxel vs paclitaxel groups. Grade 1–2 adverse events were not collected in Study E2100, and common adverse events of Avastin in combination with paclitaxel for metastatic breast cancer are not known. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs 18%), hypertension (16% vs 1%), fatigue (11% vs 5%), infection without neutropenia (9% vs 5%), neutrophils (6% vs 3%), vomiting (6% vs 2%), diarrhea (5% vs 1%), bone pain (4% vs 2%), headache (4% vs 1%), nausea (4% vs 1%), cerebrovascular ischemia (3% vs 0%), dehydration (3% vs 1%), infection with unknown ANC (3% vs 0.3%), rash/desquamation (3% vs 0.3%) and proteinuria (3% vs 0%).

The rate of congestive heart failure (CHF) (defined as NCI-CTC grade 3–4) in the Avastin plus paclitaxel arm was 2.2% vs 0.3% in the control arm. Among patients receiving prior anthracyclines, the rate of CHF was 3.8% for Avastin-treated patients and 0.6% for patients receiving paclitaxel alone. Fatal adverse reactions occurred in 1.7% (6/363) of patients who received Avastin plus paclitaxel in Study E2100. Causes of death were GI perforation (2), myocardial infarction (2), diarrhea/abdominal pain/weakness/hypotension (2) References: 1. Avastin Prescribing Information. Genentech, Inc. July 2009. 2. Data on file. Genentech, Inc. 3. Kirkwood BR, Sterne JAC. Essential Medical Statistics. 2nd ed. Malden, MA: Blackwell Science Ltd; 2003.

©2010 Genentech USA, Inc.

All rights reserved.

9046203

Printed in USA.

(02/10)

Significant PFS† benefit achieved Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in metastatic breast cancer is based on an improvement in progression free survival.

There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

Median PFS1,2

11.3 vs 5.8 mo

Percentage Progression Free

100

(95% Cl, 10.5–13.3 vs 5.4–8.2)

80

risk of progression 52% Reduced (HR=0.48, P<0.0001, 95% Cl, 0.39–0.61)

60

Avastin + paclitaxel (n=368)

40

Paclitaxel (n=354)

20

0

6

12

18

24

30

36

Progression-free Survival (Months) *MBC=metastatic breast cancer. † Primary analysis of progression-free survival (PFS) was based on the retrospective blinded review of tumor data by an independent review facility.2

PFS nearly doubled vs paclitaxel alone—11.3 vs 5.8 months (HR=0.48, P<0.0001, 95% CI, 0.39–0.61) (95% CI, 10.5–13.3 vs 5.4–8.2)1 On average during study follow-up, there was a 52% reduction in the risk of disease progression (HR=0.48, P<0.0001, 95% CI, 0.39–0.61)1,3

Important treatment considerations—Dose modifications There are no recommended dose reductions. Discontinue Avastin in patients with gastrointestinal (GI) perforations (GI perforations, fistula formation in the GI tract, intra-abdominal abscess), fistula formation involving an internal organ, wound dehiscence and wound healing complications requiring medical intervention, serious hemorrhage (ie, requiring medical intervention), severe arterial thromboembolic event (ATE), hypertensive crisis or hypertensive encephalopathy, reversible posterior leukoencephalopathy syndrome (RPLS) (symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae), and nephrotic syndrome. Temporarily suspend Avastin for at least 4 weeks prior to elective surgery, severe hypertension not controlled with medical management, moderate to severe proteinuria pending further evaluation, and severe infusion reactions. The safety of resumption of Avastin therapy in patients that experienced RPLS, ATE, and moderate to severe proteinuria is unknown.

Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

www.avastin.com

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery g y and Wound Healing g Complications p The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).]

Hemorrhage g Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).]] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).

[See Use in Specific Populations (8.5).]] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin.

[See Clinical Studies (14).]] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with and resolved without medical intervention. Grade 1 or 2 hemorrhagic gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy following a venous thromboembolic event. Among these patients, an additional The overall incidence of Grade 3–4 venous thromboembolic events in following Grade 3–4 venous thromboembolic events was higher in intra-abdominal venous thrombosis (10 vs. 5 patients).

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.

Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).]

Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving presented in Table 1.

PRN

AVASTIN® (bevacizumab) Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

NCI-CTC Grade 3-4 Events Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra-Abdominal Thrombosis Syncope Digestive g Diarrhea Constipation Hemic/Lymphatic y p Leukopenia Neutropeniaa a

Arm 1

Arm 2

(n = 396) 74%

(n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1 Arm 1

Arm 2

Arm 3

(n = 98)

(n = 102)

(n = 109)

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6%

52% 43% 40% 32% 24% 24%

47% 35% 29% 30% 17% 19%

2% 1%

7% 6%

4% 1%

0%

5%

5%

Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive g Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Dry Mouth Colitis Hemic/Lymphatic y p Thrombocytopenia Nervous Dizziness Respiratory p y Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages pp g Alopecia Skin Ulcer Special p Senses Taste Disorder Urogenital g Proteinuria

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/ pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs.

3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs.

0.3%) and proteinuria (3% vs. 0%).

Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).

Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all

75ha_d.indd 3

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

may be influenced by several factors, including sample handling, timing of

Asthenia Headache Pain Cardiovascular Hypertension Digestive g Stomatitis Metabolic/Nutrition Musculoskeletal Myalgia Respiratory p y Dyspnea Epistaxis Skin/Appendages pp g Exfoliative dermatitis Urogenital g Albuminuria

Capecitabine (n = 215)

Capecitabine + Avastin (n = 229)

47% 13% 25%

57% 33% 31%

2%

24%

19%

25%

8%

14%

18% 1%

27% 16%

75%

84%

7%

22%

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving α) plus Avastin compared to 304 patients receiving α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving α α plus placebo arm are presented in Table 4.

Table 4 NCI-CTC Grades 1−5 Adverse Events in Study 9 α α + Placebo) Preferred term* Gastrointestinal disorders Diarrhea General disorders and administration site conditions

α (n = 304) 16%

α + Avastin (n = 337)

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

21%

Investigations g Metabolism and nutrition disorders Anorexia Musculoskeletal and connective tissue disorders Myalgia Back pain Nervous system y disorders Headache Renal and urinaryy disorders Proteinuria Respiratory, p y, thoracic and mediastinal disorders Epistaxis Dysphonia Vascular disorders Hypertension

reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration Hemic and lymphatic: Pancytopenia Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia

31%

36%

14% 6%

19% 12%

16%

24%

3%

20%

4% 0%

27% 5%

9%

28%

*Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the α α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay

greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.

Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs.

2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Manufactured by: Genentech, Inc. 94080-4990

7453214 4835706 © 2009 Genentech, Inc

1/27/10

Around the Water Cooler Fine Levied for Radiation Mistakes

T

he Nuclear Regulatory Commission (NRC) has proposed a $227,500 fine against the Department of Veterans Affairs (DVA) for medical errors involving cancer patients identified at the Veterans Affairs Medical Center in Philadelphia (VA Philadelphia). It is the NRC’s second-largest fine ever against a medical institution.

Medical errors at VA Philadelphia involved the incorrect placement of iodine-125 seeds to treat prostate cancer.

Of 116 procedures performed between 2002 and 2008, 97 were executed incorrectly. One radiation oncologist, Gary D. Kao, MD, was found responsible for the great majority of the mistakes. Dr. Kao no longer works at the hospital.

“The lack of management oversight, the lack of safety culture to ensure patients are treated safely, the potential consequences to the veterans who came to this facility and the sheer number of medical events show the gravity of these violations,” said Mark Satorius, regional administrator for the NRC’s Region III office in Lisle, Ill. The principal violations, assessed at $208,000, are associated with the lack of written procedures to provide high confidence that each treatment was implemented as prescribed and the lack of a procedure to verify that the treatment was implemented correctly. Additional violations, assessed at $19,500, involve the wrong dose of radioactive seeds being ordered and implanted into a patient on May 5, 2008, because no procedure existed to verify correct implementation of treatment; the lack of training in the NRC’s definition of a medical event and associated reportability requirements; and the failure to report medical events to the NRC no later than the next calendar day.

People on the Move Douglas Blayney, MD, has accepted the position of medical director of the Stanford Cancer Center, in Stanford, Calif. He was previously medical director of the University of Michigan Comprehensive Cancer Center, in Ann Arbor.

According to the Orlando Business Journal, David Decker, MD, has been named the new executive director of the Florida Hospital Cancer Institute.

Prior to joining the cancer institute, Dr. Decker served as director of research and education at the William Beaumont 9:46 PM Cancer Treatment Center and chief of see COOLER, page 41

29

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • APRIL 2010

Breast

Hurdling the Challenges of Anti-angiogenic Therapy Orlando, Fla.—Anti-angiogenic therapy was once predicted to cure cancer, but with a better understanding of the complexity of the process, the challenges now seem daunting.

This is according to Lee M. Ellis, MD, an angiogenesis expert, who delivered a lecture discussing current efforts to target the vascular endothelial growth factor (VEGF) in colorectal cancer (CRC) at the recent 2010 Gastrointestinal Cancers Symposium. Dr. Ellis is a professor of surgical oncology and interim chair of the Department of Cancer Biology at the University of Texas M.D. Anderson Cancer Center, in Houston.

Dr. Ellis pointed out that the “scorecard” for Phase III clinical trials has more losses than wins for VEGF-targeted agents in CRC. “Most trials have not met their primary end point, and we don’t seem to be making much progress,” he said. “We must do better.”

Although progress has been slow, some lessons have been learned, he continued. These include “more drugs are not better”; all VEGF-targeted agents are not created

Vasoconstriction can rapidly cause hypoxia, which can induce hypoxia-inducible factor (HIF) and subsequently induce the angiogenic genes that regulate cell migration, survival, proliferation and invasion, he said. Intentional HIF inhibitors are being developed, but unintentional inhibitors include topotecan, anthracyclines, HSP90 inhibitors, mTOR inhibitors and proteosome inhibitors.

“Just because some agents historically have not shown activity in CRC does not mean they will not have value when combined with the right drugs,” Dr. Ellis said. For example, daily administration of topotecan in combination with bevacizumab inhibits tumor growth and even leads to tumor regression in preclinical models.

in this setting, the goal should be cure, and therefore the trial end point should be overall survival. “Disease-free survival is not really meaningful without an improvement in overall survival in asymptomatic patients,” he said.

He said the field has learned that long-term treatment with a VEGF inhibitor may contribute to toxicity without adding meaningful efficacy. He pointed out that the NSABP C-08 adjuvant colon cancer trial presented by Wolmark et al at the 2009 annual meeting of the American Society of Clinical Oncology (abstract LBA4) found no benefit from 12 months of bevacizumab in stage 2 to 3 cancer, and many predict the AVANT study will be negative as well, he said. The AVANT trial is randomizing 3,451 patients to FOLFOX, FOLFOX plus bevacizumab, or capecitabine plus oxaliplatin (XELOX) plus bevacizumab.

Bevacizumab will be continued to 48 weeks. In the FOLFOX/Bev arm, 40% discontinued due to adverse

‘We must fully understand the mechanisms of action of VEGF-targeted therapies before we will be able to extract maximal benefit from therapy.’

—Lee M. Ellis, MD

equal; single agents are not good options; toxicities are real; and predictive biomarkers are not easy to identify.

Dr. Ellis maintained that the goal should be to significantly improve overall survival, which is not likely to be accomplished with “me too” drugs. Improvements will require “creative” trial design rather than the current practice of adding a VEGF-targeted agent to standard chemotherapy. “While this approach is necessary for companies to pursue drug registration and approval, it is not likely to lead to major advances,” he said.

Moving New Approaches Forward “For the front-line treatment of metastatic CRC, there are only a few ways to improve outcomes with VEGF-targeted therapies,” Dr. Ellis commented. Better drug combinations and different targets (and agents) may advance the field, he said, but first “we must fully understand the mechanisms of action of VEGF-targeted therapies before we will be able to extract maximal benefit from therapy.” Researchers should focus on means of targeting pathways for resistance before resistance occurs, and this means resistance to regimen, not just to bevacizumab (Avastin, Genentech), he pointed out.

Of the potential mechanisms of action outlined, he believed vascular constriction to be the most important.

MARKERS continued from page 9

gastric cancer at increased risk for disease recurrence and poor prognosis. “[I

Courtesy of Genentech

30

Other approaches exist. Inhibition of the Notch signaling pathway, which leads to non-functional blood vessels, could also be important. Several Notch inhibitors are now in clinical trials. Dual inhibition of the VEGF and angiopoetin/Tie2 pathways is another approach.

Signaling inhibitors to mTOR, PI3K, Src, MAPK/Mek, in addition to HIF, could be effective, along with cell surface/growth factor receptor inhibitors, he said.

Some of the more interesting experimental combinations already in clinical trials include the mTOR inhibitor sirolimus plus bevacizumab, fluorouracil and irinotecan (Camptosar, Pfizer), and the Src inhibitor dasatinib plus 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) and cetuximab (Erbitux, Bristol-Myers Squibb).

In Adjuvant Setting, Limit Anti-VEGF Treatment

events, 12% higher than with FOLFOX alone (Hoff P et al. ESMO/ECCO 2009; abstract O-6010). “The benefit of bevacizumab lasts only as long as it is given. We would need to either give it forever, which is not feasible, or not at all,” Dr. Ellis said.

Dr. Ellis’ recommendations were to conduct Phase II trials of triplets that include chemotherapy plus a VEGF-targeted agent plus another compound directed at tumor endothelial cells that is “rationally selected.”

He also suggested that for regimens that appear promising, one of the cytotoxic agents might be dropped up front, for example, keeping 5-fluorouracil plus the targeted agent first-line but deferring irinotecan and oxaliplatin for second-line therapy, which would limit the duration of long-term toxicity, he pointed out.

“Let’s be more creative,” he said, “and not just throw another ‘me too’ drug into a Phase III trial.”

In his talk, Dr. Ellis also discussed anti-angiogenesis treatment in the adjuvant setting. According to him,

am] not sure that it can help to individually tailor therapy at this point, although the hope would be that this work may help to facilitate new therapies that target CD44,” Dr. Chu said. “The CD44 marker has been used to identify cancer

stem cells from a number of different cancers, including breast cancer, colon cancer and now gastric cancer, and as noted, this population expresses high levels of key signaling pathways that allow for cell growth and survival, as

—Caroline Helwick

well as increased resistance to chemotherapy and radiation therapy. Much research is now focused on targeting this particular stem cell population.”

—Caroline Helwick

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • APRIL 2010

CLL

Alemtuzumab Is Active but Toxic in CLL New Orleans—In the treatment of chronic lymphocytic leukemia (CLL), alemtuzumab (Campath, Bayer HealthCare Pharmaceuticals) is effective and safe in relapsed patients, but not in the consolidation setting after first-line therapy, according to two recent studies.

The studies were presented at the recent meeting of the American Society of Hematology. In a study of patients with relapsed CLL, the addition of alemtuzumab to fludarabine (Fludara, Bayer) significantly improved progression-free survival (PFS) with acceptable safety compared with fludarabine alone (abstract 537).

“With significantly longer PFS, higher overall and complete response rates, and an acceptable safety profile, the combination of fludarabine and alemtuzumab has been shown in our study to be safe and effective in patients with relapsed CLL,” said Andreas Engert, MD, an investigator from the Center of Integrated Oncology, University of Cologne, in Cologne, Germany. Providing the secondary interim results of a trial that was stopped early because of the superiority of this combination over fludarabine alone, Dr. Engert concluded that this approach “should be pursued” in relapsed CLL. In a second study, alemtuzumab consolidation after fludarabine and rituximab (Rituxan, Biogen Idec/Genentech) (FR) in first-line therapy of patients with CLL increased response rates, but also increased severe infections (abstract 210). Grade 3 to 5 infections, including six deaths, associated with alemtuzumab consolidation after treatment with FR in first-line therapy is the reason that the Cancer And Leukemia Group B (CALGB) “will not pursue further studies of alemtuzumab in this setting,” said Thomas S. Lin, MD, PhD, formerly of the Division of Hematology and Oncology, Ohio State University, in Columbus, and now director of clinical development at GlaxoSmithKline Research and Development.

PFS climbed from 20.7 months with fludarabine alone to 29.6 months with the combination. This was consistent with greater anti-tumor activity. While the overall response rate climbed from 68% to 84.8% (P<0.001), the CR rate almost doubled (16.4% vs. 30.4%; P=0.002).

“For maybe some of you, surprisingly, the safety of this combination—fludarabine and Campath as opposed to fludarabine alone—resulted in no difference in the number of patients dying and a similar incidence of grade 3 or 4 infectious complications. FluCAM, from our point of view, is safe in this relapsed population with CLL,” Dr. Engert said. The multinational study included data on 317 patients randomized to the two study arms. In this study, the infection rates were higher among those taking alemtuzumab (47% vs. 35%), but there were no grade 4 infections in either arm and the rate of death on therapy was higher in the group receiving fludarabine alone than in those also receiving alemtuzumab (5% vs. 2%).

Although Dr. Engert reported that the safety and tolerability observed for alemtuzumab encourages further studies in second-line treatment of CLL, a Phase II study combining alemtuzumab with fludarabine and cyclophosphamide in the

second-line setting also generated significant toxicity, including a variety of infectious complications. That study, led by Thomas Elter, MD, Center for Integrated Oncology, Bonn, Germany, produced a far more circumspect conclusion about the future of alemtuzumab, even in secondline treatment. In the study, which included Dr. Engert as a co-author, response rates in the 61 relapsed CLL patients studied on the regimen were substantial, including an overall response rate of 63% and a CR rate of 22%. The toxicity, however, led the authors to question the viability of this approach if safer alternatives can be used.

Consolidation Patients receiving fludarabine and alemtuzumab Patients receiving fludarabine

30

29.6

25 20.7

Relapsed CLL

20

PFS, mo

The differences between these trials appear to be linked to the stage of disease. Although alemtuzumab showed good activity in both settings, safety was a major issue in the consolidation setting, particularly in patients who had achieved a complete remission with initial therapy, but was not as much of an issue in second-line treatment, setting the stage for a progression-free survival advantage. When PFS, the primary end point, was evaluated by an independent review board in the study that evaluated alemtuzumab in the secondline treatment of CLL, there was a highly significant hazard ratio (HR) of 1.63 (P=0.005) favoring the combination.

Although Dr. Engert reported that the safety and tolerability observed for alemtuzumab encourages further studies in second-line treatment of CLL, a Phase II study combining alemtuzumab with fludarabine and cyclophosphamide in the second-line setting also generated significant toxicity, including a variety of infectious complications.

15

10

5

0

Figure. PFS in patients with relapsed CLL. CLL, chronic lymphocytic leukemia; PFS, progression-free survival

In the consolidation study of alemtuzumab in 102 patients, excessive toxicity resulted in only 58 patients’ receiving alemtuzumab consolidation. While alemtuzumab consolidation improved response rates and converted 28 (62%) of 45 patients in partial response (PR) after FR to complete response (CR), these benefits did not translate when looking at PFS. Dr. Lin noted that the two-year PFS (73%) in the intent to treat (ITT) population was not statistically superior to the 67% two-year PFS attained by FR alone in the ITT population in the previous CALGB 9712 trial.

Although alemtuzumab consolidation following FR substantially increased the CR rate from 29% to 57% and increased the minimal residual disease negative rate from 15% to 50%, the PFS rates at two years (76% vs. 70%; P=0.54) and the two-year overall survival rates (84% vs.

88%; P=0.89) did not differ significantly between patients who did (n=58) and did not (n=44) receive alemtuzumab. Investigators also found no difference in PFS or OS among those who achieved a CR

with alemtuzumab compared with those who achieved a CR without this agent.

Although a benefit is not apparent right now, it is possible that longer follow-up may reveal a survival advantage.

Toxicity was substantial when alemtuzumab was used in CLL patients in the first-line consolidation setting, producing a 43% incidence of grade 3 or 4 neutropenia and a 19% incidence of grade 3 to 4 thrombocytopenia. Alemtuzumab consolidation was also associated with a 19% incidence of grade 3/4 infections and a 19% incidence of grade 3/4 febrile neutropenia. Moreover, five patients who achieved a CR after alemtuzumab died of infections, which included cytomegalovirus, Pneumocystis carinii pneumonia and Listeria meningitis. The infectious complications occurred up to seven months after alemtuzumab therapy was administered. This led the investigators to conclude that alemtuzumab consolidation is not safe in this population.

Jennifer Brown, MD, attending physician with the CLL & Lymphoma Program, Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, both in Boston, pointed out that another study presented at ASH (abstract 538) provides further evidence of toxicity with alemtuzumab.

In that study, the GOELAMS trial, which compared FCCam to fludarabine, cyclophosphamide and rituximab in previously untreated patients with advanced CLL, was terminated early due to excessive toxicity in the FCCam arm. The investigators concluded that “the FCCam regimen for the treatment of advanced CLL appeared to be associated with an unfavorable safety profile representing a significant limitation of its use in this indication.”

—Ted Bosworth

31

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Imatinib Dose Escalation in the Management of Recurrent Gastrointestinal Stromal Tumors: A Case Study William Tap, MD Director, Sarcoma Oncology Program Co-Director, Translational Sarcoma Team Jonsson Comprehensive Cancer Center University of California at Los Angeles Health System Assistant Professor of Medical Oncology UCLA David Geffen School of Medicine Los Angeles, California

Bartosz Chmielowski, MD Clinical Instructor, Hematology and Oncology UCLA David Geffen School of Medicine Los Angeles, California

32

CLINICAL ONCOLOGY NEWS • APRIL 2010

Introduction 9

Table 1. Treatment Response to Imatinib in Phase III Trials Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the GI tract. Various studies have estimated the total number of GIST 400 mg/d, % 800 mg/d, % cases each year in the United States at Complete response 5.3 5.0 4,500 to about 6,000, with approximately 1,500 already metastasized upon diagnoPartial response 46.1 48.9 sis. GIST patients range in age from the teens to the 90s, but peak age is around 60 years.1,2 GISTs develop from the GI wall and are thought to originate from the interstitial cells of Cajal, which regulate GI motility. glycoprotein CD34, S100 protein, and to imatinib have a much worse survival Approximately 70% of GISTs produce clini- desmin.2 In addition, the presence of rate (9% at 5 years).8 cal symptoms, with the remainder found gene mutations can impact the risk for incidentally at endoscopy or computed recurrence, as the following case study SAFETY As with all treatment decisions, phytomography (CT). GISTs can develop any- illustrates. sicians must weigh the occurrence and where along the GI tract, from the esophagus to the rectum; however GISTs are most Case Presentation and Initial severity of adverse events against the benefits of treatment (ie, risk–benefit commonly seen in the stomach (60%).

Treatment ratio). Serious but rare adverse events Overall, GISTs represent the most common A 65-year-old man initially presents associated with the use of imatinib in primary small bowel tumor (32%).2,3 Approximately 50% of GISTs are clin- with profound fatigue. Laboratory work- the treatment of KIT+ GIST include heart ically malignant.4 Clinically malignant up reveals the presence of hypochro- failure, edema, and hematologic toxicibehavior includes omental, mesenteric, or mic, microcytic anemia (hemoglobin, ties. A majority of patients treated with peritoneal seeding; invasion of adjacent 7.8 g/dL) and iron deficiency. Stool stud- imatinib experience adverse events over organs; or frank metastasis. The most ies are positive for occult blood. Upper the course of treatment; most are mild to common sites for metastasis include the endoscopy reveals an ulcerated mass moderate in severity. In addition, common liver, lung, and bone.2 in the lesser curvature of the stomach. adverse events include muscle cramps or Overt GI bleeding due to an ulcerated Microscopic analysis of the tumor sam- pain, abdominal pain, and/or nausea or mass is the most common symptom when ple reveals a spindle-cell neoplasm (up vomiting.9 Patient education is essential GISTs are present, and is observed in to 7 mitoses per 50 high-power fields). in addressing these adverse events. See approximately 50% of patients. According Immunohistochemistry shows the cells the prescribing information for a complete to a retrospective study of GISTs in Ice- are positive for CD34 and CD117, and description of the safety information. land diagnosed between 1990 and 2003, negative for desmin. These findings other presenting symptoms may include are consistent with malignant GIST. A DOSE ESCALATION The patient was followed with reguabdominal pain or fullness (32%) and the CT scan of the abdomen shows a mass presence of a palpable mass (13%).5 originating from the stomach and mea- lar scanning by CT and positron emisHistologically, GISTs are composed of suring 10.5×7.5×7 cm. sion tomography, and at 3 years following fairly uniform spindle cells (70%), but in Treatment is started with Gleevec® initial treatment, CT scans revealed the some cases may be dominated by epi- (imatinib mesylate) at a dosage of 400 mg patient’s stomach mass had grown in size. thelioid cells (20%) or may consist of a daily. Several clinical trials have shown a Mutational analysis of the tumor sammixture of these 2 morphologies. 2 high overall response rate and progres- ple revealed the presence of a mutation Approximately 90% of GISTs exhibit sion-free survival in patients with KIT+ within exon 9. It was decided that imatinib mutations, usually involving the KIT GIST treated with imatinib.6-9 Objective therapy should be dose-escalated up to gene, but may also have a defect in the response rate, including complete (5.3%) 800 mg daily in 2 divided doses. platelet-derived growth factor receptor and partial (46.1%) responses, is 51.4%, Generally, dose escalation to 400 alpha-type (PDGFRA) gene.2,3 GISTs may and the median overall survival is 49 mg twice daily should be considered also stain positive for the cell surface months.9 Patients who do not respond in patients who previously responded

Supported and sponsored by Novartis Pharmaceuticals Corporation

Table 2. Severe Adverse Events Associated With the Use of Imatinib in the Treatment of KIT+ GIST9

PFS on imatinib in the Phase III trial: 400 mg/d vs 800 mg/d

18.9

400 mg/d (n=818)

(95% CI, 17.4-21.2)

Fluid retention and edema Hematologic toxicity Severe Congestive Heart Failure/ Left Ventricular Dysfunction

23.2

800 mg/d (n=822)

(95% CI, 20.8-24.9)

Hepatotoxicity Hemorrhage

0

6

12

18

Gastrointestinal Disorders

24

Hypereosinophillic Cardiac Toxicity

Months

Dermatologic Toxicities

Adapted from Gleevec package insert (reference 9).

GIST, gastrointestinal stromal tumors

Figure. Progression-free survival with imatinib in unresectable and/or metastatic KIT+ GIST.

See the prescribing information for a complete description of the safety information

to imatinib, without drug toxicities. In receiving therapy with imatinib 400 mg a study by Blanke et al, 30% to 37% of daily. When the dose was increased to patients who had disease progression 800 mg daily, he began to complain of experienced additional response when mild fatigue, lower extremity and perithe dose of imatinib was increased (Table orbital edema, and macular rash on the 1 and Figure).10 chest. The rash resolved with continued Therapy with imatinib is generally well therapy, and lower extremity edema was tolerated; however, higher doses of the treated with supportive care. drug are associated with increased freA repeat scan performed 3 months quency of side effects.10,11 Use of high- after initiation of the higher dose of imadose imatinib (800 mg per day) has been tinib revealed stabilization of the disease. associated with grades 3/4/5 adverse This finding was confirmed with a CT events such as peripheral edema (13.1%), scan at 6 months. The patient remains fatigue (12.2%), abdominal pain (11.8%), on high-dose imatinib, with tolerarash (8.9%), diarrhea (8.6%), nausea ble side effects. As this case illustrates, (7.8%), vomiting (7.5%), and anemia KIT+ GIST patients experiencing disease (6.4%) (Table 2).9 progression undergoing treatment with Therefore, in this patient, com- standard-dose imatinib (400 mg per day) plete blood count was initially moni- may benefit from increased doses of the tored weekly for 4 weeks, then every 2 drug (800 mg per day), when weighed weeks, and finally once a month. Liver against the risk for and severity of the function tests were checked at baseline adverse events associated with treatand then monthly. The patient in this ment, making high-dose imatinib anothcase had no side effects when he was er option in the treatment of KIT+ GIST.

References 1. American Cancer Society. Gastrointestinal Stromal Tumor. http://documents.cancer.org/6887.00/ 6887.00.pdf. Accessed January 11, 2010.

2. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol.

2004;22(18):3813-3825.

3.

Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130(10):1466-1478.

4.

DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg.

2000;231(1):51-58.

5. Tryggvason G, Kristmundsson T, Orvar K, Jónasson JG, Magnússon MK, Gíslason, HG. Clinical study on gastrointestinal stromal tumors (GIST) in Iceland, 1990-2003. Dig. Dis. Sci. 2007;52(9):2249-2253.

6. Demetri GD, Wang Y, Wehrle E, et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol. 2009;27(19): 3141-3147.

7.

Verweij J, van Oosterom A, Blay JY, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target: results from an EORTC soft tissue and bone sarcoma group phase II study. Eur J Cancer.

2003;39(14):2006-2011.

8. Blanke CD, Demetri GD, von Mehren M, et al.

Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26(4):620-625.

9. Gleevec [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2009.

10. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26(4):626-632.

11. Harrison ML, Goldstein D. Management of metastatic gastrointestinal stromal tumour in the Glivec era: a practical case-based approach. Intern Med J. 2006;36:367-377.

GLI-300080

Hyperthyroidism

BB0959

GIST, gastrointestinal stromal tumor; PFS, progression-free survival

CLINICAL ONCOLOGY NEWS • APRIL 2010

33

‘GLEEVEC® (imatinib mesylate) tablets are indicated for: • Patients with KIT (CD117)–positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST) • Adjuvant treatment of adult patients following resection of KIT (CD117)–positive GIST

Important Safety Information • GLEEVEC is often associated with edema and occasionally severe fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life-threatening, and be advised to report any rapid, unexpected weight gain. Rapid weight gain tended to be among older patients (>65 years) or those taking higher doses of GLEEVEC. • Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months).

• Dose adjustments may be necessary due to hematologic adverse reactions, hepatotoxicity, and other nonhematologic adverse reactions.

• In Phase 3 unresectable or metastatic GIST trials (400 mg/ day; 800 mg/day) severe (NCI Grades 3/4/5) lab abnormalities—including anemia (5%; 6%) and neutropenia (3%; 4%)— and severe adverse reactions (NCI Grades 3/4/5), including abdominal pain (14%; 12%), fluid retention and edema (9%; 13%), fatigue (12%; 12%), nausea (9%; 8%), vomiting (9%; 8%), diarrhea (8%; 9%), rash (8%; 9%), and myalgia (6%; 4%) were reported among patients receiving GLEEVEC. • In the adjuvant treatment of GIST trials (GLEEVEC; placebo) severe (NCI Grades 3 and above) lab abnormalities— increase in liver enzymes (ALT) (3%; 0%), (AST) (2%; 0%), and decrease in hemoglobin (1%; 0%)—and severe adverse reactions (NCI Grades 3 and above), including abdominal pain (3%; 1%), diarrhea (3%; 1%), rash (3%; 0%), fatigue (2%; 1%), nausea (2%; 1%), vomiting (2%; 1%), and periorbital edema (1%; 0%) were reported among patients receiving adjuvant treatment with GLEEVEC. • Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

• In patients with hypereosinophilic syndrome and cardiac involvement, cardiogenic shock and left ventricular dysfunction have been associated with initiation of GLEEVEC. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding GLEEVEC.

• Hepatotoxicity, occasionally severe, may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.

• Patients with moderate renal impairment (CrCL = 20-39 mL/ min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated.

Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment.

• In the Phase 3 unresectable or metastatic GIST studies, 13% of patients reported (NCI Grades 3/4) hemorrhage at any site.

In the Phase 2 unresectable or metastatic GIST study, 5% of patients were reported to have severe gastrointestinal (GI) bleeds and/or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds.

• There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation.

• Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.

• Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. TSH levels should be closely monitored in such patients.

• Consider potential toxicities—specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.

• Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking GLEEVEC tablets and to avoid breast-feeding while taking GLEEVEC tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use adequate contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus.

• GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of GLEEVEC should increase by at least 50% and clinical response should be carefully monitored in patients receiving GLEEVEC with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with GLEEVEC include ketoconazole, acetaminophen, warfarin, erythromycin, and

phenytoin. (Please see full Prescribing Information for other potential drug interactions.)

• For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.

Common Side Effects of GLEEVEC Tablets • The majority of patients who received GLEEVEC in the Phase 3 unresectable or metastatic GIST study experienced adverse reactions at some time. The most frequently reported adverse reactions (400 mg/day; 800 mg/day) (all Grades) were edema (77%; 86%), fatigue (69%; 75%), nausea (58%; 65%), abdominal pain (57%; 55%), diarrhea (56%; 58%), rash and related terms (56%; 70%), vomiting (37%; 41%), myalgia (32%; 30%), anemia (32%; 35%), anorexia (31%; 36%), and arthralgia (14%; 12%). Therapy with GLEEVEC was discontinued for adverse reactions in 5% of patients at both dose levels studied.* • In the adjuvant treatment of GIST trials, the majority of both GLEEVEC- and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include (GLEEVEC; placebo) (all Grades) diarrhea (59%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), abdominal pain (21%; 22%), anorexia (17%; 9%), arthralgia (15%; 15%), and myalgia (12%; 12%).* • In the adjuvant GIST trial, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebo-treated patients. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.* • Supportive care may help management of some mild-tomoderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary.

• GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation. GLEEVEC tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.

• Patients should be informed to take GLEEVEC exactly as prescribed, not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose. *For more detailed study information, please see full Prescribing Information.

GLEEVEC (imatinib mesylate) tablets for oral use Initial U.S. Approval: 2001 BRIEF SUMMARY: The following information refers to adult patients with Kit-positive GIST. Experience with other indications may differ. Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Fluid Retention and Edema Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1) in the full prescribing information]. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.11)].

5.2 Hematologic Toxicity Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy [see Dosage and Administration (2.11) in the full prescribing information].

5.3 Severe Congestive Heart Failure and Left Ventricular Dysfunction Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.3)]. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with interruption and/or dose reduction of the treatment with Gleevec [see Dosage and Administration (2.10) in the full prescribing information].

When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.

5.5 Hemorrhage In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site.

In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages.

5.6 Gastrointestinal Disorders Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation.

5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered at the initiation of therapy.

5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec.

5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.

5.10 Toxicities from Long-Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals.

An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans).

Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Nonneoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.

5.11 Use in Pregnancy Pregnancy Category D Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec.

Sexually active female patients taking Gleevec should use adequate contraception. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.

6.2 Hematologic Toxicity Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 4 and 5 in the full prescribing information). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5 in the full prescribing information). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.

These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but in rare cases require permanent discontinuation of treatment.

6.3 Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5 in the full prescribing information) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.

6.5 Adverse Reactions in Other Subpopulations In older patients (≥65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.

6.11 Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials the majority of Gleevec-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see Dosage and Administration (2.10) in the full prescribing information]. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%).

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 9.

Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.

Table 9: Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg N=818 Reported or Specified Term

All Grades %

Edema Fatigue/lethargy, malaise, asthenia Nausea Abdominal pain/cramping Diarrhea Rash/desquamation Vomiting Myalgia Anemia Anorexia Other GI toxicity Headache Other pain (excluding tumor related pain) Other dermatology/skin toxicity Leukopenia Other constitutional symptoms Cough Infection (without neutropenia) Pruritus Other neurological toxicity Constipation Other renal/genitourinary toxicity Arthralgia (joint pain) Dyspnea (shortness of breath)

Imatinib 800 mg N=822

Grades 3/4/5 %

All Grades %

Grades 3/4/5 %

76.7 69.3 58.1 57.2 56.2 38.1 37.4 32.2 32.0 31.1 25.2 22.0

9.0 11.7 9.0 13.8 8.1 7.6 9.2 5.6 4.9 6.6 8.1 5.7

86.1 74.9 64.5 55.2 58.2 49.8 40.6 30.2 34.8 35.8 28.1 19.7

13.1 12.2 7.8 11.8 8.6 8.9 7.5 3.8 6.4 4.7 6.6 3.6

20.4 17.6 17.0 16.7 16.1 15.5 15.4 15.0 14.8 14.2 13.6 13.6

5.9 5.9 0.7 6.4 4.5 6.6 5.4 6.4 5.1 6.5 4.8 6.8

20.8 20.1 19.6 15.2 14.5 16.5 18.9 15.2 14.4 13.6 12.3 14.2

5.0 5.7 1.6 4.4 3.2 5.6 4.3 4.9 4.1 5.2 3.0 5.6 (continued)

Table 9: Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg N=818 Reported or All Grades Specified Term % Fever in absence of neutropenia (ANC <1.0 x 109/L) 13.2 Sweating 12.7 Other hemorrhage 12.3 Weight gain 12.0 Alopecia 11.9 Dyspepsia/heartburn 11.5 Neutropenia/granulocytopenia 11.5 Rigors/chills 11.0 Dizziness/lightheadedness 11.0 Creatinine increase 10.8 Flatulence 10.0 Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9.2 Lymphopenia 6.0

Grades 3/4/5 %

All Grades %

Grades 3/4/5 %

4.9 4.6 6.7 1.0 4.3 0.6 3.1 4.6 4.8 0.4 0.2

12.9 8.5 13.3 10.6 14.8 10.9 16.1 10.2 10.0 10.1 10.1

3.4 2.8 6.1 0.6 3.2 0.5 4.1 3.0 2.8 0.6 0.1

5.4 0.7

10.0 10.1

4.3 1.9

Table 10: Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial 400 mg (n=73) %

600 mg (n=74) %

Grade 3

Grade 4

Grade 3

Grade 4

3 0 7

0 0 3

8 1 8

1 0 3

0 3 1

0 0 0

3 4 1

0 0 3

0 4 6

0 0 0

3 3 7

0 3 1

Grades: neutropenia (Grade 3 ≥0.5-1.0 x 109/L, Grade 4 <0.5 x 109/L), thrombocytopenia (Grade 3 ≥10-50 x 109/L, Grade 4 <10 x 109/L), anemia (Grade 3 ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), albumin (Grade 3 <20 g/L)

1CTC

Adjuvant Treatment of GIST The majority of both Gleevec and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Gleevec and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin and rash were the most frequently reported adverse reactions at the time of discontinuation.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Gleevec are shown in Table 11.

Table 11: Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1) All CTC Grades

Preferred Term Diarrhea Fatigue Nausea Periorbital Edema Hemoglobin Decreased Peripheral Edema Rash (Exfoliative) Vomiting Abdominal Pain Headache Dyspepsia Anorexia Weight Increased Liver Enzymes (ALT) Increased Muscle Spasms Neutrophil Count Decreased Arthralgia White Blood Cell Count Decreased Constipation Dizziness Liver Enzymes (AST) Increased Myalgia Blood Creatinine Increased Cough Pruritus

All CTC Grades

Imatinib 800 mg N=822

Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 10.

CTC Grades1 Hematology Parameters – Anemia – Thrombocytopenia – Neutropenia Biochemistry Parameters – Elevated Creatinine – Reduced Albumin – Elevated Bilirubin – Elevated Alkaline Phosphatase – Elevated SGOT (AST) – Elevated SGPT (ALT)

Table 11: Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1)

Gleevec (n=337) %

Placebo (n=345) %

59.3 57.0 53.1 47.2 46.9 26.7 26.1 25.5 21.1 19.3 17.2 16.9 16.9 16.6 16.3 16.0 15.1 14.5 12.8 12.5 12.2 12.2 11.6 11.0 11.0

29.3 40.9 27.8 14.5 27.0 14.8 12.8 13.9 22.3 20.3 13.0 8.7 11.6 13.0 3.3 6.1 14.5 4.3 17.7 10.7 7.5 11.6 5.8 11.3 7.8

CTC Grade 3 and above Gleevec (n=337) % 3.0 2.1 2.4 1.2 0.6 0.3 2.7 2.4 3.0 0.6 0.9 0.3 0.3 2.7 0 3.3 0 0.6 0 0 2.1 0 0 0 0.9

Placebo (n=345) % 1.4 1.2 1.2 0 0 0 0 0.6 1.4 0 0 0 0 0 0 0.9 0.3 0.3 0.3 0.3 0 0.3 0.3 0 0 (continued)

Preferred Term Weight Decreased Hyperglycemia Insomnia Lacrimation Increased Alopecia Flatulence Rash Abdominal Distension Back Pain Pain in Extremity Hypokalemia Depression Facial Edema Blood Alkaline Phosphatase Increased Dry Skin Dysgeusia Abdominal Pain Upper Neuropathy Peripheral Hypocalcemia Leukopenia Platelet Count Decreased Stomatitis Upper Respiratory Tract Infection Vision Blurred

CTC Grade 3 and above

Gleevec (n=337) %

Placebo (n=345) %

Gleevec (n=337) %

Placebo (n=345) %

10.1 9.8 9.8 9.8 9.5 8.9 8.9 7.4 7.4 7.4 7.1 6.8 6.8

5.2 11.3 7.2 3.8 6.7 9.6 5.2 6.4 8.1 7.2 2.0 6.4 1.2

0 0.6 0.9 0 0 0 0.9 0.3 0.6 0.3 0.9 0.9 0.3

0 1.7 0 0 0 0 0 0.3 0 0 0.6 0.6 0

6.5 6.5 6.5 6.2 5.9 5.6 5.0 5.0 5.0 5.0 5.0

7.5 5.2 2.9 6.4 6.4 1.7 2.6 3.5 1.7 3.5 2.3

0 0 0 0.3 0 0.3 0.3 0 0.6 0 0

0 0 0 0 0 0 0 0 0 0 0

adverse reactions occurring in ≥5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

(1)All

6.12 Additional Data from Multiple Clinical Trials The following adverse reactions have been reported during clinical trials of Gleevec.

Cardiac Disorders: Estimated 0.1%-1%: congestive cardiac failure, tachycardia, palpitations, pulmonary edema Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion Vascular Disorders: Estimated 1%-10%: flushing, hemorrhage Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynauds phenomenon, hematoma Clinical Laboratory Tests: Estimated 0.1%-1%: blood CPK increased, blood LDH increased Estimated 0.01%-0.1%: blood amylase increased Dermatologic: Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, nail disorder, purpura, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, erythema multiforme, leucocytoclastic vasculitis Digestive: Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease General Disorders and Administration Site Conditions: Estimated 1%-10%: weakness, anasarca, chills Estimated 0.1%-1%: malaise Hematologic: Estimated 1%-10%: pancytopenia, febrile neutropenia Estimated 0.1%-1%: thrombocythemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia Hepatobiliary: Estimated 0.1%-1%: hepatitis, jaundice Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1 Hypersensitivity: Estimated 0.01%-0.1%: angioedema Infections: Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01%-0.1%: fungal infection Metabolic and Nutritional: Estimated 1%-10%: weight decreased Estimated 0.1%-1%: hypophosphatemia, dehydration, gout, increased appetite, decreased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia Estimated 0.01%-0.1%: hyperkalemia, hypomagnesemia Musculoskeletal: Estimated 1%-10%: joint swelling Estimated 0.1%-1%: joint and muscle stiffness Estimated 0.01%-0.1%: muscular weakness, arthritis

Nervous System/Psychiatric: Estimated 1%-10%: paresthesia, hypesthesia Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis Renal: Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive: Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory: Estimated 1%-10%: epistaxis Estimated 0.1%-1%: pleural effusion Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Special Senses: Estimated 1%-10%: conjunctivitis, vision blurred, eyelid edema, conjunctival hemorrhage, dry eye Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss Estimated 0.01%-0.1%: papilledema1, glaucoma, cataract 1Including

some fatalities

6.13 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of Gleevec.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous system disorders: cerebral edema1 Eye disorders: vitreous hemorrhage Cardiac disorders: pericarditis, cardiac tamponade1 Vascular disorders: thrombosis/embolism, anaphylactic shock Respiratory, thoracic and mediastinal disorders: acute respiratory failure1, interstitial lung disease Gastrointestinal disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation1 [see Warnings and Precautions (5.6)], diverticulitis Skin and subcutaneous tissue disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysaesthesia syndrome Musculoskeletal and connective tissue disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/ myopathy Reproduction disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst 1Including

some fatalities

In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

777DRUG INTERACTIONS 7.1 Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly (p<0.05) decreased mean Cmax and AUC. Similar findings were observed in patients receiving 400-1200 mg/day Gleevec concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAEDs decreased by 73% compared to patients not receiving EIAED. Concomitant administration of Gleevec and St. John’s Wort led to a 30% reduction in the AUC of imatinib.

Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Gleevec doses up to 1200 mg/day (600 mg BID) have been given to patients receiving concomitant strong CYP3A4 inducers [see Dosage and Administration (2.9) in the full prescribing information].

7.2 Agents Inhibiting CYP3A Metabolism There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Gleevec was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering Gleevec with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations.

7.3 Interactions with Drugs Metabolized by CYP3A4 Gleevec increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Gleevec. Particular caution is recommended when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus).

Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolobenzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).

888USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.11)].

Gleevec can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses ≥100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by either early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤30 mg/kg (one-third the maximum human dose of 800 mg).

There are no adequate and well-controlled studies with Gleevec in pregnant women. Women should be advised not to become pregnant when taking Gleevec. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

8.3 Nursing Mothers Imatinib and its active metabolite are excreted into human milk. Based on data from three breastfeeding women taking Gleevec, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breast-fed infant could receive up to 10% of the maternal therapeutic dose based on body weight. Because of the potential for serious adverse reactions in nursing infants from Gleevec, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Gleevec safety and efficacy have been demonstrated in children with newly diagnosed Ph+ chronic phase CML and in children with Ph+ chronic phase CML with recurrence after stem cell transplantation or resistance to interferon-alpha therapy. There are no data in children under 2 years of age. Follow-up in children with newly diagnosed Ph+ chronic phase CML is limited.

As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a Cmax of 2-4 hours. Apparent oral clearance was similar to adult values (11.0 L/hr/m2 in children vs.

10.0 L/hr/m2 in adults), as was the half-life (14.8 hours in children vs. 17.1 hours in adults). Dosing in children at both 260 mg/m2 and 340 mg/m2 achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs. Day 1 at 260 mg/m2 and 340 mg/m2 dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose.

8.5 Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema [see Warnings and Precautions (5.1)]. The efficacy of Gleevec was similar in older and younger patients.

In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.

In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Gleevec was similar in patients older than 65 years and younger patients.

8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment (Table 12) at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function [see Dosage and Administration (2.10) in the full prescribing information].

Table 12: Liver Function Classification Liver Function Test

7.5 Interaction with Acetaminophen In vitro, Gleevec inhibits acetaminophen O-glucuronidation (Ki value of 58.5 μM) at therapeutic levels.

Systemic exposure to acetaminophen is expected to be increased when co-administered with Gleevec.

No specific studies in humans have been performed and caution is recommended.

Mild (n=30)

Moderate (n=20)

Severe (n=20)

Total Bilirubin

≤ULN

>1.0-1.5x ULN

>1.5-3x ULN

>3-10x ULN

SGOT

≤ULN

>ULN (can be normal if Total Bilirubin is >ULN)

Any

Any

ULN=upper limit of normal for the institution 8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment (Table 13) at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment.

The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment.

Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Dose reductions are necessary for patients with moderate and severe renal impairment [see Dose Modification Guidelines (2.9) in the full prescribing information].

Table 13: Renal Function Classification

Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.

7.4 Interactions with Drugs Metabolized by CYP2D6 Gleevec increased the mean Cmax and AUC of metoprolol by approximately 23% suggesting that Gleevec has a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.

Normal (n=14)

Renal Dysfunction

Renal Function Tests

Mild Moderate Severe

CrCL = 40-59 mL/min CrCL = 20-39 mL/min CrCL = <20 mL/min

CrCL = Creatinine Clearance T2009-124 Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 ©Novartis

Her struggle is fresh, but she can

move on with new confidence.

GLEEVEC® (imatinib mesylate) tablets are indicated for the adjuvant treatment of adult patients following complete gross resection of KIT (CD117)–positive GIST. Important Safety Information ■ GLEEVEC is often associated with edema and occasionally severe fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life-threatening.

■ Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months).

■ Dose adjustments may be necessary due to hematologic adverse reactions, hepatotoxicity, and other nonhematologic adverse reactions.

■ In the adjuvant treatment of GIST trials (GLEEVEC; placebo) severe (NCI Grades 3 and above) lab abnormalities—increase in liver enzymes (ALT) (3%; 0%), (AST) (2%; 0%), and decrease in hemoglobin (1%; 0%)—and severe adverse reactions (NCI Grades 3 and above), including abdominal pain (3%; 1%), diarrhea (3%; 1%), rash (3%; 0%), fatigue (2% to 1%), nausea (2%; 1%), vomiting (2%; 1%), and periorbital edema (1%; 0%) were reported among patients receiving adjuvant treatment of GLEEVEC. ■ Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

■ Hepatotoxicity, occasionally severe, may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.

■ Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment.

■ There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation.

■ Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.

■ Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. TSH levels should be closely monitored in such patients.

■ Consider potential toxicities—specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.

■ Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking GLEEVEC tablets and to avoid breast-feeding while taking GLEEVEC tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use adequate contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus.

1 in 2 patients experiences recurrent disease after surgery1

GLEEVEC for adjuvant therapy in KIT+ GIST

■

■

With a median follow-up of 14 months, more than double the number of patients in the placebo arm experienced disease recurrence compared with those in the GLEEVEC arm (P<0.0001): GLEEVEC 30/359 = 8.4%, placebo 70/354 = 19.8%.2

GLEEVEC Significantly Improves RFS vs Placebo2 100

Patients with RFS (%)

■

Some serious adverse reactions may occur, including severe congestive heart failure, left ventricular dysfunction, hepatotoxicity, edema, hemorrhage, GI perforation, and hypothyroidism.2 The most frequently reported common adverse reactions were gastrointestinal disturbances, fatigue, edema, decreased hemoglobin, and rash.2

80

60 TREATMENT PERIOD

FOLLOW-UP PERIOD

40 GLEEVEC (n=359)

20

Placebo (n=354)

0 0

6

12

18

24

30

36

42

48

54

Time to recurrence (months)

Patients at risk: GLEEVEC

359

258

207

166

105

60

33

23

5

Placebo

354

243

186

138

89

57

34

19

8

1

A Phase III, randomized, double-blind study of adjuvant GLEEVEC versus placebo was conducted in 713 patients following resection of primary KIT+ GIST. The efficacy end point of the study was recurrence-free survival (RFS), defined as the time from date of randomization to the date of recurrence, or death from any cause.2

■

■

GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of GLEEVEC should increase by at least 50% and clinical response should be carefully monitored in patients receiving GLEEVEC with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with GLEEVEC include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions.)

For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.

Common Side Effects of GLEEVEC Tablets ■ In the adjuvant treatment of GIST trials, the majority of both GLEEVEC- and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include (GLEEVEC; placebo) (all Grades) diarrhea (60%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), and abdominal pain (21%; 22%).* ■ In the adjuvant GIST trial, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebo-treated patients. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.* ■ Supportive care may help management of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary.

■ GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation. GLEEVEC tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.

■ Patients should be informed to take GLEEVEC exactly as prescribed, not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose. *For more detailed study information, please see full Prescribing Information.

References: 1. National Comprehensive Cancer Network. Soft tissue sarcoma. Clinical Practice Guidelines in Oncology—V.1.2009. http://www.nccn.org. Accessed July 20, 2009. 2. GLEEVEC® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2009.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2009 Novartis

Printed in USA

7/09

C-GLI-100051

40

PRN

CLINICAL ONCOLOGY NEWS • APRIL 2010

Patents

BRCA continued from page 1

is organized by the American Civil Liberties Union (ACLU) and the Public Patent Foundation. The ruling marks the first time a court has found patents on genes unlawful and it makes the future of patents held on other human genes uncertain.

In early February, Robert W. Sweet, U.S. District Judge, Southern District of New York, heard a motion for summary judgment and ruled in March in favor of the ACLU. Myriad said it will appeal the decision, and many believe the case will end up in the Supreme Court.

If upheld, the impact will be far-reaching—researchers estimate that roughly 20% of the human genome has been patented.

The ACLU case has attracted wide support from the medical community. In addition to groups like the Association for Molecular Pathology and the American College of Medical Genetics, which joined the case as plaintiffs, groups including the American Medical Association, the March of Dimes and the Council for Responsible Genetics filed amicus briefs supporting the ACLU’s position in the case.

‘At the most basic level, the notion that the government can give exclusive control over human genes is inherently troubling.’

—Christopher A. Hansen

Wendy Chung, MD, PhD, director of clinical genetics at Columbia University in New York City, is one of the 20 plaintiffs in the case. When patients ask Dr. Chung if they’ll face the breast or ovarian cancer that killed their mothers, she offers Myriad’s BRACAnalysis test that analyzes BRCA1 and BRCA2.

The test might answer the question, but cannot always guarantee a clear result. “In some cases, patients are left with ambiguous interpretations, not knowing how to act upon that information,” Dr. Chung said. Because Myriad owns the patents, no other test is available to patients.

A Product of Nature Attorneys for the plaintiffs in the case argue that by granting patents on the genes, the government has given Myriad exclusive control over all knowledge about the gene, a clear violation of First Amendment freedoms, and an act that hinders research and the development of new tests. For this reason, some say the success of the lawsuit could stimulate research, but others fear a win by the ACLU would eliminate the capital that drives innovation.

Everyone agrees that DNA in the body is a product of nature and is not patentable, but the defendants claim that the isolation of the BRCA genes, the separating of the gene from other DNA, makes the genes

‘Uncovering a law of nature—while deserving of praise for the time, ingenuity and hard work that it takes—is not patentable.

Einstein certainly deserved praise and awards for discovering E=mc2, but he could not patent it.’

—Christopher A. Hansen

patentable. The plaintiffs argue that isolating a gene does not alter the structure of the DNA itself, and so what has been patented is indeed a product of nature.

“At the most basic level, the notion that the government can give exclusive control over human genes is inherently troubling,” said Christopher A. Hansen, the ACLU’s lead attorney in the case. He said it also runs against a foundation of patent law. “Patenting of human genes is a patenting of a product of nature, that there was no inventiveness, no human discovery.

They simply identified what nature is already doing,” Mr. Hansen said. “Uncovering a law of nature—while deserving of praise for the time, ingenuity and hard work that it takes—is not patentable. Einstein certainly deserved praise and awards for discovering E=mc2, but he could not patent it.”

Dr. Chung said the case presented a few of the issues physicians face in using the Myriad diagnostic test.

Some patients cannot afford the $3,000 cost of the test and some insurance companies simply will not cover it, but there is another issue that is as important, she said. “With some patients, the test comes across a genetic variation for which they don’t have enough experience to either classify it as completely normal or pathogenic and disease-associated,” Dr. Chung said.

“That is [the] worst of all scenarios.”

Dr. Chung said these situations are complicated because they often involve patients from ethnic groups that make up a smaller proportion of the Myriad variation database, meaning that it is unclear if the variations are in fact normal in these groups. Patients tend to think that variations mean they will develop cancer, Dr. Chung said. While there are now researchers outside of Myriad looking into these variations, she said, they do not have access to all the information available through Myriad’s proprietary database.

“If a therapy is developed for BRCA1/ BRCA2 mutation carriers, it’s possible that Myriad

could have some reach-through ability to have part of the patent on that therapy,” Dr. Chung said. Fergus J. Couch, PhD, a professor in the Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minn., one of the researchers looking into gene variations, declined comment for this story.

Patents Needed To Drive Research Stacy L. Taylor, a partner at DLA Piper in San Diego, who secures, manages and enforces intellectual property rights for biomedical companies, said the patenting of genes is needed for the same reasons it is needed in all biotechnical fields. “There is a compelling rationale, from a capitalistic standpoint, for issuing patents for medical treatments, drugs and diagnostics in general because of the amount of investment that has to go into their identification and development, and the time frame it takes to test and bring those products to market,” she said.

Ms. Taylor pointed out that other similar court cases have come down in favor of having patents on products of nature. “The question discussed in the context of the ACLU case is ‘should we be granting patents for products derived from nature?’ The U.S. Supreme Court has consistently answered yes, starting in a 1911 case involving adrenaline developed by Parke-Davis to a case last year involving a diagnostic test like this one,” she said.

Ms. Taylor fears that an ACLU win could inhibit investment in product development. According to her, a win would mean “anything derived from nature would be susceptible to no longer being patented, including drugs used to treat conditions like breast cancer,” she said.

Myriad hopes the court decision will be reversed.

“While we are disappointed that Judge Sweet did not follow prior judicial precedent or Congress’s intent that the Patent Act be broadly construed and applied, we are very confident that the Court of Appeals for the Federal Circuit will reverse this decision and uphold the patent claims being challenged in this litigation,” said Peter Meldrum, President and CEO of Myriad Genetics. “More importantly, we do not believe that the final outcome of this litigation will have a material impact on Myriad’s operations due to the patent protection afforded Myriad by its remaining patents.”

—David Jakubiak

Letter to the Editor

A

n article featured in the February 2010 issue of Clinical Oncology News, “Another Year of Belt Tightening,” states G8443 as the code to be used when reporting that an eRx is generated. This code has since been changed to G8553, per Centers for Medicare & Medicaid Services Measure Specifications for 2010 E-Prescribing Initiative. This change has not been widely publicized and is on the Part B News Blog. Please inform your readers, as my physician questioned the discrepancy and others may as well.

Thank you!

Amy Yarnall Practice Manager South Wind Oncology Associates, Garden City, Kansas

PRN

CLINICAL ONCOLOGY NEWS • APRIL 2010

COOLER continued from page 29

the Hematology and Oncology Division at William Beaumont Hospital, in Royal Oak, Mich. He is a clinical professor of medicine at Wayne State University, in Detroit.

Cancer physician and researcher Patrick J. Loehrer Sr., MD, has been named director of the Indiana University Melvin and Bren Simon Cancer Center, in Indianapolis. Dr. Loehrer also will serve as associate dean for cancer research and hold the title H.H.

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Copyright © 2010 by McMahon Publishing, New York, NY 10036. All rights reserved. Clinical Oncology News (ISSN 1933-0677) is published monthly for $70.00 per year by McMahon Publishing. Application for Periodicals Postage Rate is pending at New York, NY and other mailing offices. www.mcmahonmed.com POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036.

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Gregg Professor of Oncology, pending approval by the board of trustees, at the Indiana University School of Medicine, also in Indianapolis.

Dr. Loehrer is the second person to lead the cancer center since its founding in 1992.

He had been serving as interim director since February 2009, following the death of Stephen D. Williams, MD, the founding director.

Abonour Honored

F

or his work with Miles for Myeloma, Rafat Abonour, MD, an oncologist and researcher at the Indiana University Melvin and Bren Simon Cancer Center and professor of medicine at the Indiana University School of Medicine, Indianapolis, has received a Sagamore of the Wabash, the highest honor an Indiana governor can bestow. Miles for Myeloma began as a group of Dr. Abonour’s patients who wanted to organize a run/walk event to raise funds for multiple myeloma research at Indiana University. Rather than have his patients plan a standard participatory event,

Dr. Abonour of fered to cover the miles— and the state of Indiana—himself.

He reasoned that because his pati e n ts tr av e l from all parts of Indiana to visit him, he should make an effort to go to them. In the past five years, since starting Miles for Myeloma, he has run and biked more than 700 miles and raised more than $1 million.

41

CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS • APRIL 2010

New Phase II and III Clinical Trials

Age

Protocol ID

Trial Sites

Trial of Gemcitabine/Carboplatin With or Without BSI-201 (a PARP1 Inhibitor) in Patients With Previously Untreated Advanced Squamous Cell Lung Cancer, Phase III

18 and over

20090321

TN

Proton Beam Radiation Therapy and Chemotherapy in Treating Patients With Stage III Non-Small Cell Lung Cancer That Can 18 and over Be Removed By Surgery, Phase I/II

UPCC 25508

PA

A Trial of Amrubicin and Carboplatin With Pegfilgrastim in Patients With Extensive-Stage Small Cell Lung Cancer, Phase II

18 and over

SCRI LUN 199

TN, VA

ARQ 197 in Combination With Chemotherapy in Patients With Metastatic Colorectal Cancer, Phase I/II

18 and over

ARQ 197-A-U252

OH

A Study of TPI 287 - Temozolomide Combination in Melanoma, Phase I/II

15 and over

2009-0357

TX

Temsirolimus and Bevacizumab in Treating Patients With Hormone-Resistant Metastatic Prostate Cancer That Did Not Respond to Chemotherapy, Phase I/II

18 and over

CASE7808

OH

Study of TAK-700 in Combination With Docetaxel and Prednisone in Men With Metastatic Hormone-Resistant Prostate Cancer, Phase I/II

18 and over

C21003

AK

A Safety and Efficacy Study of KX2-391 in Patients With Bone-Metastatic, Castration-Resistant Prostate Cancer Who Have Not Received Prior Chemotherapy, Phase II

18 to 65

KXO1-002-09

IL, MD

A Dose Ranging Study of Delayed Release Beclomethasone for Prevention of Acute Enteritis in Patients With Rectal Cancer, Phase I/II

18 and over

BDP-ENT-01

IL

PARP Inhibition for Triple Negative Breast Cancer (ER-/PR-/HER2-)With BRCA1/2 Mutation, Phase II

18 and over

BRE09-146

IN

Ixabepilone + Carboplatin Metastatic Breast Cancer, Phase II

18 and over

08007

AZ, CA, CO, FL, IL, IN, MD, MN, MO, NC, NJ, NV, NY, OH, OR, PA, SC, TX, VA, WA, WV

Estrogen for Triple Negative Breast Cancer, Phase II

18 and over

CO09711

WI

Study of a HER2/Neu Vaccine for Stage IV HER2/Neu Positive Breast Cancer Patients on Herceptin, Phase II

18 and over

BC 030289

WA

Open Label, Single Center Study of Sunitinib in Subjects With High Risk Renal Cell Carcinoma, Phase II

18 and over

09-07-068

CA

Vitespen (HSPPC-96) for Immune Response Assessment Following Treatment of Resectable Renal Cell Carcinoma, Phase II

18 and over

2009-0092

TX

Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine for Recurrent Glioblastoma Multiforme, Phase II

18 and over

2009-0597

TX

Regorafenib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor, Phase II

18 and over

09-400

MA

FLT PET Imaging for Cervical Cancer, Phase II

18 and over

200906786

IA

Study of [F 18]HX4 Positron Emission Tomography as a Tool to Detect Hypoxia in Tumors, Phase II

18 and over

HX4-200

NJ

Substudy to Assess the Effect of Treatment With Bendamustine in Combination With Rituximab on QT Interval in Patients With Advanced Indolent Non-Hodgkin’s Lymphoma or Mantle Cell Lymphoma, Phase III

18 and over

C18083/3070

CO

[Ofatumumab in] Patients With Relapsed or Refractory Diffuse Large B Cell Non Hodgkin Lymphomas, Phase II

18 and over

OFT113588 (0908)

IL

Exercise and Lung Cancer Trial, Phase III

21 to 80

00018255

NC

Tools for Improving Colorectal Cancer Screening Rates: Multimedia Versus Print, Phase III

50 to 80

0910001-E

IL

Vitamin D Levels in Stage IV Colorectal Cancer Patients, Phase II

18 and over

09-143

NJ, NY

Solid Tumors

Protocol Type

Hematologic

Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to March 15, 2010. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Supportive

42

The WAITING ROOM

by Joan Chiverton

Antifungal Prophylaxis Educational Review Available EXCLUSIVELY ONLINE GO TO

www.clinicaloncology.com

and click on Educational Reviews on the left side of the page.

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Be on the Lookout for Clinical Oncology Special Edition with numerous educational reviews, including:

Â&#x2122; Updates in Non-Hodgkinâ&#x20AC;&#x2122;s Lymphoma Â&#x2122; Management of Treatment-NaĂŻve Patients With Renal Cell Carcinoma Â&#x2122; Management of Chemotherapy-Induced Nausea and Vomiting

For more information about GEMZAR, please see your Lilly sales professional or visit GEMZAR.com.

GEMZAR® is a registered trademark of Eli Lilly and Company.

GC58323 0509 PRINTED IN USA © 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.