Clinical Oncology News - July 2010 - Digital Edition

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Advances in Cancer Care CLINICALONCOLOGY.COM • July 2010 • Vol. 5, No. 7

SOLID TUMORS

8

Eribulin improves survival in heavily treated metastatic breast cancer.

10

Bevacizumab improves PFS in ovarian cancer. Experts debate its use in practice.

12

Adding radiation to hormone therapy improves survival in locally advanced prostate cancer.

14

Novel targeted agent shows remarkable activity in difficult-to-treat NSCLC.

HEMATOLOGIC DISEASE

19

Long-awaited study proposes new standard of care for follicular lymphoma.

Battle of SecondGeneration TKIs Declared in CML

Ipilimumab Improves Survival In Advanced Melanoma

Chicago–Second-generation tyrosine kinase inhibitors (TKIs) appear likely to replace imatinib (Gleevec, Novartis) as first-line therapy in previously untreated chronic myelogenous leukemia (CML). New data from separate head-to-head Phase III trials have demonstrated that both nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol-Myers Squibb) are superior to imatinib for major prognostic indicators, particularly complete molecular and cytogenetic responses. Neither TKI has demonstrated a survival benefit compared with imatinib in the relatively brief follow-up so far, but a survival benefit is anticipated based on prognostic markers. At press time, the FDA approved nilotinib in the firstline setting.

Chicago—A monoclonal antibody with a unique mechanism of action has become the first drug ever ver to demonstrate a survival benefit in previously ously treated advanced melanoma. The benefit of ipilimumab (Bristol-Myers Squibb), b), achieved with relatively modest toxicicity, was demonstrated in a multinationonal Phase III study presented at the annunnual meeting of the American Societyy of Clinical Oncology (ASCO; abstract 4).. It is considered a major step forward in a disease that has been notoriously resis-tant to pharmacologic therapy in dozens ns of prior controlled studies.

Although the drug increased median overerall survival by almost four months in patients nts relative to controls (10 vs. 6.4 months; P<0.0004) 4) (Figure 1), an equally impressive result was that more re than 40% of patients were alive at one year and more than 20% at two years. These survival rates are unprecedented in the types of patients who entered the study.

see TKIs, page 25

see IPILIMUMAB, page 18

FDA NEWS

26

Agency approves cabazitaxel for prostate cancer, nilotinib for first-line CML. Mylotarg withdrawn from market.

New indication sought for trastuzumab.

PRN

27

Around the Water Cooler brings you news about people and places in oncology.

CLINICAL TRIALS

32

A list of all Phase II and Phase III clinical trials initiated within the past 30 days.

Investigational Agent Stops Potentially Fatal 5-FU Toxicity Chicago—Uridine triacetate, an investigational, orally administered drug, is an effective, lifesaving antidote for 5-fluorouracil toxicity, according to a new study reported at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO).

The study is the second in two years to show that 100% of patients given the antidote survived 5-fluorouracil (5-FU) overdoses. Yet fatalities continue from toxic reactions to 5-FU because hospitals don’t realize that the FDA allows uridine triacetate to be obtained on an emergency basis.

“These reactions need not be fatal,” see 5-FU ANTIDOTE, page 28

APC (Antigen-presenting cells)

T Cell

Pictured above is a graphic of T-cell activation.

Ipilimumab potentiates T-cell activation.

POLICY & MANAGEMENT

QOPI Certification: What Will It Mean for Oncology Practices?

Chicago–A new certification program run by the American Society of Clinical Oncology (ASCO) is offering oncology practices an objective and plug-in methodology to receive independent verification that they are meeting current standards. At press time, the first 16 community-based oncology programs across the United States had just been certified through this Quality Oncology Practice Initiative (QOPI). The certification is entirely voluntary and, according to ASCO, “demonstrates a commitment to excellence.” As of yet, it is unclear how

widely or quickly certification will catch on among other practices, but those who have gone through the certification are pleased.

Practical Benefits QOPI certification has the potential to improve care by verifying measures of performance, but it also might be characterized as an ASCO seal of approval.

Therefore, it may provide a competitive advantage for community-based cancer treatment facilities that are attempting see QOPI, page 16

McMahonMedicalBooks.com Atlas of Diagnostic Oncology: Expert Consult - Online and Print Arthur T. Skarin For more information, see page 33

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

T2009-95

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2010

Breast

Eribulin Improves Survival in Metastatic Breast Cancer Chicago—A new chemotherapy drug, eribulin mesylate (Eisai), improves median overall survival by roughly 2.5 months over standard therapies in heavily pretreated women with locally recurrent or metastatic breast cancer, according to a Phase III clinical trial.

The study was presented at the recent annual meeting of the American Society of Clinical Oncology (ASCO; CRA1004).

“These results potentially establish eribulin as a new and effective treatment for women with heavily pretreated metastatic breast cancer,” said lead investigator Christopher Twelves, MD, head of the Clinical Cancer Research Groups at the University of Leeds and St. James’s Institute of Oncology in Leeds, England. “Eribulin is actually the only single agent, be that chemotherapy, biotherapy or endocrine therapy, that has shown [an improvement in] overall survival in such heavily pretreated women with metastatic breast cancer.”

The drug surprised some experts.

“I think many of us thought there weren’t new chemotherapy drugs being

developed, but lo and behold, a new chemotherapy drug seems to add to the treatment armamentarium that we have for women with advanced breast cancer,” said Eric Winer, professor of medicine at Harvard Medical School, and director of the Breast Oncology Center at Dana-Farber Cancer Institute, both in Boston.

Eisai has submitted an application to the FDA to market the drug to patients.

Detailing the EMBRACE Trial Eribulin mesylate, derived from a marine sponge, is a microtubule dynamics inhibitor that interferes with cell division. The international, multicenter trial, called EMBRACE (Eisai Metastatic BReast cancer study Assessing physician’s Choice versus Eribulin), compared the new drug with a treatment of

the physician’s choice (TPC) because no standard therapy exists for this patient population. A variety of single agents and standard regimens are available, but there is remarkably little consensus on how best to utilize these in either the first-line setting or in patients who have had multiple lines of therapy.

EMBRACE revealed that median overall survival was 13.12 months in patients who received eribulin and 10.65 months in the control arm (hazard ratio, 0.81; 95% confidence interval, 0.66-0.99; P=0.041). In the study, 508 women with heavily pretreated metastatic breast cancer received eribulin 1.4 mg/m2 two to five minutes IV bolus on days 1 and 8 of a 21-day cycle. Then 254 women received a treatment chosen by their physician, which was any single-agent cytotoxic,

Control arm Patients receiving eribulin

Median Overall Survival, mo

8

15 13.12

P<0.04

10.65 10

5

0

Figure. Comparison of

overall survival. hormonal or biologic therapy, or supportive care only. No doctors chose biologic therapy or best supportive care alone; 96% of patients received chemotherapy and 4% received hormone therapy. Women already had received an average of see ERIBULIN, page 34

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CLINICAL ONCOLOGY NEWS • JULY 2010

Ovarian

Bevacizumab: Ready for Prime Time in Ovarian Cancer?

Chicago—In women with advanced ovarian cancer, bevacizumab (Avastin, Genentech) added to initial chemotherapy and then given as maintenance improves median progression-free survival (PFS) by roughly four months compared with chemotherapy alone, according to a Phase III study.

The study also revealed this therapeutic approach reduced the risk for progression by approximately 28% compared with chemotherapy alone. The Gynecologic Oncology Group (GOG) conducted the study, which was presented at the annual meeting of the American Society of Clinical Oncology (ASCO; LBA 1). “Bevacizumab is the first molecular-targeted and first antiangiogenic agent to demonstrate benefit in this population,” said lead researcher Robert A. Burger, MD, director of the Women’s Cancer Center at Fox Chase Cancer Center in Philadelphia, and GOG lead investigator. “Bev [bevacizumab] combined with chemotherapy followed by bev maintenance should be considered one standard option for these patients.”

According to Maurie Markman, MD, vice president for clinical research at the University of Texas M.D. Anderson Cancer Center in Houston, the preliminary results of the trial “are important and will likely lead many oncologists and patients to consider the use of this agent in this clinical setting.” Some experts, however, say this is jumping the gun.

“I believe the use of bevacizumab in standard clinical practice may be premature,” said Elizabeth Eisenhauer, MD. “A progression-free survival gain of only 3.8 months may not be meaningful to patients. We need the mature overall survival [OS] and quality-of-life results and ideally the results of the other frontline trial of bevacizumab in this disease, ICON7, to understand the full story of the impact of this advance.” Dr. Eisenhauer is director of the Investigational New Drug Program with the National Cancer Institute of Canada’s Clinical Trials Group and professor in the Department of Oncology at the Queen’s University, Kingston, Ontario, Canada.

Three-Armed Study The international, double-blind, placebo-controlled Phase III trial included 1,873 women with newly diagnosed, previously untreated stage III/IV ovarian, primary peritoneal or fallopian tube cancer.

All women were required to have abdominal surgery for staging as well as a maximal effort at tumor debulking surgery performed no more than 12 weeks prior to enrollment. Patients were stratified by key prognostic factors, performance status and a combination of stage and tumor debulking level, and then were randomized equally into three regimens. In all

regimens, the first six cycles included standard chemotherapy and the remaining 16 cycles were maintenance therapy.

Arm 1, the control arm, consisted of standard chemotherapy with IV carboplatin with an area under the curve of 6 and paclitaxel at 175 mg/m2 plus concurrent placebo. This was followed by placebo maintenance therapy. Arm 2 consisted of the standard chemotherapy plus concurrent bevacizumab at 15 mg/kg and placebo maintenance. Arm 3 consisted of the standard chemotherapy plus concurrent bevacizumab at 15 mg/kg, followed by maintenance with bevacizumab 15 mg/kg. Stage III optimally debulked (34%), stage III suboptimally debulked (40%) and stage IV (26%) patients were similarly distributed in each treatment group.

Treatment was discontinued for disease progression, treatment toxicity or voluntary withdrawal. Disease progression was based on RECIST (Response Evaluation Criteria In Solid Tumors) criteria and global clinical deterioration at any time after enrollment. The

‘Why are the PFS gains seen in these other bevacizumab trials not being carried forward into more striking overall survival improvements?’

—Elizabeth Eisenhauer, MD

Bevacizumab Approved for • Metastatic colorectal cancer • Metastatic non-small cell lung cancer • Metastatic breast cancer • Metastatic renal cell cancer • Glioblastoma

Tested and failed in • Prostate cancer • Stomach cancer • Non-Hodgkin’s lymphoma

definition also included CA-125 elevation by Gynecologic Cancer Intergroup Criteria only during the maintenance phase of treatment.

No statistically significant difference in PFS was found between arms 1 and 2, but there was a statistically significant difference between arm 1 and arm 3 (median PFS, 10.3 vs. 14.1 months, respectively; hazard ratio, 0.717; P<0.0001). A benefit in OS could not be detected at the time of the analysis—76% of participants were still alive at this time. Grade 3/4 hypertension was greater in the arms that received bevacizumab: arm 1, 1.6%; arm 2, 5.4%; and arm 3, 10%. Grade 2 or greater gastrointestinal perforation, hemorrhage or fistula occurred in 1.2% of arm 1, 2.8% of arm 2 and 2.6% of arm 3.

Controversy Over Change In Practice Dr. Eisenhauer said the study was well constructed, but she pondered why there was no meaningful effect of bevacizumab in the concurrent-only arm. “It is possible that the high response rates in ovarian cancer with standard chemotherapy alone is sufficiently high that the incremental benefits of bevacizumab were obscured,” Dr. Eisenhauer said.

She argued that more data were needed before the study could be deemed practice-changing. Sparse data support the argument that improvement in PFS improves quality of life in ovarian cancer, and it is uncertain whether the PFS benefit in this trial will translate into an OS benefit. Highlighting data from 13 first-line trials of chemotherapeutic agents in ovarian cancer, Dr. Eisenhauer pointed out that when a trial showed a benefit in PFS, it translated into an even greater gain in OS. The hazard ratios for PFS and OS were the same or very similar. In one trial, a PFS gain of four months translated into a gain of 11.8 months for OS, but this represented the same proportional gain in OS as had been seen in PFS. In fact, based on these chemotherapy data, a recent workshop that involved the FDA and ASCO concluded that for first-line trials in advanced ovarian cancer, PFS is a surrogate for OS. “In maintenance studies, however, the data are less clear and GOG218 is a blend of both of these,” Dr. Eisenhauer said.

Patients receiving chemotherapy only Patients receiving chemotherapy plus concurrent bevacizumab and maintenance bevacizumab

15

Median PFS, mo

10

14.1

10.3 10

5

0

Figure. Comparison of median PFS in patients with ovarian cancer.

PFS, progression-free survival

In addition, the fact that the agent tested in this trial was bevacizumab raises the question of whether data from chemotherapy trials showing a strong relationship between the proportional changes in PFS and OS can be extrapolated to this class of agent. Highlighting data from nine mature, published trials of bevacizumab in colorectal, breast, pancreas, renal and lung cancers, she showed that gains in PFS sometimes did not translate into robust gains in OS. “Why are the PFS gains seen in these other bevacizumab trials not being carried forward into more striking overall survival improvements?

Do tumors behave differently after angiogenesis inhibition?” she questioned. “If [this current study] follows these trends, then we cannot yet conclude that the delay in progression will translate into survival improvement.”

She also calculated the median cost of giving concurrent plus maintenance bevacizumab using a “back of the envelope approach” that included the prescribed dose per kilogram, average patient size, median number of cycles delivered on the trial, and cost per milligram of bevacizumab. This worked out to be roughly $72,000 and when that number is used to calculate the costeffectiveness of the median gain in PFS, the result is just over $229,000 per year.

“Many would not consider this a costeffective therapy for the gains seen,” Dr. Eisenhauer said.

Several Phase III trials of angiogenesis inhibitors are under way or closed in ovarian cancer, but this study is the first to be reported. Other agents include BIBF 1120 (Vargetef, Boehringer Ingelheim), cediranib (Recentin, AstraZeneca) and pazopanib (Votrient, GlaxoSmithKline).

—Kate O’Rourke

In Previously Untreated Multiple Myeloma I M P O R TA N T 3 - Y E A R U P D AT E — S U S TA I N E D B E N E F I T UPDATED VISTA* OVERALL SURVIVAL (OS) ANALYSIS: VcMP† vs MP (36.7-month median follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

90

% Patients Without Event

80 70 60 50 40 30 20 10

■ VELCADE+MP (n=344) ■ MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

3

6

Kaplan-Meier estimate.

9

12

15

18

21

24

27

30

33

36

39

42

45

48

51

Months

▼ Patients treated with VELCADE® (bortezomib) + MP as initial therapy sustained an overall survival benefit over patients randomized to MP alone ▼ The overall survival benefit was sustained despite subsequent treatments ▼ Median duration of VcMP treatment was 46 weeks/54 planned ▼ At the initial analysis (median 16.3-month follow-up), median TTP was 20.7 months with VELCADE in combination with MP vs 15 months for MP alone (P=0.000002)

VELCADE Warnings, Precautions, and Adverse Events VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral neuropathy, sometimes severe may occur—manage with dose modifications or discontinuation and carefully consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication.

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on next page.

VELCADE is indicated for the treatment of patients with multiple myeloma. *VISTA, a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. Primary endpoint was TTP and secondary endpoints were CR, ORR, PFS, and OS. At a prespecified interim analysis (median follow-up 16.3 months) VcMP resulted in significantly superior results for TTP, PFS, OS, and response rates. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. †VcMP=VELCADE + melphalan/prednisone (MP).

For Patient Assistance Information or Reimbursement Assistance call 1-866-VELCADE (835-2233), OPTION 2, or visit www.VELCADE.com.

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CLINICAL ONCOLOGY NEWS • JULY 2010

Prostate

Hormone Therapy and Radiation Is New Standard Chicago–Adding radiation to androgen deprivation therapy (ADT) improves overall survival (OS) in men with locally advanced prostate cancer, according to interim results from a randomized Phase III trial.

Presented at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO; abstract CRA4504), the multinational trial is the largest of a series of studies demonstrating an advantage for this combination over either modality alone. Disease-specific

survival at 12 years was 11% greater in patients who received the combination therapy than in patients who received ADT alone. Several experts, including the senior author of the study, concluded that this combination deserves to be considered the new standard of care.

“This study was conceived in 1993, but we believe that the results are still relevant. The CapSure database suggests that 50% of high-risk patients are still receiving ADT alone,” said Padraig R. Warde, MBChB, deputy head of the Radiation Medicine Program, Princess Margaret Hospital, Toronto, Canada. Although some guidelines already identify this combination as an option for patients with locally advanced or high-risk prostate cancer, the accumulation of data, including another smaller

Androgen deprivation therapy (ADT) plus radiation ADT

100 90 80

Patients, %

12

79

60 40 20 0

Figure. Disease-specific survival at seven years.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events ( Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone.

The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.

Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is 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 VELCADE, 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.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency.

Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at www.VELCADE.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139 Copyright © 2010, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA V1238

03/10

‘We need prospective, level 1 evidence to support the combination in specific patient subgroups with comorbidities to validate an advantage over ADT alone when the life expectancy is short.’

—Anthony D’Amico, MD, PhD

trial also presented at this year’s ASCO meeting, have been consistent in demonstrating significant clinical advantages for using both ADT and radiation.

In the larger study, 1,205 patients were randomized to continuous treatment with ADT (either orchiectomy or luteinizing hormone-releasing hormone) alone or ADT plus a radiation regimen that included 65 to 69 Gy to the prostate with or without 45 Gy to the pelvic lymph nodes (75% received radiation to both). Approximately 90% of patients had T3 or T4 prostate cancer, although patients with T2 disease were eligible if they had a high prostate-specific antigen (PSA; >40 ng/mL) or both a high PSA (>20 ng/mL) and a Gleason score of 8 to 10. Overall, 80% had a Gleason score of 7 or less, and 25% of patients had a PSA greater than 50 ng/mL. At the end of seven years of followup, 74% of those who received the combination compared with 66% of those who received ADT alone were still alive.

This translated into a 23% reduction in the risk for death (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.770.98; P=0.0331). Disease-specific survival was 90% compared with 79%, which produced a 43% reduction in the risk for

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2010

Prostate

Dr. Warde raised the possibility that results with this combination might be even better today with improvements in the technology and dosing of radiotherapy.

death from prostate cancer (HR, 0.57; 95% CI, 0.37-0.78; P=0.001) (Figure).

Radiation therapy was not associated with significant late toxicity, suggesting little clinical cost for the improvement in survival. Dr. Warde raised the possibility that results with this combination might be even better today with improvements in the technology and dosing of radiotherapy. He also suggested that lifelong ADT, as used in this study, may not be necessary and deserves further evaluation.

A smaller study presented during the same ASCO session (abstract 4505) did not show an OS benefit or a disease-specific survival benefit at the end of five years, but it did associate the combination with a median progression-free survival of 7.7 years versus 1.7 years for ADT alone (P<0.0001), which was the primary end point. In that study, presented by Nicholas Mottet, MD, Clinique Mutaliste, St. Etienne, France, 263 patients with locally advanced disease, of which 93% had T3 disease, were randomized to ADT alone (subcutaneous leuprorelin every three months) or the same ADT combined with radiotherapy starting within three months. The relative difference in favor of the combination increased in those patients with the highest baseline PSA levels.

Asked by ASCO to provide perspective on these results, Anthony D’Amico, MD, PhD, professor of radiation oncology, Harvard Medical School, Boston, noted that the data of the two studies are not only mutually reinforcing but are consistent with a recently published Scandinavian study (Lancet 2009;373:301308, PMID: 19091394). That 875-patient study associated a combination of radiotherapy and an endocrine regimen (three months of total androgen blockade followed by continuous endocrine treatment using flutamide) with a 56% reduction in the risk for prostate-related cancer death relative to endocrine therapy alone (HR, 0.44; 95% CI, 0.30.66; P<0.0001). He also cited a study conducted in 2002 that asked the same question in reverse, which was whether the addition of ADT to radiotherapy improves outcome over radiotherapy alone. In all studies, the combination has been superior, but Dr. D’Amico noted that the evidence points to a greater contribution from ADT than from radiotherapy.

“This is not to say that they are not both important, but we see benefit earlier

from the addition of ADT to radiotherapy than we do from the addition of radiotherapy to ADT,” Dr. D’Amico observed. This is important because, although he agreed that the combination is a new standard of care for locally advanced prostate cancer, it may not be standard in those individuals with a life expectancy of less than five years.

He cited several studies that he characterized as “hypothesis-generating” that suggest that men with known cardiovascular disease may not benefit from the combination because of a potential interaction with hormone therapy. Although he endorses the combination of ADT and radiotherapy in most patients, he called for further studies

to confirm benefit in those with other health risks.

“We need prospective, level 1 evidence to support the combination in specific patient subgroups with comorbidities to validate an advantage over ADT alone when the life expectancy is short,” Dr. D’Amico said, emphasizing competing risks in the elderly population most prone to prostate cancer.

“Even in high-risk and locally advanced prostate cancer, the natural history of the disease is long, so the issue of competing risks is important.”

—Ted Bosworth

13

SOLID TUMORS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY 2010

Lung

Targeted Agent Shows Impressive Activity in NSCLC

The degree of activity was so strong, including causing tumor shrinkage in 90% of patients and a 72% probability of remaining progression-free at six months, that the new agent, crizotinib (Pfizer), already is being embraced as a breakthrough, although only 82 patients were included in the initial trial. The data provide major support for a growing movement toward individualizing therapy in patients with lung cancer. â&#x20AC;&#x153;These data are important for a number of reasons. Most of all, they suggest that once we understand the mechanism of a specific type of cancer cell, we can rapidly develop an active treatment,â&#x20AC;? said Mark G. Kris, MD, chief of Thoracic Oncology Service and William and Joy Ruane Chair in Thoracic Oncology, Memorial Sloan-Kettering Cancer Center, New York City. Although NSCLC that is positive for the EML4-ALK fusion gene only accounts for about 5% of cases, Dr. Kris indicated that these data bring clinical practice a step closer to routinely ordering molecular tests for patients to select therapy specific for the cancer type.

Striking Activity The late-breaker study was considered impressive enough to be presented with only three others in the esteemed plenary session of the 2010 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 3). Although only 82 patients were treated with the newly developed ALK inhibitor, tumor shrinkage was achieved in 90% of patients and 72% of patients remained progression-free at six months, an unusually high response in advanced NSCLC. All patients were required to be positive for the EML4-ALK fusion gene by fluorescence in situ hybridization testing to be eligible for the study. â&#x20AC;&#x153;The responses have been durable with some patients still responding after

15 months of follow-up,â&#x20AC;? said the senior investigator, Yung-Jue Bang, MD, Seoul National University, Seoul, Korea. He reported that a Phase III trial is now open and accruing patients. He called on physicians who have NSCLC patients who are EML4-ALK-positive to contact study organizers for enrollment by calling (877) 369-9753.

The degree of activity observed in the Phase II trial is considered important because it was achieved with a relatively welltolerated, single-agent, oral therapy in patients with NSCLC who had already failed at least two anticancer regimens. The median number of previous regimens was three, and patients with brain metastases were allowed entry. Crizotinib was administered in a dose of 250 mg twice daily. Typical of an NSCLC EML4-ALK-positive population, 76% of patients were nonsmokers and only one patient was a current smoker; the median age was 51 years.

Of patients who were evaluable, an objective response was observed in 57%. Disease control, consisting of complete or partial responses and stable disease, was 90% (Figure 1).

Although the median duration of treatment in this ongoing study has now reached 25 weeks, the median progression-free survival (PFS) cannot yet be determined. The rate and duration of response was unusual for advanced NSCLC, and the response was rapid with tumor shrinkage often observed at the time of the first or second staging computed tomography scan.

Toxicities have been modest, primarily involving the gastrointestinal tract.

Although nausea of any grade has been reported in 55% of patients and vomiting in 39% of patients, grade 3/4 toxicities have been uncommon and primarily involved laboratory measures (Figure 2). Except for one case of dyspnea, these included grade 3 liver enzyme

100

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Chicagoâ&#x20AC;&#x201D;Three years after the EML4-ALK fusion gene was determined to be a key driver of a subtype of non-small cell lung cancer (NSCLC), a newly developed ALK inhibitor has demonstrated impressive activity in a Phase II trial.

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Figure 1. Response in patients receiving crizotinib.

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Figure 2. Common toxicities from crizotinib.

â&#x20AC;&#x2DC;These data are important for a number of reasons. Most of all, they suggest that once we understand the mechanism of a specific type of cancer cell, we can rapidly develop an active treatment.â&#x20AC;&#x2122;

â&#x20AC;&#x201D;Mark G. Kris, MD

elevations in 11% and grade 3 neutropenia and lymphopenia in one patient each.

The only grade 4 toxicity was an elevation of alanine aminotransferase.

For more information about enrolling patients in the ongoing trials with crizotinib, clinicians can call

Only a Phase II Study Although this is only a Phase II study, the degree of activity provides a strong proof of principle that the EML4-ALK fusion gene is, as predicted, a targetable driver of a subset of NSCLC. Although tissue typing to identify cancers positive for the EML4-ALK fusion gene is not a routine process, this may change. The discussant invited by ASCO to provide context for this study, Martin J. Edelman, MD, a professor at the University of Maryland Greenebaum Cancer Center, Baltimore, suggested strategies for targeted screening. â&#x20AC;&#x153;It appears at this time that we can perhaps restrict our testing predominantly to adenocarcinoma because there are very few reports of patients with squamous carcinoma having this mutation. In fact, there was only one in this study,â&#x20AC;? Dr. Edelman said. He also suggested that it might make sense to screen only nonsmokers or those with minimal (<15 pack-years) smoking history

(877) 369-9753. as well as patients who quit smoking many years (>20 years) before developing their cancer. Although Dr. Edelman supports further collection of data with crizotinib, he indicated that even the limited data from this trial encourage accelerated approval of the agent for treatment of patients with documented EML4-ALK translocations. â&#x20AC;&#x153;The striking activity and durable response of this agent in heavily pretreated patients with minimal toxicity is notable,â&#x20AC;? Dr. Edelman said. â&#x20AC;&#x153;Although I suspect that a broader experience may temper these results, it is hard to imagine they will change significantly.â&#x20AC;? He called crizotinib â&#x20AC;&#x153;an advance for the 6,000 to 10,000 patients in the United Statesâ&#x20AC;? with this form of NSCLC. â&#x20AC;&#x201D;Ted Bosworth McMahon Publishing

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VELCADE CRs Resulted in More Durable Responses MEDIAN DURATION OF RESPONSE IN PINNACLE* TRIAL (n=48/155) Complete responders (CR+CRu)

15.4 (95% CI, 13.4-15.4) (n=12)

All responders (CR+CRu+PR)

9.3 (95% CI, 5.4-13.8) (n=48)

0

1

2

3

4

5 6 7 8 Time (Months)

9

10 11 12 13 14 15 16

▼ VELCADE® (bortezomib) is the only FDA-approved therapy for patients with relapsed MCL ▼ VELCADE delivers a 31% overall response rate, with 8% CR (CR+CRu) ▼ Responding patients received a median of 8 cycles of treatment with VELCADE ▼ VELCADE has a well-characterized safety profile

VELCADE Warnings, Precautions, and Adverse Events VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral neuropathy, sometimes severe may occur—manage with dose modifications or discontinuation and carefully consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication. Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on next page.

VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. *PINNACLE, a single-arm, multicenter, phase 2 trial (N=155) evaluating the efficacy and safety of VELCADE in mantle cell lymphoma (MCL) patients who have received at least 1 prior therapy.

For Patient Assistance Information or Reimbursement Assistance call 1-866-VELCADE (835-2233), OPTION 2, or visit www.VELCADE.com.

16

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • JULY 2010

Certification

QOPI continued from page 1

to negotiate with insurers. If patients accept QOPI certification as an important distinction when selecting a cancer center, it also may become a valuable means of demonstrating quality and attracting patients. When asked about their reason for participating, however, oncologists from several of the newly certified centers emphasized that the real value of QOPI is to provide a reliable and reproducible method of quality assurance.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone.

The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.

Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is 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 VELCADE, 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.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency.

Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at www.VELCADE.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139 Copyright © 2010, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA CODE 03/10 V1284

“There was work involved in adopting our system to capture the information required for participation, but we think that the effort to document what we do does makes us sharper and improves our care,” said Usha Sree Chamarthy, MD, a hematologist/medical oncologist at Sparrow Regional Cancer Center, Lansing, Mich. “We have always been very engaged in quality improvement in our center because we are very committed to confirming that we were keeping up with evolving standards.

When this came around, we decided to use this approach as our platform after discussing whether we thought it was going to have value for us.”

Dr. Chamarthy’s practice and others participating in QOPI certification report that the program has helped tighten procedures and increased efforts to document quality. For example, Dr. Charmathy reported that although several routine procedures, such as smoking cessation and fertility counseling, already were being offered by physicians at her center, they were not necessarily documented. QOPI certification, which requires such documentation, has created a platform on which to demonstrate a high standard of care.

‘At our center, we found that we were significantly more likely than our peers to offer chemotherapy to patients within two weeks of their death.’

—Douglas Blayney, MD

According to those involved in helping launch the initiative, the most important function of QOPI is to reveal weaknesses so that they can be repaired. For example, outgoing president of ASCO, Douglas Blayney, MD, a leader of the initiative to launch QOPI, said the initiative’s performance measurement could identify problems. “At our center, we found that we were significantly more likely than our peers to offer chemotherapy to patients within two weeks of their death,” said Dr. Blayney, referring to his work at the University of Michigan. This led to a series of procedural changes within the oncology team, reducing the proportion of patients receiving chemotherapy shortly before death from 50% to 20%. Dr. Blayney indicated that this is a pertinent example of the types of activities that can be overlooked if they are not evaluated and assessed with rigorous and reproducible methodology. Dr. Blayney recently was appointed medical director of the Stanford Cancer Center, Stanford University, Stanford, Calif.

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POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • JULY 2010

Certification

‘There was work involved in adopting our system to capture the information required for participation, but we think that the effort to document what we do does make us sharper and improves our care.’

—Usha Sree Chamarthy, MD

as well as adding value for health plan reimbursement. According to ASCO, no information about practice performance will be released without the consent of the practice. Additionally, practices can use the data internally for recognizing areas of weakness and

How It Works QOPI certification is based on an assessment of performance by two methods. The first involves a survey of patient records, in which a series of specific quality-of-care measures are evaluated. The second is a site assessment.

In the evaluation of patient records, the measures mostly are evidence-based, although some are derived from expert consensus opinion. There are a growing number of measures, including 17 specific chemotherapy safety standards, that are being employed in the QOPI certification program. Certification must be renewed every three years.

The program was created primarily for community-based cancer care facilities, which provide more than 80% of all cancer treatment in the United States, according to ASCO estimates.

QOPI certification requires a fee to cover the expenses of the assessment, but the program may pay for itself by eliminating other quality control efforts and outcomes improvements,

We Want Your Feedback.

Dear Clinical Oncology News Reader: We want your opinions, criticisms, ideas and suggestions to help us improve this new publication. Please contact the editor at the e-mail address listed below. We would sincerely value your input.

Kate O’Rourke, Editor korourke@mcmahonmed.com (212) 957-5300, x 265

opportunities to improve.

Some oncologists are concerned that a voluntary quality assurance program eventually may be transformed into a mandatory quality assurance initiative, but not everyone is concerned that this will be a bad outcome. Although third-

party payers who insist on quality assurance may produce this result with or without QOPI certification, improved outcomes are a reasonable expectation. Dr. Blayney defended the QOPI certification initiative on this basis. He not only emphasized that it is a quality assurance program designed by oncologists for oncologists, but it really does have the potential to improve care.

“All of us want to do the right thing for our patients, and this program is a tool for getting that result,” Dr. Blayney reported.

—Ted Bosworth

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CilENgitide in combination with Temozolomide and Radiotherapy In newly diagnosed glioblastoma phase III randomized Clinical trial A randomized multicenter, open-label, controlled phase III study to evaluate cilengitide in combination with standard treatment (TMZ with concomitant RT, followed by TMZ maintenance therapy) versus standard therapy alone in newly diagnosed glioblastoma patients with methylated MGMT gene promoter status.

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Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized multicenter, open-label phase II study, investigating two cilengitide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy).

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SOLID TUMORS

CLINICAL ONCOLOGY ONCOLO NEWS • JULY 2010

Melanoma

APC

continued from page 1

“Finally we are getting some good news in melanoma,” said the senior author of the study, Steven O’Day, MD, chief of research, Angeles Clinic and Research Institute, Los Angeles. Although this drug is a potent agent that poses risks for lifethreatening immune-related side effects, it has been generally well tolerated. The longest follow-up in this Phase III study now extends past four years with survival benefit continuing to be documented.

In this multinational study, 676 patients with previously treated, unresectable stage III/IV melanoma were randomized in 3:1:1 ratio to ipilimumab (3 mg/kg every three weeks for four cycles) plus the glycoprotein (gp)100 peptide vaccine in a conventional dose, the same regimen of ipilimumab plus placebo, or gp100 vaccine plus placebo. All patients were HLAA0201-positive, an entry criterion required because of the inclusion of the gp100 vaccine. Overall survival was the primary end point. The vaccine did not appear to have any influence on the survival advantage of ipilimumab. If anything, the vaccine appeared to diminish the efficacy of ipilimumab on the secondary end points, such as progression-free survival and the rate of objective response.

The drug potentiates T-cell activation by blocking the cytotoxic T-lymphocyte antigen-4 (CTL4) receptor. The efficacy of any agent that controls melanoma by boosting the immune response is somewhat surprising after so many failures with this strategy, including vaccines.

The mechanism of blocking the CTLA-4 receptor is based on the role this target plays in turning off T-cell activation. The emergence of this receptor on the surface of the T cell approximately 48 hours after the T cell is activated appears to serve as a barrier to autoimmune diseases by turning off T cells before they begin to attack normal proteins. The antitumor effect of ipilimumab is produced by blocking this receptor to keep T cells activated. This explains the risk posed by ipilimumab for autoimmune activity, but it is an activity that may be relevant to cancers other than melanoma.

The efficacy of ipilimumab was characterized by Dr. O’Day as an “exciting advance both for patients with advanced melanoma and for the field of cancer immunology.” The discussant invited by ASCO to provide context for the findings, Vernon K. Sondak, MD, chief of the Department of Cutaneous Oncology at the H. Lee Moffitt Cancer Center, Tampa, Fla., largely agreed. Although the benefit of this mechanism for other tumors remains to be demonstrated, he said the identification of a new treatment for melanoma is a milestone. Dr. Sondak cited a study that compiled a list of 70 negative trials in melanoma over the past 30 years.

(Antigen-presenting cells)

15

‘The experience with treatment of melanoma a has not just been bad,, but consistently and monotonously bad.’

gp100 vaccine Ipilimumab

10

10 6.4 5

—Vernon K. Sondak, MD D

T Cell

0

Figure 1. Survival in patients with advanced melanoma.

The last drug to be approved by the FDA for melanoma was more than 10 years ago.

The last drug to be approved by the FDA for melanoma was more than 10 years ago, and that drug, interleukin-2, is rarely used

due to substantial toxicities and d low response rates.

“The experience with treatment ent of melanoma has not just been bad ad but consistently and monotonoussly bad,” Dr. Sondak observed. He characterized the experience of conducting melanoma clinical research as being “in a long, dark tunnel.” He indicated that the results of this study provide substantial encouragement that progress will now be made, and he is particularly hopeful that when ipilimumab is combined with other therapies, the potential to extend the survival observed in this trial will be realized. He cautioned, however, that the potential risks associated with this

61.1

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Dermatologic c 16.7

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Endocrine 1.5 Ipilimumab gp 100 vaccine 3 3.8

Hepatic c 4.5

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Figure 2. Most common immune-related adverse events.

Courtesy of BMS

IPILIMUMAB

Median Overall Survival, mo

18

therapy cannot be overlooked.

“The immune-related toxicity of ipilimumab requires a committed multidisciplinary team. This is not your 5-fluorouracil/leucovorin diarrhea,” Dr. Sondak reported. Although he believes that physicians properly trained to manage the immune-related adverse events associated with ipilimumab will permit this drug to be broadly used, he indicated that ipilimumab is not the final answer in melanoma, and that additional work is needed to understand where it exactly fits within routine clinical practice.

Due to the risk for a dysregulated immune system from CTLA-4 receptor inhibition, Dr. O’Day emphasized that patients need to be followed closely so that doctors can intervene early and quickly when this process begins.

In the study, T-cell attacks in normal tissue were most commonly observed in the skin, gastrointestinal (GI) tract, endocrine system and liver (Figure 2).

The greatest risk for significant morbidity and death was associated with attacks in the GI system. Grade 1 or 2 reactions were generally reversible with dose reductions or drug discontinuation, but high-dose steroids were required for grade 3 or 4 reactions. Approximately 3% of patients receiving ipilimumab had a treatment-related death.

With the exception of immune-related events, however, ipilimumab was generally well tolerated, which is an important attribute for therapies extending survival in advanced disease. Overall, there was a general consensus that this is a breakthrough agent for a notoriously treatment-refractory malignancy. “Ipilimumab represents a new class of T cell potentiators and an important advance for the field of immuno-oncology,” said Dr. O’Day. “Further development of ipilimumab is ongoing. We are very excited to see that it is being applied to other diseases, particularly non-small cell lung cancer and prostate cancer. We are very interested in looking at alternative combinations with this drug, as well as refining its dose and schedule.”

—Ted Bosworth

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2010

Follicular Lymphoma

New Standard of Care Proposed for Follicular Lymphoma “Rituximab maintenance after induction with rituximab plus chemotherapy significantly improves outcomes of follicular lymphoma patients, and we believe that it therefore should be considered as a standard of care in the first-line therapy for follicular lymphoma patients,” said Gilles Salles, MD, professor of medicine at the University of Lyon, Lyon, France.

He led the study presented at the annual meeting of the American Society of Clinical Oncology (abstract 8004).

PFS Benefit The study found that maintenance therapy with rituximab (Rituxan, Genentech/Biogen Idec) significantly improved two-year progression-free survival (PFS).

At 24 months, 18% of the patients who received rituximab maintenance had a recurrence of lymphoma compared with 34% of patients in the observation arm (P<0.0001). According to a representative for Genentech, the full two years of bevazicumab treatment costs $47,664.96.

Investigators not involved with the study were impressed. “This study is long awaited and likely practice-changing. It would be nice if the authors would at least comment on overall survival, which ideally should also be improved by the regimen, but the followup is not yet long enough,” said Jennifer Brown, MD, PhD, attending physician with the Chronic Lymphocytic Leukemia & Lymphoma Program, Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, both in Boston.

George Sledge Jr., MD, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine, Indianapolis, agreed and congratulated the researchers on what he called “a strikingly positive and truly important study. … I think it will be very interesting to see going forward whether the significant improvements in progressionfree survival that we saw in this study will ultimately translate into an overall

survival benefit for follicular lymphoma patients,” he said. “I think it is an important step in the right direction.”

Study Design Follicular lymphoma is the second most common lymphoma subtype. Although therapy with rituximab plus chemotherapy (immunochemotherapy) provides disease control for periods of time, the cancer usually remains incurable. The median life expectancy is 12 to 15 years, according to Dr. Salles, and patients may suffer from periodic recurrences that require them to restart therapy. The length of remission decreases with each recurrence.

than 1, 34% had elevated lactate dehydrogenase, and 32% had ß2-microglobulin greater than 3 mg/L. Varying Follicular Lymphoma International Prognostic Index (FLIPI) scores were represented in the study population: 21% were FLIPI 0-1, 36% were FLIPI 2 and 43% were FLIPI 3-5.

Of the patients, 75% received R-CHOP induction (rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone), 22% R-CVP (rituximab plus cyclophosphamide, vincristine, prednisone), and 3% FCM (fludarabine, cyclophosphamide, mitoxantrone). “[These are] classical regimens used either in the United States or Europe or across the world,” Dr. Salles said. The 1,018 patients who responded to therapy were randomized to observation or maintenance therapy

Observation arm

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80 66

Patients, %

Chicago—Clinicians have a new standard of care for patients with previously untreated follicular lymphoma, according to results from the PRIMA Phase III trial.

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Figure. Comparison of two-year PFS in patients with follicular lymphoma.

PFS, progression-free survival

‘Rituximab maintenance after induction with rituximab plus chemotherapy significantly improves outcomes of follicular lymphoma patients, and we believe that it therefore should be considered as a standard of care in the first-line therapy for follicular lymphoma patients.’

—Gilles Salles, MD

Because previous studies had suggested that rituximab maintenance might benefit patients with relapsed or previously untreated follicular lymphoma, investigators designed the PRIMA (Phase III Primary Rituximab and Maintenance) study to assess whether two-year maintenance treatment with rituximab after induction immunochemotherapy could improve PFS of untreated patients with follicular lymphoma in need of first-line therapy.

Investigators enrolled 1,217 patients with untreated follicular lymphoma and a high tumor burden from 223 centers in 25 countries. The median age of patients was 57 years, 52% were male, 90% were Ann Arbor stage III-IV, 33% had B symptoms, 56% had bone marrow involvement, 4% had an Eastern Cooperative Oncology Group status greater

with rituximab, 375-mg/m2 infusion every two months for two years.

Outcomes Dissected “When the planned interim analysis was run, we observed that the primary end point was met,” Dr. Salles said.

“Patients who received rituximab maintenance had a significantly reduced risk for tumor progression by 50%.”

Investigators identified a significant improvement in the primary end point PFS for rituximab maintenance (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.39-0.64; P<0.0001). The two-year PFS was 82% (95% CI, 78%86%) in patients who received maintenance therapy with rituximab compared with 66% (95% CI, 61%-70%) in patients in the observation arm.

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Rituximab maintenance decreased the risk for starting a new anti-lymphoma treatment by 39% (HR, 0.61; P<0.0003).

Patients benefited from rituximab regardless of age, FLIPI score, type of induction therapy, or whether they had achieved a complete or partial response from induction therapy.

Infections were the most common adverse event (AE), with 22% in the observation arm and 37% in the rituximab arm. A greater percentage of patients in the rituximab arm had grade 3/4 AEs (23% vs. 16%) and grade 2 or higher infections (37% vs. 22%) compared with the observation arm. At the time of the analysis, one patient in the observation arm and 10 patients in the maintenance arm had withdrawn because of toxicity. Quality-of-life scores calculated by Functional Assessment of Cancer Therapy-General scale and European Organization for Research and Treatment of Cancer scale, were similar in both arms but details were not provided.

The study was sponsored by the Group d’Études de Lymphomes de L’Adulte.

—Kate O’Rourke

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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

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

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2010

CML

TKIs continued from page 1

Changing Tide

50

Nilotinib 400 mg

Imatinib

Nilotinib 300 mg

80 28

20

Patients, %

30

63

20

0

0

Figure 2. Major molecular response at 18 months.

‘Whether every newly diagnosed chronic-phase CML patient should receive nilotinib or dasatinib remains unclear. Imatinib has a proven track record; over eight years of follow-up have provided reassuring long-term safety and efficacy data.’

—Richard Stone, MD

were 46% and 28%, respectively (P<0.0001; Figure 1).

The nilotinib trial evaluated two doses of the drug. In this trial, at 12 months, the CCyR rates were 80% for the 300mg dose and 78% for the 400-mg dose of nilotinib, and 65% for imatinib (P<0.001 for both nilotinib doses vs. imatinib). The MMR rates at 12 months, initially reported at the 2009 meeting of the American Society of Hematology, were 44% for the 300-mg dose and 43% for the 400-mg

39

40

10

Figure 1. Major molecular response at 12 months.

69

60

dose of nilotinib, and 22% for imatinib (P<0.001 for both comparisons).

In updated nilotinib results presented at the ASCO meeting by Richard A. Larson, MD, professor of medicine at the University of Chicago Pritzker School of Medicine, MMR rates remained almost twice as high on the second-generation TKI as imatinib at 18 months. Rates were 69%, 63% and 39% for nilotinib 300 mg, nilotinib 400 mg and imatinib 400 mg, respectively (Figure 2). Polymerase

Educational & Commercial Reprints

Trial Details In the dasatinib trial, which was presented as a late-breaking abstract by Hagop Kantarjian, MD, professor and chair of the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center, in Houston, the complete cytogenetic response (CCyR) rate was 77% for 259 patients randomized to the second-generation TKI compared with 66% for 260 patients randomized to imatinib (P=0.0067), after 12 months of follow-up. The major molecular response (MMR) rates on dasatinib and imatinib

Imatinib 400 mg

100

46

40

Patients, %

The data so far suggest that “without a tool to select patients destined for optimal response to imatinib, second-generation TKIs should be used as primary therapy in CML,” said Michael Mauro, MD, associate professor of medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, who was not involved with either study. Dr. Mauro suggested that the arguments for withholding these agents, such as the potential for inducing broad drug resistance, do not appear to outweigh the proven advantages.

The remarks from Dr. Mauro were made at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO) and directly followed the presentation of 12-month data on dasatinib (abstract LBA6500) and 18-month data on nilotinib (abstract 6501), each of which was being compared in a head-tohead study with imatinib. The results of the two trials have been remarkably similar and were published simultaneously in the June 17, 2010, edition of The New England Journal of Medicine.

Based on the superior results of the two newer TKIs relative to imatinib, each of the lead investigators concluded that the TKI they studied would become a new standard in CML. Dr. Mauro agreed that second-line TKIs are likely to replace imatinib, but declined to speculate about whether one of these newer TKIs might be a better first choice than the other.

Dr. Mauro also pointed out that there are likely predictors that could single out patients who respond equally well or better to imatinib than the newer secondline TKIs. Although use of such markers would be consistent with a general trend toward individualized therapy in oncology, they could become particularly important if second-generation agents cost substantially more than imatinib or when generics are developed for imatinib in advance of the second-generation agents. The relative sequence of TKIs also may change for specific individuals, as more is learned about susceptibility to resistance.

Dasatinib

Reprints of Clinical Oncology News articles are available in minimum quantities of 500.

Reprints can be ordered in black & white or 4-color versions and printed on 80-lb. glossy stock.

For specific price quotes, call Julianna Dawson at (212) 957-5300 x271.

chain reaction (PCR) analyses have been completed at 18 months on 525 of 846 patients randomized. At 24 months, MMR rates in 125 evaluated patients were 86% in the nilotinib 300 mg arm, 88% in the nilotinib 400 mg arm and 48% in the imatinib arm. The best CCyR rates in the follow-up completed so far are 85%, 82% and 74%, respectively.

“With longer follow-up, rates of MMR and CCyR remain superior on nilotinib when compared to imatinib,” Dr. Larson said. He said that the molecular responses “are continuing to deepen over time” and this appears to be reflected in overall survival. At 18 months, there were nine deaths in the imatinib arm versus five in the nilotinib 300 mg arm and two in the nilotinib 400 mg arm. The difference between the higher dose of nilotinib and imatinib was statistically significant (P=0.03), with the expectation that the survival differences will widen over time.

In the clinical trials so far, each agent has appeared to be at least as well tolerated as imatinib, although the types of predominant side effects have differed.

In the nilotinib study, for example, nausea, vomiting, muscle spasms and diarrhea were more common with imatinib, whereas rash, headache, pruritus and alopecia were more common with nilotinib.

Richard Stone, MD, director of the Adult Leukemia Program, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School, both in Boston, said the results were practice-changing.

“While these results are very important and make up-front use of the second-generation TKIs a reasonable option, whether every newly diagnosed chronic-phase CML patient should receive nilotinib or dasatinib remains unclear,” Dr. Stone said. “Imatinib has a proven track record; over eight years of follow-up have provided reassuring long-term safety and efficacy data.”

—Ted Bosworth

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FDA NEWS

CLINICAL ONCOLOGY NEWS • JULY 2010

Nilotinib Gets First-Line Cabazitaxel Approved Indication for CML For Advanced Prostate Cancer he FDA has approved nilotinib

T

(Tasigna, Novartis) for the first-line therapy of adult patients with newly diagnosed Philadelphia chromosome– positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). Previously, nilotinib was approved for secondline therapy in patients with this disease, and imatinib (Gleevec, Novartis) was the only drug approved for firstline therapy in these patients.

The safety and effectiveness of nilotinib were evaluated in a single clinical trial enrolling 846 patients with newly diagnosed Ph+ CML-CP. Patients received either nilotinib or imatinib until disease progression, or until unacceptable side effects developed. The study was designed to measure major molecular response at 12 months. About 44% of patients who received nilotinib experienced a major molecular response, compared with 22% of patients receiving imatinib.

When nilotinib was originally approved in October 2007, the FDA identified that the therapy placed

patients at risk for an abnormal heart rhythm called QT prolongation. In March 2010, the FDA approved a Risk Evaluation and Mitigation Strategy (REMS) for nilotinib to help patients and health care professionals to better understand this risk. The REMS includes an updated medication guide and a communication plan to help reduce medication errors involving drug–food interactions and incorrect dosing intervals.

The most commonly reported non– blood-related adverse drug reactions were rash, itching, headache, nausea, fatigue and muscle pain. Serious bloodrelated drug reactions included myelosuppression, thrombocytopenia, neutropenia and anemia.

For more information on treatments for CML, see cover story “Battle of Second-Generation TKIs Declared in CML.”

T

he FDA has approved cabazitaxel (Jevtana, Sanofi-aventis) injection to be used in combination with the steroid prednisone to treat men with advanced, hormone-refractory prostate cancer that has worsened during or after treatment with docetaxel. Cabazitaxel is the first therapy available for these patients.

Cabazitaxel, a microtubule inhibitor, was approved based on results from the Phase III TROPIC clinical study, involving 755 patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxelcontaining regimen. Results from this trial demonstrated a 30% reduction in risk for death from mCRPC among patients taking cabazitaxel in combination with prednisone compared with an active chemotherapy regimen consisting of a standard dose of mitoxantrone and prednisone [hazard ratio, 0.70; 95% confidence interval, 0.590.83; P<0.0001]. The median overall survival of patients who received the cabazitaxel regimen was 15.1 months compared with 12.7 months for those receiving the mitoxantrone regimen.

Investigator-assessed tumor response rates using Response Evaluation Criteria in Solid Tumors (RECIST) were 14.4% and 4.4% for cabazitaxel-treated and mitoxantrone-treated patients, respectively (P=0.0005). No complete responses were observed in either treatment arm.

Cabazitaxel was reviewed under the FDA’s priority review program, which provides for an expedited six-month review for drugs that may offer major advances in treatment, or provide a treatment when no adequate therapy exists. The FDA reviewed and approved the application for cabazitaxel in only 11 weeks.

Side effects in those treated with cabazitaxel included neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia and renal failure.

Mylotarg Withdrawn From Market

P

fizer Inc. has voluntarily withdrawn gemtuzumab ozogamicin (Mylotarg), a drug for patients with acute myeloid leukemia (AML), from the U.S. market.

The company took the action at the request of the FDA after results from a recent clinical trial raised new concerns about the product’s safety and the drug failed to demonstrate clinical benefit to patients enrolled in trials.

Mylotarg was approved in May 2000 under the FDA’s accelerated approval program, which allows approval of a drug with an unmet medical need based on a surrogate end point instead of a clinically meaningful end point. Under accelerated approval, the company is required to conduct additional clinical trials after approval to confirm the drug’s benefit. If those trials fail to confirm clinical benefit to patients, or if the company does not pursue the required confirmatory trials with due diligence, the FDA can withdraw the drug from the market using expedited procedures.

Mylotarg was approved to treat patients aged 60 years and older with recurrent AML who were not considered candidates for other chemotherapy. The initial approval was based on the surrogate end point of response rate, observed in 142 patients with AML across three clinical trials.

Wyeth (now Pfizer) began a confirmatory, post-approval clinical trial in 2004.

The trial was designed to determine whether adding Mylotarg to standard chemotherapy demonstrated an improvement in clinical benefit to AML patients. The trial was stopped early when no improvement in clinical benefit was observed, and after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone. At initial approval, Mylotarg was associated with a serious liver condition called veno-occlusive disease, which can be fatal. This rate has increased in the postmarket setting.

As a result of the withdrawal, Mylotarg will not be available commercially to new patients. Patients who are currently receiving the drug may complete their therapy following consultation with their health care professional. Health care professionals should inform all patients receiving Mylotarg of the product’s potential safety risks.

Following the withdrawal, any future use of Mylotarg in the United States will require submission of an investigational new drug application to FDA.

We Want Your Feedback.

Dear Clinical Oncology News Reader: We want your opinions, criticisms, ideas and suggestions to help us improve this new publication. Please contact the editor at the e-mail address listed below. We would sincerely value your input.

Kate O’Rourke, Editor • korourke@mcmahonmed.com • (212) 957-5300, x 265

Approval Sought for Trastuzumab for Gastric Cancer

G

enentech, Inc. has submitted a supplemental Biologics License Application to the FDA for trastuzumab (Herceptin) plus chemotherapy for use in patients with advanced, HER2-positive adenocarcinoma of the stomach, including gastroesophageal junction cancer.

The application is based on positive results from the Phase III ToGA trial that enrolled 594 people with locally advanced or metastatic HER2-positive gastric cancer. Patients were randomized to receive trastuzumab plus chemotherapy or chemotherapy alone.

Median overall survival was 13.8 months in patients who received trastuzumab compared with 11.1 months in patients who received standard chemotherapy (P=0.0046). The addition of trastuzumab did not compromise quality of life.

Amgen Submits BLA For Denosumab

A

mgen has submitted a Biologics License Application (BLA) to the FDA for denosumab (Prolia) for the reduction of skeletal-related events in cancer patients. The BLA submission summarizes clinical experience from nearly 6,900 patients across 18 clinical studies, including approximately 5,700 patients with advanced cancer in three Phase III, head-to-head trials comparing denosumab with zoledronic acid (Zometa, Novartis).

In early June, the FDA approved denosumab as a treatment for postmenopausal women with osteoporosis at high risk for fractures. The decision came about two months earlier than expected. Recently, the European Commission granted approval for denosumab for postmenopausal women with increased fracture risk, as well as for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk for fractures.

PRN

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY 2010

People

Around the Water Cooler A

t the recent meeting of the American Society of Clinical Oncology, Daniel D. Von Hoff, MD, received the 2010 David A. Karnofsky Memorial Award and Lecture for his outstanding achievements in cancer research and for his impact on the treatment of patients with cancer. Dr. Von Hoff is an internationally recognized physician-scientist who has contributed to the development of numerous anticancer agents, including paclitaxel, docetaxel, irinotecan (Camptosar, Pfizer) and gemcitabine (Gemzar, Eli Lilly). He currently serves as physician-in-chief for the Translational Genomics Research Institute (TGen) in Phoenix, chief scientific officer of TGen Clinical Research Services at Scottsdale Healthcare and US Oncology, and clinical professor of medicine at The University of Arizona College of Medicine, also in Phoenix.

Frank McCormick, PhD, received the 2010 ASCO Science of Oncology Award and Lecture. He is the director of the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center and professor in the Department of Microbiology and Immunology. A pioneering molecular biologist and cancer researcher, his contributions include the development of sorafenib (Nexavar, Bayer Healthcare Pharmaceuticals), a smallmolecule tyrosine protein kinase inhibitor that has been used to treat kidney and advanced liver cancer. He has also made substantial contributions in the area of translational research in cancer.

Nancy E. Davidson, MD, has been honored with the ASCO 2010 Gianni Bonadonna Award and Lecture for advancing the field of breast cancer research. Dr. Davidson has published key findings on the role of hormones, particularly estrogen, on gene expression and cell growth in breast cancer. She also guided several important national clinical trials of potential new therapies, including chemoendocrine therapy for premenopausal breast cancer and antiangiogenesis therapy for advanced disease. Dr. Davidson is currently the director of the University of Pittsburgh

Cancer Institute and professor of medicine in pharmacology and chemical biology. Previously, she served as the director of the Johns Hopkins Kimmel Cancer Centerâ&#x20AC;&#x2122;s Breast Cancer Program.

She was also president of ASCO in 20072008 and has served as a member of the scientific advisory boards of numerous foundations.

Patrick J. Loehrer Sr., MD, has received the 2010 ASCO Special Recognition Award for his outstanding

contributions to clinical oncology and cancer research and for his dedicated service to the oncology community. He currently serves as associate dean for cancer research and H.H. Gregg Professor of Oncology at the Indiana University School of Medicine and director of the Indiana University Melvin and Bren Simon Cancer Center, in Indianapolis. Dr. Loehrer is an internationally recognized researcher and specialist

(Stimulating Targeted Antigenic Responses To NSCLC)

in thymoma, genitourinary cancers and gastrointestinal cancers. He is also a past member of the ASCO board of directors who was recognized with an ASCO Statesman Award in 2008 for his service and commitment to the society.

Harvey Jay Cohen, MD, director of the Center for the Study of Aging and Human Development and Walter Kempner Professor of Medicine at Duke University Medical Center, Durham, is the recipient of the ASCO 2010 B. J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology. Dr. Cohen has written more than 300 articles and see WATER COOLER, page 31

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SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • JULY 2010

5-FU Toxicity

17/17

20/20

cases resolve

cases resolve

2009 ASCO Report

2010 ASCO Report

5-FU ANTIDOTE continued from page 1

said Mary Ann Howland, PharmD, DABAT, clinical professor of pharmacy, St. John’s University College of Pharmacy, Queens, N.Y. “Uridine triacetate works, and until it gets approved by the FDA, hospitals need to get up to speed on how to gain access to it when patients get into trouble with their 5-FU doses.”

According to the National Institutes of Health, approximately 275,000 patients in the United States are treated with 5-FU every year. The National Cancer Institute has stated that more than 8,000 are overexposed to 5-FU for one reason or another, and that 1,300 people die as a result.

Currently, there is no FDA-approved antidote for 5-FU overexposure.

5-FU toxicity: 100% symptom resolutiona a

Patients given uridine triacetate within eight to 14 hours of 5-FU overexposure.

like a fire extinguisher,” Dr. Bamat said.

‘Clearly, any patient who has received an overdose of 5-FU or is experiencing severe toxicities would be an appropriate candidate for this potentially lifesaving antidote. My hope is that the FDA will approve the use of this agent in the very near future.’

—Ed Chu, MD

The Antidote Uridine triacetate is an orally bioavailable prodrug of uridine, a direct biochemical antagonist of 5-FU toxicity. The prodrug dilutes intracellular fluorouridine nucleotide anabolites of 5-FU, reducing their lethal incorporation into RNA. Wellstat Therapeutics Corporation, Gaithersburg, Md., manufactures the drug.

In a poster at last year’s ASCO annual meeting, Michael K. Bamat, PhD, vice president for research and development for Wellstat, reported that 17 patients who had received uridine triacetate (formerly known as vistonuridine) within eight to 96 hours of overexposure to 5-FU showed a complete resolution of their toxicity symptoms.

Since then, the interest generated by that poster has resulted in 20 more patients who were unintentionally overexposed to 5-FU being referred for emergency rescue treatment, he said. All 37 patients have completely recovered, including one woman who was given 10,000 mg of 5-FU over one hour instead of the 1,000 mg 5-FU that was prescribed, in one hour.

“The word spread. With the simple publication of one poster at ASCO last year, and the fact that now a few more people know about this, we are treating about two cases a month. We believe that 27 of these 37 cases were in the lethal dose range, so we’ve saved the lives of a number of people,” said Dr. Bamat who was lead author of the study presented this year at ASCO. The antidote was provided under an FDA provision that allows for the emergency use of an investigational new drug (IND). Patients received 10 g of uridine triacetate every six hours for a total of 20 doses, and the antidote was started as soon as possible after the overdose was recognized. Outcomes were monitored and compared with historical reports of 5-FU overdoses where the antidote was not used.

Although all patients receiving the

antidote recovered, patients who did not get uridine triacetate did poorly. Of 43 historical cases of 5-FU overdose not treated with the antidote, 39 died. “This highlights the potentially severe consequences of 5-FU overdoses and the need for an effective antidote,” Dr. Bamat said.

Uridine triacetate is given as a powder sprinkled in apple sauce, pudding or similar foods. Patients given the drug are then monitored for signs of improvement, based on their white blood cell count, extent of mucositis, nausea and vomiting and other signs of 5-FU toxicity.

Mad Dashes to the Airport When Dr. Bamat’s office gets a request for the antidote from a doctor or pharmacist, standard procedure is to first ascertain whether the case involves an actual overdose. If it does, the caller is directed to the FDA to obtain the emergency IND and the drug is shipped as fast as possible.

“Usually that involves one of our employees racing to the airport and getting on the next flight to Montana or Maine or Alabama or wherever the patient might be, and then going through the chain of custody,” Dr. Bamat explained. “With airport security being what it is these days, you can imagine that carrying a jar of white powder can be quite difficult, so all documents have to be proper.

“At arrival at the designated place, the pharmacist is at the airport or at the clinical site, and we hand it off there.

Usually the patient is at the hospital or clinic, and treatment begins a couple of hours after the drug arrives. As with any antidote, speed is of the essence.”

Infusion Pump Mistakes, Transcription Errors 5-FU often is administered via an infusion pump at or near its maximum tolerated dose. This method of delivering the drug makes accidental overdoses

possible. “The common use of infusion pumps loaded with 5-FU for infusion over several days increases the possibility of potentially lethal overdoses due to pump malfunction or misprogramming,” Dr. Bamat said.

But 5-FU overdoses aren’t always caused by mistakes made in the programming of infusion pumps. “We also have seen transcription errors at the pharmacy level that ended up with the wrong dose being in the pump,” Dr. Bamat said. “But most of the time, the pumps are misprogrammed. Thus, instead of getting the 5-FU over four days, the patient gets it over four hours.

In one case, a 43-year-old woman given 5-FU for nasopharyngeal cancer died from septic shock after an overdose because the hospital did not know there was an investigational antidote available.”

Another cause of potentially lethal toxicity is lack of the dihydropyrimidine dehydrogenase (DPD) enzyme that breaks down 5-FU. Even at standard doses, patients without the DPD enzyme cannot break down the 5-FU, so it accumulates. “This situation can be more difficult to treat because you don’t realize what is happening until the patient becomes symptomatic, whereas in the case of the pump misprogramming, the pump bell goes off so you can intervene much more readily,” Dr. Bamat said.

A sister company of Wellstat Therapeutics is developing a rapid assay to determine whether 5-FU is being cleared properly from the first dose. “Then we’d know and could intervene with the antidote in these cases as well,” he said.

Wellstat has a meeting planned with the FDA in the next few months. “We’ll ask them what will be required to get [uridine triacetate] out as soon as possible. Obviously, the best thing would be if it’s on the shelf of every chemotherapy clinic, pharmacy and hospital—kind of

‘A Tremendous Advance’ Edward Chu, MD, professor of medicine and pharmacology at Yale University School of Medicine, New Haven, Conn., said that he hopes formal approval of uridine triacetate will be forthcoming.

“5-FU and the oral fluoropyrimidines remain one of the most widely used class of anticancer agents, but unfortunately, a significant number of patients will die from 5-FU overexposure mainly because of drug overdose,” he said. “In addition, patients with the dihydropyrimidine dehydrogenase deficiency syndrome experience increased severe toxicities when treated with 5-FU or with the oral fluoropyrimidine capecitabine” [Xeloda, Genentech].

Dr. Chu said the availability of uridine triacetate to overcome potentially lifethreatening 5-FU toxicity represents a “tremendous advance for the practicing oncologist, as there is no such agent on the market. Clearly, any patient who has received an overdose of 5-FU or is experiencing severe toxicities would be an appropriate candidate for this potentially lifesaving antidote. My hope is that the FDA will approve the use of this agent in the very near future.”

Dr. Howland said that she also looks forward to the FDA approving uridine triacetate for reversal of 5-FU overdoses.

Current treatments for the resultant toxicity “are simply not sufficient,” as they are limited to only supportive care with granulocyte colony-stimulating factors, hydration, antiemetics, antibiotics and so on, she noted. “Those certainly help relieve symptoms of 5-FU overdose, but they are not lifesaving.”

Dr. Howland, who co-authored a review article on uridine triacetate for the New York State Poison Center’s Toxicology Letter (January 2010) and is a consultant with the New York City Poison Control Center, added that she is not aware of any other agents waiting in the wings to treat 5-FU toxicity. “Only uridine triacetate has been shown to be effective as a rescue agent,” she said. “So if the safety profile of the drug remains untarnished, then we need it to be approved.” She declined to speculate on the likelihood of that approval coming anytime soon.

—Fran Lowry

In first-line metastatic NSCLC and first- and second-line MCRC

To reach beyond convention…

Indications 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.

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.

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 In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls 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%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

©2010 Genentech USA, Inc.

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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 and Wound Healing Complications 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 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 People

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 Diarrhea Constipation Hemic/Lymphatic 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%

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

0%

5%

5%

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

WATER COOLER

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 Stomatitis Metabolic/Nutrition Musculoskeletal Myalgia Respiratory Dyspnea Epistaxis Skin/Appendages Exfoliative dermatitis Urogenital 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 Metabolism and nutrition disorders Anorexia Musculoskeletal and connective tissue disorders Myalgia Back pain Nervous system disorders Headache Renal and urinary disorders Proteinuria Respiratory, 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

continued from page 27

book chapters on topics in geriatrics and hematology/oncology, with special emphasis on aspects of cancer and immunologic disorders in the elderly. He is a past president of the American Geriatrics Society, the Gerontologic Society of America and the International Society of Geriatric Oncology.

Sharon B. Murphy, MD, is the recipient of the ASCO 2010 Pediatric Oncology Award and Lecture. Dr. Murphy has devoted the past 35 years to improving cure rates for childhood cancers, particularly lymphomas and leukemias.

She has authored more than 220 original articles, reviews and book chapters, and has served as the inaugural director of the Greehey Children’s Cancer Research Institute and professor of pediatrics at The University of Texas Health Science Center at San Antonio. Currently, Dr. Murphy is a scholar-in-residence at the Institute of Medicine in Washington, D.C. Joseph V. Simone, MD, is the recipient of the 2010 ASCO– American Cancer Society Award and Lecture for his contributions to the prevention and management of cancer and for his leadership in the oncology field.

Dr. Simone served as physician-in-chief of Memorial Sloan-Kettering Cancer Center, New York City, and director of the University of Florida Shands Cancer Center, Gainesville, but spent the majority of his career at St. Jude Children’s Research Hospital in Memphis, where he served as director from 1983 to 1992. While there, he played a leadership role in the development of curative treatments for childhood leukemia and lymphoma. Dr. Simone was also the founding medical director and chairman of the National Comprehensive Cancer Network and was instrumental in the creation of the ASCO’s Quality Oncology Practice Initiative. He currently serves as senior advisor to the Shands Cancer Center and as president of Simone Consulting Company, which advises organizations on cancer program quality and development.

31

CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS • JULY 2010

New Phase II and III Clinical Trials

Hematologic Malignancies

Solid Tumors

Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to June 21, 2010. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Supportive Care

32

Protocol Type

Age

Protocol ID

Trial Sites

Pilot Study of Allogeneic Tumor Cell Vaccine With Metronomic Oral Cyclophosphamide and Celecoxib in Patients Undergoing Resection of Lung and Esophageal Cancers, Thymic Neoplasms, and Malignant Pleural Mesotheliomas, Phase I/II

18 and over

100138

MD

Imetelstat as Maintenance Therapy After Initial Induction Chemotherapy in Non-Small Cell Lung Cancer, Phase II

18 and over

CP14B012

FL, KY, MT, TN, WA

Study of Bavituximab Plus Docetaxel in Patients With Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer, Phase II

18 and over

PPHM 0902

CA, NB, TX

Trial of Panitumumab/Cisplatin/Fluorouracil With XRT in Esophageal Cancer, Phase I/II

18 and over

H-2009-0214

WI

Study of Platelet-Derived Growth Factor Receptor in Recurrent Malignant Gliomas, Phase II

18 and over

091728

CA

Eribulin Mesylate Administered in Combination With Gemcitabine Plus Cisplatin Versus Gemcitabine Plus Cisplatin Alone as First-Line Therapy for Locally Advanced or Metastatic Bladder Cancer, Phase I/II

18 and over

E7389-702

AZ, CO, NV, NY, VA, WA

Rapid Gastric and Pancreas Cancer Staging Utilizing Peritoneal Lavage, Phase II

18 and over

10-011

NY

A Study Evaluating IPI-926 in Combination With Gemcitabine in Patients With Metastatic Pancreatic Cancer, Phase I/II

18 and over

IPI-926-03

SC, TX

Safety and Efficacy of BKM120 in Combination With Trastuzumab in Patients With Relapsing HER2-Overexpressing Breast Cancer Who Have Previously Failed Trastuzumab, Phase I/II

18 and over

CBKM120X2107

TN

A Study of a HER2/Neu Vaccine for Stage IIIB, IIIC and IV HER2/Neu Positive Breast Cancer Patients on Herceptin, Phase II

18 and over

BC 030289

WA

4-Hydroxytamoxifen or Tamoxifen Citrate in Treating Women With Newly Diagnosed Ductal Breast Carcinoma in Situ, Phase II

18 and over

CDR0000650556

IL, MO, NC

E7080 in Combination With Carboplatin + Gemcitabine Versus Carboplatin + Gemcitabine Alone as Second-Line Therapy in Patients With Platinum-Sensitive Recurrent Ovarian Cancer by CA125, Phase I/II

18 and over

E7080-701

CA, CO, MD, TX

E7080 in Combination With Dacarbazine Versus Dacarbazine Alone as First-Line Therapy in Patients With Stage IV Melanoma, Phase I/II

18 and over

E7080-702

FL, MD, NY, SC, TX

Randomized Study of Temozolomide Versus MEK Inhibitor AZD6244 in Patients With Metastatic Uveal Melanoma, Phase II

18 and over

MSKCC-10053

CA, CT, FL, MA, NY, PA, TN, TX

Study of ONTAK in Patients With Stage IIIC and Stage IV Melanoma, Phase II

18 and over

E7272-701

CA, FL, IL, KY, NB, OH, OR

FOLFIRI Alone Versus FOLFIRI Plus Bevacizumab Versus FOLFIRI Plus E7820 as Second-Line Therapy in Patients With Locally Advanced or Metastatic Colorectal Cancer, Phase I/II

18 and over

E7820-701

CO, NC, ND, NJ, TX, WA

Study of Bevacizumab and Erlotinib in Subjects With Advanced Hereditary Leiomyomatosis and Renal Cell Cancer or Sporadic Papillary Renal Cell Cancer, Phase II

18 and over

100114

MD

Cetuximab and Lenalidomide in Head and Neck Cancer, Phase II

18 and over

09-206-B

IL

Evaluating the Combination of Everolimus and Sorafenib in the Treatment of Radioactive Iodine Refractory Thyroid Cancer, Phase II

18 and over

10-060

NY

Study of Nilotinib in Ph+ CML-CP Patients With Low Imatinib Trough Plasma Concentrations, Phase II

18 and over

CAMN107AUS20

IL, IN, TN

Study of Bafetinib as Treatment for Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia, Phase II

18 and over

BAFETINIB-P2CLL-01

TX

Autologous Transplant for Multiple Myeloma, Phase II/III

18 to 75

2004LS001

MN

Trial for Patients Not Qualifying for TT4 and TT5 Protocols Because of Prior Therapy (No Prior Transplant) [in Patients With Multiple Myeloma], Phase II

18 to 75

UARK 2008-03

AK

Bortezomib and Rituximab in Treating Patients With Post-Transplant Lymphoproliferative Disorders, Phase II

18 and over

CDR0000638557

MN

Lenalidomide and Prednisone in Low and Int-1 Myelodysplastic Syndrome Non 5q MDS, Phase II

18 and over

MCC-16099

FL

Open-label Pilot Study of Lenalidomide (Revlimid) as Adjuvant Treatment for Refractory Cutaneous T-Cell Lymphoma, Phase II

18 and over

RevMM2009

FL

Autologous Transplant in HIV Patients With Lymphoma (BMT CTN 0803)

15 and over

698

MD

Immunochemotherapy, Zevalin, and Bone Marrow Transplant for Follicular Lymphoma, Phase II

18 to 80

IRB #14228

MO

Busulfan, Melphalan, Fludarabine and T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation Followed by Post-Transplantation Donor Lymphocyte Infusions [Graft-vs.-Host Disease], Phase II

21 to 69

10-051

NY

Combination Chemotherapy in Treating Patients Who Are Undergoing a Donor Stem Cell Transplant for Fanconi’s Anemia, Phase II

0 to 44

2002LS014

MN

High-Dose Cyclophosphamide in Treating Patients With Acute Graft-vs.-Host Disease That Did Not Respond to Steroid Therapy, Phase II

75 and under CDR0000549900

MD

Randomized Study of Cyproheptadine Hydrochloride in Preventing Cancer- or Treatment-Related Weight Loss in Pediatric Patients Receiving Moderately to Highly Emetic Chemotherapy, Phase III

2 to 18

MCC-0703

FL

Reduced Intensity Hematopoietic Cell Transplantation for Patients With Resistant Langerhans Cell Histiocytosis, Phase II

Any age

UMN-2007UC002

MN

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34

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2010

Breast

ERIBULIN continued from page 8

four previous chemotherapy drugs, two of which had to be an anthracycline and a taxane; 73% had also received capecitabine. Median age was 55 years, 16% had HER2-positive tumors and 20% were triple-negative.

Harold J. Burstein, MD, PhD, a medical oncologist at the Breast Oncology Center at Dana-Farber Cancer Institute, who served as a discussant for the study at the ASCO meeting, said the study was well designed and “the options given the treating physician reflected the realworld choices that we see.”

At one year, the survival rate was 53.9% in patients who received eribulin and 43.7% in patients in the TPC arm. Median progression-free survival (PFS) determined by independent review was 3.7 months for patients receiving eribulin and 2.2 months for patients in the TPC arm, although this difference was not statistically significant (P=0.09). Overall response rate was 12.2% for patients receiving eribulin and 4.7% for patients in the control arm. Median duration of response was 4.1 months in patients receiving eribulin (56 responders) compared with 6.7 months in patients in the

TPC arm (10 responders).

The new agent was well tolerated. Serious adverse events (AEs) were identified in 25% and 25.9% of patients receiving eribulin and TPC, respectively.

Grade 3/4 AEs were 4.2% in the eribulin arm compared with 1.2% in patients receiving TPC, but AEs requiring dose interruptions, reductions, delays or discontinuations occurred with equal frequency in the two arms. Some grade 3/4 AEs were more common in the eribulin arm including neutropenia (45.2% vs. 21.1%), febrile neutropenia (4.2% vs.

1.2%) and peripheral neuropathy (8.2% vs. 2%). Grade 3/4 asthenia and fatigue, however, was more common in patients receiving TPC (10.1% vs. 8.8%).

PFS Benefit Mystifying One hard-to-understand outcome was the modest difference in PFS. “What is the meaning of better overall survival out of proportion to improvement in progression-free survival?” said Dr. Burstein. “One hypothesis might be that you are doing something that actually isn’t about treating the cancer, but is in some other way supporting the patient.” For example, a 1994 study showed that an anti-inflammatory agent compared with a placebo in the third- or fourth-line setting for advanced solid tumors produced

a survival advantage, even though h no one would have expected these agents to have a clinical impact on the course of the tumor itself (Cancer Res 1994;54:5602-5606, PMID: 7923204). “I don’t think there are any particular groundss for seeing that in this particular study, udy, but it is notable that the response rate remains low at only 12%, and we only know a little bit about what eribulin really does, although to date everything points to it having anti-neoplastic effects,” Dr. Burstein said.

Another possibility, he said, is that the RECIST criteria for response and therefore the measurement of time to progression are not as relevant in women who have been heavily pretreated. “We know that some patients often have multiple sites of disease. They often have extensive nonmeasurable disease in bone or with effusions or skin lesions that might not be available for independent review,” Dr. Burstein said. “It may simply be that the RECIST criteria for response and time to progression break down in fourth- and fifth-line treatments of advanced breast cancer.” And yet another possibility is that the eribulin therapy allowed patients to have a better performance status that allowed for ongoing lines of therapy that were not possible in the control group.

Eribulin is derived from the sea sponge pictured above, Halichondria panicea, commonly known as the breadcrumb sponge.

Dr. Burstein pointed out that although it was well designed, the study had limitations. It was not blinded, and perhaps more critically, patients in the TPC arm could receive treatments they had previously been exposed to, including anthracyclines and taxanes. He also wished to see the study results analyzed as a function of estrogen receptor status and triple-negative status, so that clinicians can figure out which patients can derive the most benefit. “Clearly, we are going to need more studies to understand how best to incorporate this agent into our standard treatment algorithms,” Dr. Burstein said.

He concluded the drug was “a most welcome addition to the armamentarium that we use to treat advanced breast cancer.”

—Kate O’Rourke

CLASSIFIED

Forbes and Fortune Small Business Magazine rank Billings, MT - the Best!

Practice medicine in a city ranked as one of the Best Small Places for Business and Careers (Forbes, 2009) and the Best Small City in which to start a business (Fortune Small Business Magazine, November 2009).

Award winning St. Vincent Healthcare and St. Vincent Children’s Healthcare in Billings, MT, seeks well-trained, compassionate physician to build our Pediatric Oncology program.

• Possible academic appointment available • Access to clinical trials • 22 bed dedicated pediatric floor and 7 bed PICU supported by Board Certified Pediatric Intensivists who are available 24 hours a day/7 days a week • Pediatric specialty clinics which serve patients from Montana and Wyoming • Pediatric rehabilitation including physical therapy, speech therapy, and occupational therapy • Thriving medical community in a family-oriented suburban location • Excellent School System • Abundant recreational activities year round – hiking, skiing, fishing, biking and camping • Excellent Benefits and Competitive Salary Structure, based on MGMA • Sign-on Incentives, Moving Allowances, and CME reimbursement. Will consider loan forgiveness.

• SVH is staffed for 250 beds and is a regional destination hospital which serves a four-state area and more than 900,000 people each year • Known for providing superb patient care • Maternal Fetal Medicine Physician and 4 Neonatologists on Medical Staff • Pediatric specialists on Medical Staff include: Neurology, Cardiology, Behavioral and Developmental, Urology, GI and Orthopedics • Pediatric Specialty Clinics include: Cleft/Craniofacial; Cystic Fibrosis; Endocrine; Gastrointestinal; Genetic High Risk Infant Follow-up; Hematology; Metabolic; Nephrology Neural Tube Defect; Neurology and Rehabilitation • AASM accredited sleep center; Level II Trauma Center; HELP Helicopter and Fixed Wing air transport program with specialty transport teams; and CARF Accredited Inpatient Rehabilitation Program • SVH invests in the latest technology: Allura Xper FD20/10 interventional angiographic X-ray lab, Toshiba Aquilion ONE dynamic volume 320-slice CT system and Da Vinci Robotics • SVH is ranked Best for Heart Attack Care and #15 for Quality in the nation

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METRO SOUTH CAROLINA Hospital employed Medical Oncology position joining Hem/Onc and Hematologist in desirable South Carolina metro area nestled in Blue Ridge Mountain and two hours to Charlotte and Atlanta associated with growing 450-bed health system with Bone Marrow Transplant Unit and new Cancer Center affiliated with MD Anderson.

1-3 call. Excellent salary, bonus and benefits. DONOHUE AND ASSOCIATES (800) 831-5475 F: (314) 984-8246 Email: donohueandassoc@aol.com.

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FARESTON® (toremifene citrate) tablets DESCRIPTION FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene.

FARESTON is a nonsteroidal antiestrogen. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro-1,2diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: OCH2CH2N

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

C

COOH

CH2COOH

and the molecular formula is C26H28 H O . The molecular weight of toremifene citrate is 598.10.

6 8 7 The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL. FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch.

CLINICAL PHARMACOLOGY Mechanism of Action: Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mam-mary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, ie, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor.

Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Pharmacokinetics: The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (deaminohydroxy) toremifene were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5L/h.

Absorption and Distribution: Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady-state concentrations were reached in about 4-6 weeks. Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly to albumin.

Metabolism and Excretion: Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state.

Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Special Populations: Renal insufficiency: The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

Hepatic insufficiency: The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients: The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. Race: The pharmacokinetics of toremifene in patients of different races has not been studied.

Drug-drug interactions: No formal drug-drug interaction studies with toremifene have been performed.

CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table).

Clinical Studies Study North American Eastern European Nordic Treatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 No. Patients 221 215 157 149 214 201 Responses 1 2 14+33 11+30 7+25 3+28 19+48 19+56 CR + PR RR3 (CR + PR)% 21.3 19.1 20.4 20.8 31.3 37.3 Difference in RR 2.2 -0.4 -6.0 95% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1 Time to Progression (TTP) Median TTP (mo.)

5.6 5.8 4.9 5.0 7.3 10.2 Hazard Ratio (TAM/FAR) 1.01 1.02 0.80 95% CI4 for Hazard Ratio (%) 0.81 to 1.26 0.79 to 1.31 0.64 to 1.00 Survival (S) Median S (mo.)

33.6 34.0 25.4 23.4 33.0 38.7 Hazard Ratio (TAM/FAR) 0.94 0.96 0.94 95% CI4 for Hazard Ratio (%) 0.74 to 1.24 0.72 to 1.28 0.73 to 1.22 1 CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of

22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months).

significant age-related differences in FARESTON effectiveness or safety were noted.

Race: Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted.

INDICATION AND USAGE FARESTON is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

ADVERSE REACTIONS Adverse drug reactions are principally due to the antiestrogenic hormonal actions of FARESTON and typically occur at the beginning of treatment.

The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

North American Study FAR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4%

CONTRAINDICATIONS FARESTON is contraindicated in patients with known hypersensitivity to the drug.

WARNINGS Hypercalcemia and Tumor Flare: As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, FARESTON treatment should be discontinued.

Tumorigenicity: Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (about 1/4 and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m2 basis).

Pregnancy: FARESTON may cause fetal harm when administered to pregnant women. Studies in rats at doses ≥1.0 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that toremifene is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies; including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Fetal anomalies may have been a consequence of maternal toxicity. Toremifene has been shown to cross the placenta and accumulate in the rodent fetus.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known.

Embryotoxicity and fetotoxicity were observed in rabbits at doses ≥1.25 mg/kg/day and 2.5 mg/kg/ day, respectively (about 1/3 and 2/3 the daily maximum recommended human dose on a mg/mt basis); fetal anomalies included incomplete ossification and anencephaly.

There are no studies in pregnant women. If FARESTON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

PRECAUTIONS General: Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment (see Warnings). Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.

Information for Patients: Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs.

Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.

Laboratory Tests: Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

Drug-drug Interactions: Drugs that decrease renal calcium excretion, eg, thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. There is a known interaction between antiestrogenic compounds of the triphenylethylene derivative class and coumarin-type anticoagulants (eg, warfarin), leading to an increased prothrombin time. When concomitant use of anticoagulants with FARESTON is necessary, careful monitoring of the prothrombin time is recommended.

Cytochrome P450 3A4 enzyme inducers, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the steady-state concentration in serum.

Metabolism of toremifene may be inhibited by drugs known to inhibit the CYP3A4-6 enzymes. Examples of such drugs are ketoconazole and similar antimycotics as well as erythromycin and similar macrolides.

This interaction has not been studied and its clinical relevance is uncertain.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (about 1/100 to 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (about 1/15 to 2 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors, and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human antiestrogenic agents that have primarily estrogenic activity in mice.

Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests).

Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). No significant adduct formation could be detected using 32P post-labeling in liver DNA from rats administered toremifene when compared to tamoxifen at similar doses. A study in cultured human lymphocytes indicated that adducting activity of toremifene, detected by 32P post-labeling, was about 1/6 that of tamoxifen at approximately equipotent concentrations. In addition, the DNA adducting activity of toremifene in salmon sperm, using 32P post-labeling, was 1/6 and 1/4 that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively.

However, toremifene exposure is fourfold the exposure of tamoxifen based on human AUC in serum at recommended clinical doses.

Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (about 3.5 times and 1/50 the daily maximum recommended human dose on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (about 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) for 52 weeks.

Pregnancy: Pregnancy Category D: (see WARNINGS).

Nursing mothers: Toremifene has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. (See WARNINGS and PRECAUTIONS).

Pediatric use: There is no indication for use of FARESTON in pediatric patients.

Geriatric use: The median ages in the three controlled studies ranged from 60 to 66 years. No

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse events occurring in patients receiving FARESTON in the three major trials are listed in the table below.

Adverse Events North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) Cardiac Cardiac Failure 2 (1) 1 (<1) 1 (<1) 2 (1) 3 (1.5) Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) 1 (<1) Arrhythmia 3 (1.5) 1 (<1) Angina Pectoris 1 (<1) 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) 5 (3) Dry Eyes 20 (9) 16 (7.5) Abnormal Visual Fields 8 (4) 10 (5) 1 (<1) Corneal Keratopathy 4 (2) 2 (1) Glaucoma 3 (1.5) 2 (1) 1 (<1) 1 (<1) Abnormal Vision/Diplopia 3 (1.5) Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) 1 (<1) Thrombophlebitis 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis 1 (<1) 1 (<1) 3 (1.5) 4 (2) CVA/TIA 1 (<1) 1 (<1) 4 (2) 4 (2) Elevated Liver Tests** SGOT 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17) Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15) Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5) Hypercalcemia 6 (3) 6 (3) 1 (<1) * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher.

Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms.

Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/ dilatation leading to interference with digestion and adrenal enlargement.

Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.

Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

HOW SUPPLIED FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white.

FARESTON Tablets are identified with TO 60 embossed on one side.

FARESTON Tablets are available as: NDC 11399-005-30 bottles of 30 NDC 11399-005-01 bottles of 100 Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Protect from heat and light.

Distributed by GTx, Inc. Memphis, TN 38163, USA Product covered by Orion Product Patents and related patent numbers. © 2004 GTx, Inc. All rights reserved.

1E Rev. 12/2004

Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

Fareston helps reduce the guess work

FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

ALREADY ACTIVE

500,000 PATIENT YEARS

UNIQUE METABOLISM

PATIENT SAVINGS

Parent compound binds to and blocks estrogen receptors

Metabolized principally by CYP3A4 CYP2D6 does not play a signiÀcant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical proÀle EfÀcacy comparable to tamoxifen in head to head trials Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON is contraindicated in patients with known hypersensitivity to the drug. FARESTON has been shown to prolong the QTc interval in a dose and concentration dependent manner. FARESTON should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice and others) increases the steady-state concentration in serum and should be avoided. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively.

References: FARESTON® Prescribing Information, 2004. Data on file, GTx, Inc.

Please see full prescribing information on the following page.

For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

© 2010 GTx, Inc., Memphis, TN 38103. All rights reserved. FAR-071R0 June 2010