Clinical Oncology News - June 2010 - Digital Edition

McMahon Publishing

Advances in Cancer Care CLINICALONCOLOGY.COM • June 2010 • Vol. 5, No. 6

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Breast cancer guidelines released Alarming pattern identified for bone metastases

HEMATOLOGIC DISEASE

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Benefits of allo-HSCT debated for elderly MDS patients Omacetaxine promising for CML patients SUPPORTIVE CARE

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Concern revving up over REMS for ESAs Cost analysis for end-stage cancer pain: intrathecal therapy more affordable than opioids FDA NEWS

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Approvals include Provenge for prostate cancer, Tarceva as maintenance therapy for lung cancer, new opioid

POLICY & MANAGEMENT

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How to sift through 340B resources

EDUCATIONAL REVIEW

Update on Approaches to the Treatment of Follicular Lymphoma After page 20.

WWW.CMEZONE.COM

IOM Report Predicts Troubled Future for Cancer Research

Paradigm Change Suggested for Ovarian Cancer

W

omen with biochemically recurrent ovarian cancer who take tamoxifen can gain an additional month of progression-free survival and have fewer side effects than women taking thalidomide, according to a study presented at the recent Society for Gynecologic Oncology’s annual meeting (abstract 2).

“This is a very well-tolerated, very inexpensive drug, and now we have a randomized controlled, Phase III trial conducted by a cooperative group showing that it actually improves the time to subsequent disease progression,” said Maurie Markman, MD, vice president for clinical research at the University of Texas M.D. Anderson Cancer Center in Houston, who was not involved with the study.

The Gynecologic Oncology Group see PARADIGM, page 3

BATTLE May Redefine Treatment Approach to Lung Ca Washington—Results from a major, ongoing initiative to revolutionize the treatment of lung cancer bolsters the idea that cancer therapy can be individualized effectively to the specific molecular features of a tumor. Many clinical research groups have studied the possibility that therapy can be selected on the basis of specific mutations suspected of driving cancer growth, but the new initiative, called BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination), is testing the hypothesis with a high degree see BATTLE, page 4

The Clinical Trials Cooperative Group Program comprises 10 groups involving more than 3,100 institutions. Above are the chair locations of the 10 clinical trials groups. For details, see page 22.

C

ancer research in the United States faces a bleak future unless sweeping changes are made to the current clinical trials system, according to a new report from the Institute of Medicine (IOM).

The nation’s largest network of clinical trials is hamstrung by a tangled bureaucracy, inadequate financial support and insufficient innovation, according to the 295-page report, “A National Cancer Clinical Trials System for the 21st

Century: Reinvigorating the NCI Cooperative Group Program.”

Plethora of Problems The stakes could not be higher, in the view of John Mendelsohn, MD, president of the University of Texas M.D. Anderson Cancer Center, Houston, and chair of the 17-member committee responsible for the findings. “If the clinical trials system see IOM REPORT, page 22

POLICY & MANAGEMENT

Comparative Effectiveness Programs Should Involve Community Oncologists

A

s the recently approved health reform legislation makes its way into everyday health care, some doctors will choose to spend their energy fighting to keep things the way they are—known imperfections being preferred over the unknown.

Others will welcome the opportunity to create new paradigms, such as using comparative effectiveness studies to improve patient care and control health care costs.

There is a fear that comparative effectiveness initiatives might compromise doctor–patient relationships and interfere with individualized treatment. But why don’t oncologists embrace the concept that oncology has long held, that innovation will lead to a cure? Instead of arming for a fight over standardization, clinicians should push ahead to discover see INITIATIVES, page 34

Treatment Options for Suboptimal Response to Standard-Dose Gleevec In the Treatment of Chronic-Phase Ph+ Chronic Myelogenous Leukemia See page 14

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CLINICAL ONCOLOGY NEWS • JUNE 2010

Ovarian

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

Gastrointestinal Cancer

David Bronstein, Editorial Director, Hospital Group

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

Gastrointestinal Cancer and Sarcoma

Community Oncology

Ronald M. Bukowski, MD

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

Gynecologic Cancer

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

—Gordon Rustin, MD

Patients taking thalidomide

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Figure 1. Comparison of PFS in biochemically recurrent ovarian cancer.

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Lung, and Head and Neck Cancers

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Figure 2. Comparison of grade 3/4 toxicities.

PFS, progression-free survival

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Bone Metastases

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Solid Tumors

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Oncology Nursing

Policy and Management

Patients taking tamoxifen

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Maurie Markman, MD

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

see PARADIGM, page 4

‘If you have a patient who’s desperate to have some treatment because they know their CA-125 is going up, now oncologists can say, “Rather than start you on toxic chemo, we know tamoxifen actually does something that might delay your need for that chemo.”’

Ephraim Casper, MD

Genitourinary Cancer

desperate to have some treatment because they know their CA-125 is going up, now oncologists can say, ‘Rather than start you on toxic chemo, we know tamoxifen actually does something that might delay your need for that chemo.’”

Both Drs. Rustin and Markman, as

Patients, %

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(GOG) study randomized 139 women with biochemically recurrent cancer to either oral thalidomide 200 mg daily with escalation to a maximum of 400 mg or tamoxifen 20 mg orally twice daily. Treatment continued until disease progression (RECIST 1.0 criteria), adverse effects prohibited additional therapy or one year had passed, whichever came first. Biochemically recurrent cancer was defined as a rising CA-125 exceeding twice the upper limit of normal without evidence of disease. The study was led by Jean Hurteau, MD, a gynecologic oncologist with NorthShore University HealthSystem in Evanston, Ill., and University of Chicago, Pritzker School of Medicine.

Median progression-free survival was 4.5 months in the tamoxifen arm and 3.2 months in the thalidomide arm (Figure 1). Women randomized to thalidomide had an increased risk for disease progression (hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.93-1.85) and death (HR, 1.76; 95% CI, 1.16-2.68). Women taking thalidomide also experienced a greater amount of grade 3/4 toxicity (55% vs. 3%) compared with women in the tamoxifen arm (Figure 2).

This is a first-of-its-kind study in more ways than one, said Dr. Markman.

was to stop people from using cytotoxic chemotherapy when it wasn’t necessary,” Dr. Rustin said. (All the patients in Dr. Rustin’s trial were placed on standard, cytotoxic chemo; there was no hormonal treatment arm to the study.) “This [GOG abstract] actually fits quite nicely with that. If you have a patient who’s

PFS, mo

PARADIGM

“There’s never been a randomized trial of any kind on the effects of any drug on progression and survival in biochemically recurrent ovarian cancer,” he said. “Here we have a randomized trial that demonstrated that tamoxifen had a more favorable effect than thalidomide. Although there was no ‘no treatment’ control, unless one believes that thalidomide caused the worsening of the outcome, this suggests that patients actually benefited from the tamoxifen.

This would be the first time that a randomized trial shows that giving therapy to a patient with rising CA-125 levels has had an effect.”

At the plenary session of last year’s American Society for Clinical Oncology (ASCO) annual meeting, Gordon Rustin, MD, director of medical oncology at Mount Vernon Cancer Center in Middlesex, England, presented results of a large, multicenter trial whose findings, on their face, might seem to contradict the GOG results. In that study, patients with rising CA-125 levels began therapy for recurrence about five months earlier than those whose treatment was delayed until symptomatic recurrence.

But after four years, there was no notable difference in overall survival—suggesting that starting therapy for disease recurrence based on rising CA125 levels alone has no benefit.

According to Dr. Rustin, however, the two studies actually have quite compatible messages. “What I was trying to do

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CLINICAL ONCOLOGY NEWS • JUNE 2010

Lung

BATTLE continued from page 1

of rigor. In BATTLE, molecular features of the tumor entirely drive the treatment selection.

“The basis is to stop looking at the drugs and start looking at the individual tumors. We feel that we may do better by targeting therapy at unique tumor characteristics,” said Edward S. Kim, MD, assistant professor of medicine in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, and the trial’s principal investigator.

First BATTLE Results Presenting preliminary results at the recent annual meeting of the American Association for Cancer Research (AACR), Dr. Kim reported that the data so far validate the strategy and support a major change in the treatment approach of lung cancer and possibly other malignancies. He presented data generated by 255 patients enrolled in the first of a series of planned BATTLE studies.

In this initial trial, lung cancer patients with stage IIIB, stage IV, or advanced, incurable non-small cell lung cancer who had received at least one chemotherapy regimen underwent tissue biopsy in order to characterize tumors by the presence of specific molecular features, such as the presence of epidermal growth factor receptor and K-ras mutations. Although the participating patients were initially randomized to erlotinib (Tarceva, OSI/Genentech), vandetanib (Zactima, AstraZeneca), sorafenib (Nexavar, Bayer Healthcare/Onyx Pharmaceuticals) or erlotinib plus bexarotene (Targretin, Eisai), an adaptive randomization model allowed initial response relationships to funnel subsequently enrolled patients to therapies that did best with given tumor characteristics. The primary end point of the Phase II study was

‘[BATTLE is] a very important study that shows that it is possible to collect tissue and evaluate it for biomarkers in a time frame that is acceptable for directing therapy. It also shows that an adaptive randomization design can reduce patient numbers.’

—Paul Bunn, MD

disease control at eight weeks.

The study revealed that 46% of patients achieved disease control at eight weeks, a promising rate of response compared with historical rates of closer to 30% for heavily pretreated lung cancer patients.

The more exciting result, however, was the correlation between specific markers and likelihood of response with specific targeted therapies. For example, disease control rates in patients with K-ras mutations ranged from 0% in those who received vandetanib to 76% in those who received sorafenib. Disease control rates in those who received erlotinib ranged from 0% for RXR/cyclin D expression to 40% for vascular endothelial growth factor expression.

Patients who achieved disease control at eight weeks, determined by one of several quantitative imaging techniques such as computed tomography, are being maintained on their assigned drug as part of an overall BATTLE program to further explore the concept of individualized therapy. According to the authors, the early results of the study already have established that biopsy-driven treatment based on markers is possible. The authors described the treatment approach in BATTLE as “real-time” management in that treatment choices are made immediately on the basis of the tumor molecular profile.

This approach takes the work of molecular profiling to a new level in the management of patients with lung cancer.

“The traditional way has been a retrospective analysis of tissue samples to stratify response rates by tumor characteristics. The new way is to base therapy on the tissue characteristics of the biopsy taken at diagnosis, and we have

shown that this is possible,” said Roy Herbst, MD, chief of the Section of Thoracic Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

Inevitable Culmination In essence, the BATTLE concept is the logical and perhaps inevitable culmination of more than a decade of advances in which drugs targeted at specific signaling pathways have shown promise in treating cancers that respond poorly or are no longer responding to conventional chemotherapy. According to Deepa Subramaniam, MD, assistant professor, Department of Hematology/Oncology, Georgetown University Lombardi Cancer Center, Washington, D.C., this type of initiative is critical because “we have hit the ceiling with chemotherapy agents” in patients with lung cancer.

She acknowledged that some practicing clinicians may be concerned about obtaining and analyzing the core biopsies needed to base therapy on molecular characteristics, but she reported that her institution is among those initiating clinical trials based prospectively on the presence or absence of these characteristics.

Paul Bunn, MD, director of the University of Colorado Cancer Center, Denver, was the invited discussant of the study at the AACR meeting. He called BATTLE “a very important study that shows that it is possible to collect tissue and evaluate it for biomarkers in a time frame that is acceptable for directing therapy. It also shows that an adaptive randomization design can reduce patient numbers.” Although Dr. Bunn suggested that there were some

Patients receiving vandetanib

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PARADIGM continued from page 3

well as a number of other gynecologic oncologists, already have been offering tamoxifen to their patients with biochemically recurrent ovarian cancer for years, simply because it’s relatively nontoxic and inexpensive. Now, the GOG study appears to provide the kind of randomized, controlled data to support that decision. (It should be noted that only the study abstract was presented

—Gina Shaw

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Figure. Disease control rates of lung cancer patients with K-ras mutations in the BATTLE trial.

‘The new way is to base therapy on the tissue characteristics of the biopsy taken at diagnosis, and we have shown that this is possible.’

—Roy Herbst, MD

weaknesses in this study, including “too many biomarker groups and too many therapies, some of which were not as specific as they could be,” he concluded that “this sets several new standards for conducting clinical trials.”

Based on a general consensus that this study has validated its design and the potential for new avenues in gaining response to therapy by individualizing the targets, it seems likely that this direction of research will be pursued.

Dr. Kim said that although this initial study was conducted in patients with advanced disease and few options, he expects that the same principles eventually also will be used in the first-line treatment of patients with lung cancer.

Ovarian

at the meeting; full results have not yet been released.)

At this year’s annual ASCO meeting, Dr. Rustin plans to present an abstract from a CA-125 doubling trial, also looking at tamoxifen in patients with biochemically recurrent ovarian cancer. “Our results show that it benefits about 40% of patients, based on the rate of rise of CA-125 levels,” he said. At the time Clinical Oncology News went to press, however, the study details were not available.

Patients receiving sorafenib

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CLINICAL ONCOLOGY NEWS • JUNE 2010

Breast

Breast Cancer Guidelines Released Immunohistochemistry (IHC) testing for hormone receptor expression in breast cancers has become standard practice, but as many as one in five tests worldwide currently is inaccurate.

Hoping to improve the accuracy of testing methods to get patients to the appropriate treatments, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have issued a joint guideline with new recommendations for

physicians and laboratories.

The guideline states that estrogen receptor (ER) and progesterone receptor (PR) status should be determined on all invasive breast cancers and breast cancer recurrences, and that those assays be considered positive if at least

1% of the tumor tests positive. IHC testing measures protein amounts of ER and PR in breast cancer cells, helping oncologists identify which patients should be considered for endocrine therapies such as tamoxifen or aromatase inhibitors compared with other types of treatments.

An international panel of experts from both organizations, working with Cancer Care Ontario, reviewed medical literature to develop the guideline, which was published in recent issues of

the Journal of Clinical Oncology (2010 Apr 19 Epub ahead of print, PMID: 20404251) and CAP’s Archives of Pathology & Laboratory Medicine (2010;134:728-734, PMID: 20441503).

The main goal is to improve the accuracy of test results and ensure that all patients receive appropriate care, said Antonio C. Wolff, MD, co-chair of the expert panel and associate professor of oncology at Johns Hopkins Kimmel Cancer Center in Baltimore. Breast cancer is the most common cause of cancer death in women in low- and middle-income countries, he says, and most of those patients have ER- or PRpositive disease.

Overall, about 65% of breast cancers are ER-positive, 15% to 20% are positive for human epidermal growth factor 2 (HER2), and 15% are “triple negative,” meaning they lack receptors for estrogen, progesterone and HER2, Dr. Wolff said. Although endocrine treatments can substantially improve survival in patients with hormone receptor-positive invasive breast cancer, as many as 20% of IHC tests worldwide may be inaccurate. Most issues with testing have occurred because of inadequate handling of tissue specimens prior to arriving in pathology and variations in thresholds for positivity or interpretation criteria.

The literature review showed patients could derive a survival benefit from endocrine therapies even with as little as 1% of cells testing positive for ER and/or PR, Dr. Wolff said, but many laboratories had arbitrary cutoffs. Studies in Europe found that by using a criterion of 10% of tumor cells testing positive for ER and/or PR, up to 17% of test results were false-negative; by using a criteria of between 1% to 9% of tumor cells testing positive for ER and/or PR, an additional 4% to 5% were false-negatives.

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CLINICAL ONCOLOGY NEWS • JUNE 2010

Breast

False-positives were reported in up to 8% of cases in the United States, Dr. Wolff said.

Just changing how tissue samples are handled and subsequently analyzed can increase the number of ER-positive cases from 60% to almost 70%, Dr. Wolff said, adding, “Some of us believe this is a big deal, not only in the U.S. and Europe but around the world.”

The guideline recommendations include the following: • Testing ER and PR status on all newly diagnosed invasive breast cancers (primary site and/or metastatic site), and when appropriate, repeat testing in patients with a known breast cancer diagnosis who present with a local or distant recurrence.

• Establishing uniform testing measures that focus on proven, reliable and reproducible assays and procedures.

• Having testing laboratories validate their assays against existing and clinically validated tests. Results should agree at least 90% of the time with those of the clinically validated assays for positive receptor status and at least 95% for negative receptor status.

• Transporting breast tissue specimens from the operating room to the pathology laboratory as soon as they are available for gross assessment.

The time from tumor removal to initiation of fixation should be kept to one hour or less. Fixation of the sample in neutral buffered formalin must extend for at least six hours and no longer than 72 hours.

• Performing ER and PR testing in a CAP-accredited laboratory or in a laboratory that meets the accreditation requirements spelled out in the guideline. The CAP will require that every accredited lab performing testing participate in a mandatory proficient testing program.

• Considering an ER and PR test performed by an IHC assay as positive if at least 1% of the tumor in the sample tests positive. Oncologists should discuss the pros and cons of endocrine therapy with patients whose tumors contain low levels of ER (1% to 10% weakly positive cells) and make an informed decision.

Carey Anders, MD, assistant professor at the University of North Carolina’s Lineberger Comprehensive Cancer Center in Chapel Hill, said the guideline should help standardize IHC test methods and their results. “If 5% of the tumor expresses ER, that might read as positive at one center and negative at another. Now, the variability should be less and patients should be treated in a more uniform fashion.”

Dr. Anders says the recommendation to repeat tests on patients with local or distant recurrences is an important one.

“Many times, a substantial amount of time has passed between original breast

Just changing how tissue samples are handled and subsequently analyzed can increase the number of ER-positive cases from 60% to almost 70%.

cancer diagnosis and recurrence, thus you need to reconfirm receptor status on the recurrent disease,” she says. “Up to 20% of cases can change (lose or gain) receptor status. It’s important to know if you’re dealing with a different phenotype, although sometimes discrepant results could be due to chance.”

Dr. Wolff says he hopes the guideline

also will improve communication between patients and their cancer specialists. As such, he and his colleagues compiled a patient guide encouraging women to discuss their test results with their doctors, including whether the test result is consistent with the overall pathology assessment of the tumor and whether the testing was done in a manner

consistent with the new guideline.

“A key step to prodding the system is when patients start walking into their doctors’ offices and asking questions,” he says. “Hopefully, this will change behavior to the point where it would be inconceivable not to do these tests in the most accurate way.”

The guideline and other resources are available online at www.asco.org/guidelines/erpr. A corresponding patient guide is available on ASCO’s patient Web site, www.cancer.net, and on CAP’s patient Web site, www.MyBiopsy.org.

— Karen Blum

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CLINICAL ONCOLOGY NEWS • JUNE 2010

Bone

Alarming Pattern Identified for Bone Metastases It is well known that bone metastases can cause severe pain necessitating urgent assessment and management. Less well known, but equally important for health care providers to consider, is that the anatomic site of bone metastases is more strongly related to interference with functional ability than pain severity.

Lower body bone metastasis was found to correlate with substantial interference in the ability to function compared with upper body bone metastasis, even in cancer patients with mild and moderate pain, in a recent study appearing in the Journal of Pain and Symptom Management (2010:39:230-240, PMID: 20152587).

“This is an alarming pattern. This study tells us that it is not only the pain, but the site of the metastases that interferes with the ability to perform such activities as turning in bed, getting in and out of a car and bending over,” explained ng over, lead investigator Jackson kson S.Y. Wu, MD, associate professor at the Tom Baker Cancer Centre of the he University of Calgary in Alberta, Canada. nada.

The main implication on of this finding, according to Dr. Wu, is that patients with symptoms from lower body bone metastases should be fast-tracked for intervention regardless dless of pain level. He noted that patients with severe pain usually are treated with fast-access radiation ation therapy, whereas radiotherapy herapy is delayed for those with h mild and moderate pain.

He also said that health care practitioners should be aware that certain activities could hasten bone damage in this patient population.

“We and our patients prize independence, but certain types of exercise and activities can exacerbate the problems associated with already compromised skeletal structure,” Dr. Wu said. “Physical and occupational therapists can be helpful in educating patients about ways

to avoid repetitive trauma and maximize existing function.”

The study included 258 patients with clinically significant bone metastases requiring rapid-access radiation therapy between July 2002 and November 2006.

The study met one of its primary goals, namely to validate the Pain and Interference subscales of the Brief Pain Inventory (BPI) in this patient population.

“These measurable domains of the BPI had not been previously validated specifically in patients with painful bone metastases,” Dr. Wu said.

of dysfunction is distinguishable even in patients with only mild pain,” he stated.

“This is a clinically meaningful finding that is easy for practitioners to miss.”

Dr. Wu and his co-authors hope that this study will encourage cancer care providers to recognize that dysfunction related to lower body bone metastases is as important as pain severity in recommending earlier radiation therapy palliation. “Many of these patients could be seen and treated earlier to improve their ability to function and quality of life,” he said.

Sleep Interference Sleep interference, known to affect function, was removed from the model used to validate the BPI subscales in this study.

is provost at the Institute for Palliative Medicine in San Diego, Calif.

“Metastases that affect weight-bearing bone interfere with function. Since preserving function is a high priority for patients living with cancer, it makes sense that we should act to prevent deterioration in function, rather than react once it has already deteriorated,” Dr. von Gunten stated. “In Canada and much of the rest of the world, radiation treatment facilities are limited in number. Prioritization of patients for radiation therapy is important, and the results of this study add a new feature to a prioritization scheme.”

Radiation and Other Treatments These results suggest that early radiation should be considered for symptomatic bone metastases of the lower body, said Mellar P. Davis, MD, professor of medicine at the Cleveland Clinic Lerner School of Medicine, Taussig Cancer Institute, Cleveland. Dr. Davis also recommended surgical correction

‘Prioritization of patients for radiation therapy is important, and the results of this study add a new feature to a prioritization scheme.’

—Mellar P. Davis, MD

The second goal of the study was to confirm the a priori hypothesis that lower body bone metastases interfere more with activity level than upper body bone metastases.

“Although the relationship between lower body bone metastases and greater interference of function is intuitive to clinicians, we showed that the level

“We found that sleep disturbance had no clear correlation with function in this study, which included many patients on morphine, so we removed it from the analysis,” Dr. Wu said. “However, sleep disturbance and its relationship to functioning is a worthwhile area of study in this group of patients.”

Prioritizing Patients The results of this new study make sense clinically, and will help prioritize patients for radiation treatment, said Charles F. von Gunten, MD, PhD, who

early in the course of the cancer for highly painful bone metastases that interfere with daily activities. Kyphoplasty should be considered for lumbar lesions to improve functional activities and reduce pain severity. Procedures that relieve continuous pain but destabilize bone—including radiofrequency ablation, cryoablation and ethanol injections into bone metastases—“are likely to have little influence on function and may even worsen pain interference,” he noted.

—Alice Goodman

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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.

IN BRIEF New Legislation

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

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

Bill Aims To Illuminate Health Care Costs

A

bill introduced in the U.S. House of Representatives aims to provide transparency in health care pricing. If passed, the Transparency in All Health Care Pricing Act of 2010 would require health care providers—including hospitals, physicians, nurses, pharmacies, pharmaceutical manufacturers, dentists and insurance entities—to publicly disclose, on a continuous basis, all prices for such health care items, products, services or procedures. Disclosure would be made in an open and conspicuous manner and be available at the point of purchase, in print and on the Internet. The bill aims to cast a spotlight on all wholesale, retail, subsidized, discounted or other such prices that health care providers charge for items, products, services or procedures.

The bill was introduced by Rep. Steve Kagen, MD (D-Wis.), who has experience in the health care field. Before joining Congress, Dr. Kagen founded the Kagen Allergy Clinics in Appleton, Green Bay, Oshkosh and Fond du Lac, and served as an assistant clinical professor of allergyimmunology at the Medical College of Wisconsin, in Milwaukee.

“When was the last time you bought anything without knowing what it cost?

My patients, and my constituents, want to know the price of a pill before they swallow it, and certainly before they buy it,” Dr. Kagen said in a press statement.

“Prices for our prescription drugs, hospital services and health insurance premiums have shot through the roof, primarily because of an opaque, nontransparent medical marketplace. Everywhere I go, people are saying, ‘Just show me the price, so I will know if I can afford it.’

Everyone knows how much they pay for a cup of coffee, and it is time we finally have a chance to see all of the prices an insurance company has accepted as payment in full for their services.”

The bill states that the secretary of Health and Human Services will be allowed to investigate any individuals or businesses that fail to comply with the requirements of the bill and impose penalties as appropriate. The bill, referred to the House Oversight and Government Reform Committee on Feb. 25 was debated on May 6.

—Kate O’Rourke

11

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JUNE 2010

MDS

In a Retrospective Analysis …

Older, Higher-Risk MDS Patients Benefit From Transplant New Orleans—A retrospective analysis has validated the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in elderly patients with myelodysplastic syndromes (MDS).

Although the practice of offering alloHSCT to patients over the age of 65 has become more popular at many centers, data confirming an advantage of alloHSCT over best supportive care (BSC) have been scarce. Although the most recent study did not randomize patients but used a paired analysis of controls, the median overall survival rate at five years among individuals over the age of 60 was almost twice as great in patients who underwent allo-HSCT when compared with those receiving BSC (45% vs. 25%; P=0.008).

“The median overall survival among those who received an allogeneic hematopoietic cell transplant was five years, which is pretty astonishing given the high risk of the population,” said Uwe Platzbecker, MD, Medical Clinic, University Hospital, Dresden, Germany.

He presented the data at the most recent annual meeting of the American Society of Hematology (ASH; abstract 596).

Dr. Platzbecker acknowledged that a randomized study is needed to confirm these findings, but the relative advantage of allo-HSCT in this study was large.

Additionally, allo-HSCT offers at least the possibility of a cure in patients with no such previous option.

In the study, 126 patients over the age of 60 who were treated with allo-HSCT between the years 1995 and 2008 were matched with patients managed with BSC who were enrolled in an MDS registry. All of those in the BSC group had to be receiving BSC at the time that their match was receiving allo-HSCT. In the allo-HSCT group, cytogenetics permitted International Prognostic System Scoring (IPSS) in 107 patients.

This permitted pairings by IPSS category along with French-American-British

(FAB) category, age, gender and marrow blast count.

The average age of the study participants was 65, but patients as old as 77 were included. Prior to allo-HSCT, most of the patients had progressed to advanced disease. Of the 126 patients, 45 had refractory anemia with excess blasts (RAEB), 10 had RAEB in trans-

who received allo-HSCT was 10%. Yet, the data suggest that a substantial proportion of older patients with MDS can benefit from allo-HSCT and that the current standard of BSC for all patients over the age of 60 should be reconsidered.

“The studies evaluating HSCT have been performed in patients younger than age 60 with the belief that older

‘The median overall survival among those who received an allogeneic hematopoietic cell transplant was five years, which is pretty astonishing given the high risk of the population.’

—Uwe Platzbecker, MD

formation, 10 had chronic myelomonocytic leukemia, and 61 had acute myeloid leukemia. The median blast count was 12% prior to allo-HSCT. The majority of patients had received some form of chemotherapy prior to allo-HSCT, but 40% had received BSC only. A variety of conditioning regimens were used to prepare patients for allo-HSCT, including reduced-intensity regimens, but 38% received intensive conditioning. Approximately 50% of patients were judged to have good-risk cytogenetics prior to alloHSCT, whereas 36% were considered to have poor risk. Prior to transplant, 50% of patients had already progressed.

Although the survival advantage of allo-HSCT over BSC at five years was impressive, Dr. Platzbecker acknowledged that the advantage was concentrated in patients with better cytogenetics and fewer comorbidities. There also was a trend for better survival in patients with less-intensive conditioning. The mortality at 100 days in those

patients will not tolerate transplant due to comorbidities,” Dr. Platzbecker said.

However, the average age of patients first diagnosed with MDS is closer to age 70, and these patients often are denied the potential for a curative intervention.

Although Dr. Platzbecker reported that there has been a steep rise in the number of centers offering allo-HSCT to patients over the age of 60 over the last five to 10 years, this study provides data to suggest that the 60-year cutoff may be arbitrary.

“As a retrospective study, we cannot rule out the possibility of a selection bias, but these data suggest an important advantage for survival over five years,” Dr. Platzbecker reported. He further indicated that newer conditioning regimens and other aspects of care surrounding allo-HSCT may be making this approach better tolerated and more suitable for older patients, particularly those who have good performance status. He indicated that prospective

Allogeneic hematopoietic stem cell transplant Best supportive care

50 45

40 P=0.008

Patients, %

12

30 25

20

10

0

Figure. Comparison of median overall survival at five years.

studies would be useful not only for confirming the advantage of allo-HSCT observed in this retrospective analysis, but in further defining appropriate selection criteria for allo-HSCT in MDS patients of advanced age.

According to Harry Erba, MD, PhD, associate professor of internal medicine, University of Michigan, Ann Arbor, a retrospective analysis cannot answer the question of whether allo-HSCT is better than BSC. “Patients who receive BSC are likely very different from patients selected for allo-HSCT,” he said. “In fact, the retrospective analysis of Dr. Platzbecker did not indicate that patients were matched based on performance status, comorbid illnesses and socioeconomic status, all of which can affect the survival of older patients with high-grade hematologic malignancies.” See article “Retrospective Study Cannot Determine Benefit of HSCT.” —Ted Bosworth

Retrospective Study Cannot Determine Benefit of HSCT Commentary by Harry Erba, MD, PhD Associate Professor of Internal Medicine, University of Michigan, Ann Arbor, Michigan

Over the past two decades, clinicians have witnessed important advances in the practice of allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Supportive care of patients receiving allo-HSCT has improved with the use of azole antifungal antibiotics,

instead of the more toxic amphotericin preparations, and the use of antiviral prophylaxis to prevent recurrence

of cytomegalovirus. The pool of donors has increased over time as well. Furthermore, donor selection has improved with the use of molecular human leukocyte antigen typing using DNA-based technologies in place of serologic methods.

Many different reduced-intensity conditioning regimens have been developed, leading to a lower incidence of severe mucositis and less early mortality.

For these reasons, it is clear that the

prior practice of restricting allo-HSCT to younger patients can no longer be accepted. It is possible for patients in their seventh and even eighth decade of life to undergo allo-HSCT with acceptable morbidity and mortality. AlloHSCT can decrease the risk for relapse and offers the possibility of a cure for patients with hematologic malignancies including myelodysplastic syndromes (MDS) and acute myeloid leukemia.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JUNE 2010

MDS

Despite these clinical advances, a survival benefit has not been shown for alloHSCT over alternative therapies. At the most recent American Society of Hematology (ASH; abstract 596) meeting, a study led by Uwe Platzbecker, MD, Medical Clinic, University Hospital, Dresden, Germany, discussed a retrospective analysis that concluded that allo-HSCT offered a survival advantage over best supportive care (BSC). In my opinion, however, retrospective analysis with case controls cannot answer this important question. Patients who receive BSC likely are very different from patients selected for allo-HSCT. In fact, Dr. Platzbecker’s retrospective analysis did not indicate that patients were matched based on performance status, comorbid illnesses and socioeconomic status, all of which can affect the survival of older patients with high-grade hematologic malignancies. Several recent prospectively validated clinical assessments of frailty in older patients may help clinicians in the future appropriately select patients for therapy.

In the study presented at ASH, 60% of the 126 transplant patients underwent

Patients who receive BSC likely are very different from patients selected for allo-HSCT. —Harry Erba, MD, PhD

chemotherapy prior to allo-HSCT. This factor is important for several reasons.

The implication is that these transplant patients had chemotherapy-sensitive disease and likely responded to the pretransplant chemotherapy. These also were patients who were shown to be able to tolerate chemotherapy as well as comply with follow-up care. Finally, the contribution of the pretransplant chemotherapy to the survival benefit is difficult to discern.

A final factor to consider when analyzing the implications of the study

for clinical practice is that the control group received BSC alone. Patients with advanced MDS can now be offered treatment with the DNA methyltransferase inhibitors azacitidine (Vidaza, Celgene) and decitabine (Dacogen, Supergen, Inc.).

These agents have been shown to induce both complete remissions and hematologic improvement. In fact, azacitidine has been shown to improve the overall survival (OS) of older patients with intermediate-2– and high-risk MDS compared with patients receiving BSC. The improvement in OS was identified regardless of patient age, initial marrow blast count, World Health Organization (WHO) classification, International Prognostic System Scoring (IPSS) and cytogenetic risk group. Therefore, a more appropriate group for comparison with recipients of allo-HSCT would be high-grade/highrisk MDS patients treated with the DNA methyltransferase inhibitors.

The authors state that allo-HSCT offers the prospect of cure, implying that there is a plateau in the disease-free survival curve by Kaplan-Meier analysis.

However, the report does not indicate the chronic morbidities associated with

allo-HSCT. Older patients may have difficulty complying with the intensive follow-up care that is required in the post– allo-HSCT period.

In summary, allo-HSCT is a potentially curative option for patients with highrisk and high-grade MDS. Given the advances in transplant science, the procedure can be offered to older patients as one of several options for treatment. The choice of therapy will depend on characteristics of the patient’s disease state (WHO class, IPSS, cytopenias, cytogenetic analysis), patient physical status (frailty index, comorbid illness and performance status), patient goals and desires and donor availability. However, only a well-designed, randomized trial of allo-HSCT versus alternative therapeutic intervention (e.g., DNA methyltransferase inhibitors) will be able to evaluate survival benefit of either of these options. These randomized trials could examine questions of sequence as well, for example, allo-HSCT at diagnosis followed by maintenance with a DNA methyltransferase inhibitor versus DNA methyltransferase inhibitor followed by allo-HSCT at progression.

PRN

Around the Water Cooler People on the Move Al B. Benson III, MD, has become the president of the Association of Community Cancer Centers (ACCC). Dr. Benson is a professor of medicine in the Division of Hemat o l o g y/ O n c o l o gy at Northwestern University Feinberg School of Medicine in Chicago. He also is associate director for clinical investigations, Robert H. Lurie Comprehensive Cancer Center, at Northwestern.

Dr. Benson has served on ACCC’s board of directors since 2003.

Dr. Benson was an assistant professor of medicine at the University of Illinois and co-medical director for the National Public Health Service in Champaign, Ill. He then served as a clinical oncology fellow at the University of Wisconsin Clinical Cancer Center, Madison, prior to joining the faculty at Northwestern. Dr. Benson’s research is primarily in the areas of gastrointestinal cancer clinical trials, biologic therapies and cancer guideline development. He is the chair of the Eastern Cooperative Oncology Group Gastrointestinal and Data Monitoring Committees.

Neal J. Meropol, MD, has been appointed chief of the Division of Hematology and Oncology in the Department

of Medicine at University Hospitals (UH) Case Medical Center and Case Western Reserve University School of Medicine, Cleveland. Dr. Meropol, who also is associate director for clinical research at the Case Comprehensive Cancer Center, is an internationally known colon cancer clinical researcher whose work spans the spectrum from cancer prevention to treatment.

Dr. Meropol joined Case Western Reserve University and UH Case Medical Center as section chief of medical oncology in August 2009 from Fox Chase Cancer Center in Philadelphia. He has an international reputation for his contributions in gastrointestinal malignancies, having conducted important studies of new treatments that have become standard of care, and his research to improve methods for helping patients communicate with their doctors and make decisions about their care. Additionally, Dr. Meropol holds a variety of national positions that impact cancer care and health care policy, including chair-elect of the American Society of Clinical Oncology (ASCO) Cancer Research Committee, and chair of a new ASCO task force on comparative

effectiveness research.

Radiation oncologist Elizabeth Ceilley, MD, has been named medical director of Boulder Cancer Care, in Colorado.

Dr. Ceilley earned a medical degree from the University of Iowa Medical School, Iowa City, and completed her residency in radiation oncology at Massachusetts General Hospital at Harvard Medical School, Boston.

Oncologist Pleads Guilty To Fraud

A

ccording to a story in the Mercury News, an oncologist in Orange County, Calif., has pleaded guilty to defrauding Medicare, Blue Shield and Blue Cross of up to $1 million by submitting bills for expensive cancer drugs that were never given to patients. Glen R. Justice, MD, recently entered the pleas to five federal counts of fraud.

The 65-year-old Corona del Mar oncologist remains free until sentencing in February 2011, when he could be sentenced to 50 years in prison. Dr. Justice is the ex-director of the cancer center at Orange Coast Memorial Medical Center and the former chief of Pacific Coast Hematology-Oncology Medical Group, both in Fountain Valley, Calif.

Electronic Medical Records Lead to Faulty Lawsuit

I

n an example of unintended consequences from the use of electronic medical records, an attending anesthesiologist at a Florida medical school was sued for medical malpractice even though

he was not involved in a patient’s surgery.

Due to human error, the clinician’s name was entered into the hospital’s anesthesia information management system (AIMS).

He was deposed and spent $10,000 in legal fees before eventually being dropped from the suit. He still must report the suit when applying for future medical licenses and hospital privileges.

“Despite the enthusiastic push to adopt electronic medical records, the importance of software design and attention to the user interface must be paramount,” said Michael Vigoda, MD, MBA, director of the Center for Perioperative Informatics in the Department of Anesthesiology at the University of Miami School of Medicine, in Florida, where the episode occurred.

In the University of Miami’s hospital AIMS, anesthesia care team members are selected through a drop-down menu system and not an electronic signature (e-signature). In this case, a nurse anesthetist erroneously selected the attending anesthesiologist and the actual supervising anesthesiologist as being involved in the surgery. Both were named as defendants in a legal action, even though there was no e-signature in the record and no evidence that the attending anesthesiologist participated in the patient’s care.

“Poor system design contributed to faulty identification of a supervising anesthesiologist with resultant costs,” Dr. Vigoda said. “Rather than requiring manual specification of care team members, members could be derived from e-signature entries.”

13

Supported and sponsored by Novartis Oncology

Treatment Options for Suboptimal Response to Standard-Dose Gleevec in the Treatment of Chronic-Phase Ph+ Chronic Myelogenous Leukemia Stuart L. Goldberg, MD Chief, Division of Leukemia John Theurer Cancer Center Hackensack University Medical Center Hackensack, New Jersey Associate Clinical Professor of Medicine University of Medicine and Dentistry of New Jersey Newark, New Jersey

muscle cramps (49%) were the most common adverse events (AEs) among the study participants. Serious (grade 3 and 4) AEs commonly reported at 60 months were neutropenia (17%), thrombocytopenia (9%), and elevated liver enzymes (5%). Discontinuation due to an AE occurred in 4% of patients receiving imatinib and 6% of patients in the IFN alfa plus cytarabine treatment arm.8,9 Additional serious AEs associated with imatinib treatment include: • Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain with drug interruption and diuretics.

• Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction or dose interruption and in rare cases discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter.

• Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Patients with cardiac disease or risk factors for cardiac failure should be monitored and treated accordingly.

• Severe hepatotoxicity 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.

See Table 2 for additional serious AE information and the prescribing information for a complete description of the safety information.8

Table 1. Overview of Current Recommendations For the Treatment of CMLa Months of Treatment

Response

Treatment Recommendation

3

HR

Continue imatinib 400 mg/d

No HRb

Nilotinib, dasatinib, or clinical trials

CCyR, PCyR

Continue imatinib 400 mg/d

6

(Ph <35%)

Introduction The management of chronic myelogenous leukemia (CML) has changed significantly in the past decade as a result of an improved understanding of the molecular pathogenesis of the disease. CML is a myeloproliferative disease characterized by the Philadelphia (Ph) chromosome, which arises from the exchange of genetic material between chromosomes 9 and 22, and the related oncogene or fusion product bcr-abl, a cytoplasmic 210 kDa protein considered essential for the growth of leukemic cells.1-3 It has been noted that bcr-abl may cause changes in the cell surface adhesion proteins as well as genetic changes throughout the cell involving numerous signaling pathways.2 Alterations in expression of intracellular signaling molecules such as γ catenin/plakoglobin and phospholipase Cγ isoform and Cδ isoform are noted in the presence of bcr-abl. The upregulation of DNA binding inhibitors also may affect transcription.2 Downstream signaling molecules and pathways may include phosphoinositide 3-kinase, and p38 mitogen-activated protein kinase are triggered by bcr-abl and may act together to promote malignant transformation.4,5 It has been demonstrated that the STAT5, Akt, and Ras signaling pathways which were once thought to contribute to the oncogenic activity of bcr-abl do not play a significant role in the proliferation of Ph+ CML cells.6

Treatment of Ph+ CML The National Comprehensive Cancer Network (NCCN) has published guidelines for the treatment and monitoring of patients with Ph+ and/or bcr-abl-positive CML (Table 1).7 Standard-dose imatinib (400 mg/d; Gleevec, Novartis) is recommended by the NCCN as first-line treatment for patients newly diagnosed with Ph+ CML.7 As a tyrosine kinase inhibitor (TKI), imatinib binds to the inactive conformation of the bcr-abl fusion protein, 14

CLINICAL ONCOLOGY NEWS • JUNE 2010

Minor CyR

12

18

(Ph 35%-90%)

Continue imatinib 400 mg/d or escalate to 800 mgc as tolerated

No CyRb

Nilotinib, dasatinib, or clinical trials

CCyR (Ph 0%)

Continue imatinib 400 mg/d

PCyR (Ph 1%-34%)

Continue imatinib 400 mg/d or escalate to 800 mgc as tolerated

Cytogenetic relapsed

Nilotinib, dasatinib, or increase the dose of imatinib to a maximum of 800 mgc as tolerated, or clinical trials

Minor or no CyRb

Nilotinib, dasatinib, or clinical trials

CCyR

Continue imatinib 400 mg/d

PCyR (Ph 1%-34%) or cytogenetic relapsed

Nilotinib, dasatinib, or increase the dose of imatinib to a maximum of 800 mgc as tolerated, or clinical trials

Minor or no CyRb

Nilotinib, dasatinib, or clinical trials

CCyR, complete cytogenetic response; CyR, cytogenetic response; HR, hematologic response; HSCT, hematopoietic stem cell transplant; PCyR, partial cytogenetic response; Ph, Philadelphia chromosome; NCCN, National Comprehensive Cancer Network a Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology™ Chronic Myelogenous Leukemia V.2.2010. © National Comprehensive Cancer Network, Inc 2010. All rights reserved. Accessed March 22, 2010. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. b Mutational analysis should be considered and patient compliance with imatinib therapy should be evaluated. Evaluation of the patient for HSCT is recommended (reference 7).

Identifying the Suboptimal Patient

c In Ph+ CML, a dose increase from 400 to 600 mg in adult patients with chronic-phase disease, or from 600 to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction. Please refer to the complete prescribing information (reference 8). d

Mutational analysis should be considered. Evaluation of the patient for HSCT is recommended.

blocking the binding of adenosine triphosphate, inhibiting catalytic activity of the oncogenetic tyrosine kinase.8-10 Multiple studies have demonstrated the efficacy of imatinib in the treatment of Ph+ CML.8,9 For instance, the IRIS (International Randomized Study of Interferon and STI-571) trial, an open-label, multicenter, international, randomized, Phase III study, compared patients treated with standarddose imatinib (n=553) with patients treated with combination therapy of interferon (IFN) alfa plus low-dose cytarabine (5 million units/m2 of body surface area and 20 mg/

m2 per month for 10 cycles, respectively; n=553).9 The primary end point of the study was progression-free survival (PFS). Crossover to the alternate treatment arm was permitted and occurred most often in patients receiving the IFN alfa plus cytarabine therapy (359 vs 14 in the imatinib treatment arm). Patients in the imatinib group had an estimated overall survival (OS) of 86%, with a PFS of 81% at 84 months in the intent-totreat population.

IMPORTANT SAFETY INFORMATION Edema

(60%),

nausea

(50%),

and

Not all patients respond to treatment.

In 2009, the European LeukemiaNet (ELN) updated its guidelines for classifying the responses of patients with chronic-phase Ph+ CML to standard-dose imatinib (Table 3).11 An optimal response, based on time-based guidelines, indicates that it is unlikely that altering treatment will increase a near 100% projected survival rate. Failure means that alternative treatment should be considered, as continuing imatinib treatment at the current dose will not likely result in a favorable response. A suboptimal response indicates that the patient still may benefit significantly from continuing imatinib therapy, but that the long-term outcome of treatment may not be

Supported and sponsored by Novartis Oncology

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Patient (%)

Fluid retention and edema

1.3-6

Hematologic toxicity

Variesa

Severe congestive heart failure/left ventricular dysfunction

0.7

Hepatotoxicity

5

Hemorrhage

1.8

Gastrointestinal disorders

Variesa

Hypereosinophilic cardiac toxicity

Variesa

Dermatologic toxicities

Variesa

Hyperthyroidism

Variesa

CML, chronic myelogenous leukemia a

See Tables 2-5 in the Brief Summary that follows.

See the prescribing information for a complete description of the safety information.

favorable. According to the ELN criteria, at 3 months no cytogenetic response (noCyR with >95% Ph+ metaphases) is suboptimal. At 6 months, a suboptimal response is less than partial CyR (PCyR; >35% Ph+ metaphases).

When classifying patient response, it is important to note the newly defined warning criteria that indicate disease characteristics that warrant increased monitoring.11 Recommended treatment goals for evaluation at 12 months include achieving a complete cytogenetic response (CCyR with no Ph+ metaphases in a 20-cell bone marrow karyotype examination). Molecular monitoring using a quantitative polymerase chain reaction helps define the suboptimal response at 18 months, with a goal being achieving major molecular response (by ELNs definition MMR; ratio of BCR-ABL to ABL [or other housekeeping genes] ≤0.1% on the international scale). At any time, the acquisition of additional chromosomal abnormalities, loss of a previously achieved MMR, or development of low-level insensitivity mutations also would constitute a suboptimal response worthy of consideration of treatment optimization.8,11 In the IRIS trial conducted by Drucker and colleagues using the 2006 ELN guidelines, 31% of patients did not achieve a CCyR by 12 months, although with continued imatinib therapy including dose optimization, additional late complete responses were achieved as described below. Additionally, approximately 10% of patients who had achieved a cytogenetic remission subsequently experienced relapse. As per the ELN guidelines (Table 3), failure to achieve CCyR

Treatment of Patients With Suboptimal Response Limited data are available to guide the management of patients achieving only a suboptimal response, as most studies, including the major trials on second-generation TKIs, have focused on patients meeting the 2006 ELN failure criteria.12 The concept of dose escalation as an effective treatment strategy among CML patients with a suboptimal response is supported by data from the IRIS trial. This trial allowed for a stepwise dose escalation when certain response criteria were not met, including failure to achieve CHR by 3 months, failure to achieve any CyR by 6 months or a major CyR at 12 months, or loss of response at any time.8,9 Nonetheless, the NCCN recommends dose escalation as an option in patients with suboptimal response to standard-dose imatinib therapy (Table 1).7,8 Kantarjian and colleagues recently conducted a retrospective analysis of the IRIS trial to evaluate the safety and efficacy of dose escalation. Of the 553 patients with Ph+ CML who were initially randomized to receive imatinib, 106 (19%) had dose escalation. Of these patients, 52% achieved additional response as per IRIS protocol. Among all 106 doseescalated patients, the rates of PFS and OS were 89% and 84% at 3 years following dose increase, respectively. Following dose escalation, there was an increased rate of grade 3 and 4 AEs (excluding superficial edema). The most common grade 3 and 4 AEs observed in patients receiving 400 mg imatinib as well as those who were doseescalated were thrombocytopenia (8.2% and 10.4%, respectively), anemia (3.1% and 7.5%, respectively), and abdominal pain (3.1% and 4.5%, respectively).13 In a 2009 study published in Blood, Jabbour and colleagues observed a cohort of patients identified from 626 patients who were treated with standarddose imatinib over a 7-year period either as initial therapy or following failure of IFN therapy. Of the original 626, 84 consecutive patients were identified who met the 2006 ELN criteria for failure. These patients underwent dose escalation of imatinib and were followed for up to 89 months (median 61 months). Forty percent attained CCyR within 12 months of dose escalation, including 52% of patients with cytogenetic failure and 5% of those with hematologic failure. For the entire cohort, the estimated 3-year event-free survival (EFS) and OS rates were 47% and 76%, respectively. Among those dose-escalated for cytogenetic (but not hematologic) failure, the 3-year EFS and OS rates were 58% and 83%, respectively.13 These studies highlight the possible benefits of dose escalation among patients classified as suboptimal

Table 3. 2009 ELN Definitions of Response During Imatinib Therapy Response Months of Treatment Optimal

Suboptimal

Failure

Warnings

Baseline

NA

NA

NA

High risk; CCA/ Ph+

3

CHR and at least mCyR

noCyR

Less than CHR

NA

6

At least PCyR

Less than PCyR

noCyR

NA

12

CCyR

PCyR

Less than PCyR

Less than MMR

18

MMR

Less than MMR

Less than CCyR

NA

Anytime

Stable or improving MMR

Loss of MMR; mutations

Loss of CHR; loss of CCyR; CCA/Ph+

Increase in transcript levels; CCA/Ph-

CCA, clonal chromosome abnormalities; CHR, complete hematologic response (WBC <10 × 109/L; Basophils <5%); No myelocytes, promyelocytes, myeloblasts in differential; platelet count <450 × 109/L; spleen nonpalpable); CCyR, complete cytogenetic response (no Ph+ metaphases); ELN, European LeukemiaNet; mCyR, minor cytogenetic response (Ph+ ≤65%); NA, not applicable; noCyR, no cytogenetic response (Ph+ >95%) MMR, major molecular response (ratio ≤ 0.1% BCR-ABL to ABL transcripts); PCyR, partial cytogenetic response (1%-35% Ph+); Ph, Philadelphia chromosome Reprinted with permission © 2009 American Society of Clinical Oncology. All rights reserved. Baccarani M, et al. J Clin Oncol. 27. (35), 2009:6041-6051.

responders or failure upon treatment with standard-dose imatinib.13,14 The ELN definitions of imatinib failure and suboptimal response have proven useful in identifying patients in whom outcomes are less than desired with standard-dose imatinib. As with any treatment, there are risks associated with the use of imatinib. Thus, the clinician must carefully consider risk–benefit ratio throughout the course of treatment. The most common AEs associated with imatinib are fluid retention including superficial edema, nausea, and muscle cramps. Serious grade 3 and 4 AEs include musculoskeletal pain, diarrhea, and rash.8 Patients who continue to show unsatisfactory response to imatinib following dose escalation may consider alternate treatment options. For instance, 2 potent, secondgeneration TKIs have been approved for the treatment of chronic-phase Ph+ CML in patients who are classified as imatinib-resistant.11 However, neither agent has been tested in patients meeting suboptimal, rather than failure, criteria and thus neither agent is currently recommended by the NCCN nor currently licensed for the suboptimal patient.

Additional trials are required with secondgeneration TKIs in this response category before their use can be advocated. Until these studies are completed, dose escalation represents the major treatment option for the suboptimal-responding patient.

References

Goldman JM, Melo JV. BCR-ABL tyrosine kinase activity regulates the expression of multiple genes implicated in the pathogenesis of chronic myeloid leukemia. Cancer Res. 2000;60(7):2049-2055.

4. Skorski T, Kanakaraj P, Nieborowska-Skorska M, et al. Phosphotidylinositol-3 kinase activity is regulated by BCR/ABL and is required for growth of Philadelphia chromosome-positive cells. Blood.

1995;86(2):726-736.

5. Sànchez-Arèvalo Lobo VJ, Aceves Luquero CI, Alvarez-Vallina L, et al. Modulation of p38 (mitogen-activated protein kinase) pathway for Bcr/Abl: implications in the cellular response to Ara-C. Biochem J. 2005;287(Pt 1):231-238.

6. Hoover RR, Gerlach MJ, Koh EY, Daley GQ. Cooperative and redundant effects of STAT5 and Ras signaling in BCR/ABL transformed hematopoietic cells. Oncogene. 2001;20(41):5826-5835.

7.

National Comprehensive Cancer Network Practice Guidelines in Oncology: Chronic Myelogenous Leukemia V.2.2010™. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed March 22, 2010.

8. Gleevec [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2009.

9. Drucker BJ, Guilhot F, O’Brien SG, et al. Fiveyear follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408-2417.

10. Goldberg SL, Masood A. Identifying and treating imatinib failure in chronic myelogenous leukemia: a practical review of treatment guidelines and available agents. Community Oncology.

2009;6:113-125.

11. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(25):6041-6051.

12. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myelogenous leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108(6):1809-1820.

1. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining.

Nature. 1973;243(5405):290-293.

13. Kantarjian HM, Larson RA, Guilhot F, et al. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer.

2009;115(5):551-560.

2. Ray S, Lu Y, Kaufmann SH, et al. Genomic mechanisms of p210BCR-ABL signaling. J Biol Chem.

2004;270(34):35604-35615.

14. Jabbour E, Kantarjian HM, Jones D, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenic failure on standard-dose imatinib therapy. Blood. 2009;113(10):2154-2160.

3. Denninger MWN, Vieira S, Mendiola R, Schultheis B,

CLINICAL ONCOLOGY NEWS • JUNE 2010

15

GLI-300071

Adverse Event

at 12 months constitutes a suboptimal response.11.12 Because of the implications for treatment outcomes, physicians must be able to recognize patient responses and alter therapy appropriately.9,10

BB0958

Table 2. Severe Adverse Events Associated With the Use of Imatinib in the Treatment of Ph+ CML8

GLEEVEC® (imatinib mesylate) tablets are indicated for the treatment of: • Newly diagnosed adult patients with Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in the chronic phase.

• Patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in the chronic phase (CP) after failure of interferonalpha therapy.

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 hepatotoxicity, other nonhematologic adverse reactions, or hematologic adverse reactions.

• In Ph+ CML trials*, severe (NCI Grades 3/4) lab abnormalities—including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (approx 5%)—and severe adverse experiences (NCI Grades 3/4), including hemorrhage (1.8%-19%), fluid retention (eg, pleural effusion, pulmonary edema, and ascites) (2.5-11%) and superficial edema (1.5%-6%), and musculoskeletal pain (2%-9%) were reported among patients receiving GLEEVEC. Severe fluid retention appears to be dose-related, was more common in the advanced phase studies (where the dosage was 600 mg/day), and is more common in the elderly.

• Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other co-morbidities 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.

• In the newly diagnosed CML trial, 2% of patients had (NCI Grades 3/4) hemorrhage.

• There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation.

• Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.

• Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.

• Consider potential toxicities—specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.

• Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking GLEEVEC tablets and to avoid breast-feeding while taking GLEEVEC tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use adequate contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus.

• GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of GLEEVEC should increase by at least 50%, and clinical response should be carefully monitored, in patients receiving GLEEVEC with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with GLEEVEC include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions).

• For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron.

Common Side Effects of GLEEVEC Tablets • The majority of adult Ph+ CML patients who received GLEEVEC in clinical studies experienced adverse reactions at some time, but most were mild to moderate in severity. The most frequently reported adverse reactions (all Grades) were superficial edema (60%-74%), nausea (50%-73%), diarrhea (43%-57%), musculoskeletal pain (38%-49%), rash and related terms (36%-47%), muscle cramps (28%-62%), and vomiting (23%-58%).* • Supportive care may help management of some mild-tomoderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary.

• GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation. GLEEVEC tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.

• Patients should be informed to take GLEEVEC exactly as prescribed, not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose. * Numbers indicate the range of percentages in 4 studies among adult patients, with newly diagnosed Ph+ CML, patients in blast crisis, accelerated phase, and in the chronic phase after failure of interferon-alpha therapy.

GLEEVEC (imatinib mesylate) tablets for oral use Initial U.S. Approval: 2001 BRIEF SUMMARY: The following information refers to adult patients newly diagnosed with Ph+ CML in chronic phase, unless otherwise noted. Experience with other indications may differ.

Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase.

1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

1.3 Pediatric Patients with Ph+ CML in Chronic Phase Pediatric patients with Ph+ CML in chronic phase who are newly diagnosed or whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy. There are no controlled trials in pediatric patients demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

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)].

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. Non-neoplastic 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.

6.1 Chronic Myeloid Leukemia The majority of Gleevec-treated patients experienced adverse reactions at some time. Most reactions were of mild-to-moderate grade, but drug was discontinued for drug-related adverse reactions in 2.4% of newly diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated phase and 5% in blast crisis.

The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 for newly diagnosed CML, Table 3 for other CML patients).

Edema was most frequently periorbital or in lower limbs and 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]. The frequency of severe superficial edema was 1.5%-6%.

A variety of adverse reactions represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting Gleevec treatment and using diuretics or other appropriate supportive care measures. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the Gleevec treated patients are shown in Tables 2 and 3.

Table 2: Adverse Reactions Reported in Newly Diagnosed CML Clinical Trial (≥10% of Gleevec Treated Patients)(1) All Grades Preferred Term

CTC Grades 3/4

Gleevec N=551 (%)

IFN+Ara-C N=533 (%)

61.7 59.9

11.1 9.6

2.5 1.5

0.9 0.4

6.9 49.5 49.2 47.0 45.4 40.1 38.8 37.0 31.4 36.5 30.5 28.9 1.6 0.2 24.1 22.5 18.9 20.0 18.1

1.9 61.5 11.8 44.8 43.3 26.1 67.0 43.3 38.1 25.9 8.8 21.2 1.1 0.4 38.8 27.8 8.3 23.1 11.4

1.3 1.3 2.2 5.4 3.3 2.9 1.8 0.5 2.5 4.2 0 1.8 0.5 0 1.5 2.0 0 0.2 0.2

0.6 5.1 0.2 8.6 3.2 2.4 25.1 3.8 7.7 3.9 0.4 1.7 0.2 0.4 8.3 3.4 0.8 0.6 0

21.2 19.4 17.8 15.6 14.7 14.9 13.8 11.3 11.4 11.4

8.4 24.4 42.6 2.6 18.6 35.8 6.2 15.6 14.4 6.0

0.2 0.9 0.9 2.0 0 0.5 0.2 1.6 0.7 0.2

0.4 3.8 3.0 0.4 2.3 13.1 0.2 3.4 0.2 0.2

Fluid Retention – Superficial Edema – Other Fluid Retention Reactions(2) Nausea Muscle Cramps Musculoskeletal Pain Diarrhea Rash and Related Terms Fatigue Headache Joint Pain Abdominal Pain Nasopharyngitis Hemorrhage – GI Hemorrhage – CNS Hemorrhage Myalgia Vomiting Dyspepsia Cough Pharyngolaryngeal Pain Upper Respiratory Tract Infection Dizziness Pyrexia Weight Increased Insomnia Depression Influenza Bone Pain Constipation Sinusitis

Gleevec N=551 (%)

IFN+Ara-C N=533 (%)

adverse reactions occurring in ≥10% of Gleevec treated patients are listed regardless of suspected relationship to treatment.

(2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

(1) All

Table 3: Adverse Reactions Reported in Other CML Clinical Trials (≥10% of All Patients in any Trial)(1) Myeloid Blast Crisis (n=260) % Preferred Term Fluid Retention – Superficial Edema – Other Fluid Retention Reactions(2) Nausea Muscle Cramps Vomiting Diarrhea Hemorrhage – CNS Hemorrhage – GI Hemorrhage Musculoskeletal Pain Fatigue Skin Rash Pyrexia

Accelerated Phase (n=235) %

Chronic Phase, IFN Failure (n=532) %

All Grades

Grade 3/4

All Grades

Grade 3/4

All Grades

Grade 3/4

72 66

11 6

76 74

6 3

69 67

4 2

22 71 28 54 43 53 9 8 42 30 36 41

6 5 1 4 4 19 7 4 9 4 5 7

15 73 47 58 57 49 3 6 49 46 47 41

4 5 0.4 3 5 11 3 5 9 4 5 8

7 63 62 36 48 30 2 2 38 48 47 21

2 3 2 2 3 2 1 0.4 2 1 3 2 (continued)

Table 3: Adverse Reactions Reported in Other CML Clinical Trials (≥10% of All Patients in any Trial)(1) Myeloid Blast Crisis (n=260) % Preferred Term

All Grades

Arthralgia Headache Abdominal Pain Weight Increased Cough Dyspepsia Myalgia Nasopharyngitis Asthenia Dyspnea Upper Respiratory Tract Infection Anorexia Night Sweats Constipation Dizziness Pharyngitis Insomnia Pruritus Hypokalemia Pneumonia Anxiety Liver Toxicity Rigors Chest Pain Influenza Sinusitis (1) (2)

Grade 3/4

Accelerated Phase (n=235) %

Chronic Phase, IFN Failure (n=532) %

All Grades

Grade 3/4

All Grades

25 27 30 5 14 12 9 10 18 15

5 5 6 1 0.8 0 0 0 5 4

34 32 33 17 27 22 24 17 21 21

6 2 4 5 0.9 0 2 0 5 7

40 36 32 32 20 27 27 22 15 12

Grade 3/4 1 0.6 1 7 0 0 0.2 0.2 0.2 0.9

3 14 13 16 12 10 10 8 13 13 8 10 10 7 0.8 4

0 2 0.8 2 0.4 0 0 1 4 7 0.8 5 0 2 0.4 0.4

12 17 17 16 13 12 14 14 9 10 12 12 12 10 6 11

0.4 2 1 0.9 0 0 0 0.9 2 7 0 6 0.4 0.4 0 0.4

19 7 14 9 16 15 14 14 6 4 8 6 10 11 11 9

0 0 0.2 0.4 0.2 0 0.2 0.8 0.8 1 0.4 3 0 0.8 0.2 0.4

All adverse reactions occurring in ≥10% of patients are listed regardless of suspected relationship to treatment.

Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

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). 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). 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.

Table 4: Lab Abnormalities in Newly Diagnosed CML Clinical Trial Gleevec N=551 %

CTC Grades

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.

6.6 Acute Lymphoblastic Leukemia The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps and rash, which were easily manageable. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were rarely severe and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Gleevec.

6.7 Myelodysplastic/Myeloproliferative Diseases Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec for MDS/MPD in the phase 2 study, are shown in Table 6.

Table 6: Adverse Reactions Reported (More than One Patient) in MPD Patients in the Phase 2 Study (≥10% All Patients) All Grades

Grade 4

Grade 3

Grade 4

13.1 8.5 3.3

3.6 0.4 1.1

20.8 15.9 4.1

4.5 0.6 0.2

0 0.9

0 0.2

0.4 0.2

0 0

0.2 4.7

0 0.5

0.8 7.1

0 0.4

Nausea Diarrhea Anemia Fatigue Muscle Cramp Arthralgia Periorbital Edema

6.9 Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of Gleevec observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being gastrointestinal, cutaneous and musculoskeletal disorders.

Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia and anemia.

6.10 Dermatofibrosarcoma Protuberans Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with Gleevec for DFSP in the phase 2 study are shown in Table 7.

Table 7: Adverse Reactions Reported in DFSP Patients in the Phase 2 Study (≥10% All Patients) All Grades N=12 Preferred Term n (%) Nausea Diarrhea Vomiting Periorbital Edema Face Edema Rash Fatigue Edema Peripheral Pyrexia Eye Edema Lacrimation Increased Dyspnea Exertional Anemia Rhinitis Anorexia

Table 5: Lab Abnormalities in Other CML Clinical Trials

CTC Grades1 Hematology Parameters – Neutropenia – Thrombocytopenia – Anemia Biochemistry Parameters – Elevated Creatinine – Elevated Bilirubin – Elevated Alkaline Phosphatase – Elevated SGOT (AST) – Elevated SGPT (ALT)

Grade 3

Grade 4

Accelerated Phase (n=235) 600 mg n=158 400 mg n=77 % Grade 3

Grade 4

Chronic Phase, IFN Failure (n=532)

5 (41.7) 3 (25.0) 3 (25.0) 4 (33.3) 2 (16.7) 3 (25.0) 5 (41.7) 4 (33.3) 2 (16.7) 4 (33.3) 3 (25.0) 2 (16.7) 3 (25.0) 2 (16.7) 2 (16.7)

Clinically relevant or severe laboratory abnormalities in the 12 patients treated with Gleevec for DFSP in the phase 2 study are presented in Table 8.

400 mg % Grade 3

4 (57.1) 3 (42.9) 2 (28.6) 2 (28.6) 3 (42.9) 2 (28.6) 2 (28.6)

6.8 Aggressive Systemic Mastocytosis All ASM patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash and lower respiratory tract infection. None of the 5 patients in the phase 2 study with ASM discontinued Gleevec due to drug-related adverse reactions or abnormal laboratory values.

*p<0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups) Myeloid Blast Crisis (n=260) 600 mg n=223 400 mg n=37 %

N=7 n (%)

Preferred Term

IFN+Ara-C N=533 %

Grade 3

Hematology Parameters* – Neutropenia* – Thrombocytopenia* – Anemia Biochemistry Parameters – Elevated Creatinine – Elevated Bilirubin – Elevated Alkaline Phosphatase – Elevated SGOT/SGPT

6.4 Adverse Reactions in Pediatric Population The overall safety profile of pediatric patients treated with Gleevec in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Although most patients experienced adverse reactions at some time during the study, the incidence of Grade 3/4 adverse reactions was low.

Table 8: Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study

Grade 4

N=12 16 30 42

48 33 11

23 31 34

36 13 7

27 21 6

9 <1 1

1.5 3.8

0 0

1.3 2.1

0 0

0.2 0.6

0 0

4.6 1.9 2.3

0 0 0.4

5.5 3.0 4.3

0.4 0 0

0.2 2.3 2.1

0 0 0

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 (hemoglobin ≥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 (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), elevated SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN)

1CTC

6.3 Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5) 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.

CTC Grades1 Hematology Parameters – Anemia – Thrombocytopenia – Neutropenia Biochemistry Parameters – Elevated Creatinine

Grade 3

Grade 4

17% 17% 0%

0% 0% 8%

0%

8%

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)

1CTC

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.

Table 11: Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1)

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 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) Fever in absence of neutropenia (ANC <1.0 x 109/L) Sweating Other hemorrhage Weight gain Alopecia Dyspepsia/heartburn Neutropenia/granulocytopenia Rigors/chills Dizziness/lightheadedness Creatinine increase Flatulence Stomatitis/pharyngitis (oral/pharyngeal mucositis) Lymphopenia

Imatinib 800 mg N=822

All Grades %

Grades 3/4/5 %

All Grades %

Grades 3/4/5 %

76.7

9.0

86.1

13.1

69.3 58.1 57.2 56.2 38.1 37.4 32.2 32.0 31.1 25.2 22.0

11.7 9.0 13.8 8.1 7.6 9.2 5.6 4.9 6.6 8.1 5.7

74.9 64.5 55.2 58.2 49.8 40.6 30.2 34.8 35.8 28.1 19.7

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

13.2 12.7 12.3 12.0 11.9 11.5 11.5 11.0 11.0 10.8 10.0

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

9.2 6.0

5.4 0.7

10.0 10.1

4.3 1.9

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.

Table 10: Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial 400 mg (n=73) % CTC Grades1 Hematology Parameters – Anemia – Thrombocytopenia – Neutropenia Biochemistry Parameters – Elevated Creatinine – Reduced Albumin – Elevated Bilirubin – Elevated Alkaline Phosphatase – Elevated SGOT (AST) – Elevated SGPT (ALT)

600 mg (n=74) %

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 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) %

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 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

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 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

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 0 0.6 0.9 0 0 0 0.9 0.3 0.6 0.3 0.9 0.9 0.3

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 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.

Grade 3

Grade 4

Grade 3

Grade 4

3 0 7

0 0 3

8 1 8

1 0 3

0 3 1 0 4 6

0 0 0 0 0 0

3 4 1 3 3 7

0 0 3 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.

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 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. If alternative treatment cannot be administered, a dose adjustment should be considered [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).

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.

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 breastfed 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

Normal (n=14)

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 Renal Dysfunction

Renal Function Tests

Mild

CrCL = 40-59 mL/min

Moderate

CrCL = 20-39 mL/min

Severe

CrCL = <20 mL/min

CrCL = Creatinine Clearance

Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).

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 In vitro, Gleevec inhibits the cytochrome P450 isoenzyme CYP2D6 activity at similar concentrations that affect CYP3A4 activity. Systemic exposure to substrates of CYP2D6 is expected to be increased when coadministered with Gleevec. No specific studies have been performed and caution is recommended.

REV: MAY 2009 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2009-72

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Update on Approaches to the Treatment of

Follicular Lymphoma ANDREW M. EVENS, DO, MS Assistant Professor of Medicine

JANE N. WINTER, MD Professor of Medicine Northwestern University Feinberg School of Medicine Robert H. Lurie Comprehensive Cancer Center Chicago, Illinois

F

ollicular lymphoma (FL) comprises more than 70% of all “low-grade” histologies and 22% of all cases of

non-Hodgkin’s lymphoma (NHL), second only to diffuse large B-cell lymphoma.1,2

Survival rates for patients with FL remained unchanged from the 1950s through the early 1990s, but recent evidence suggests that outcomes are improving.3-5 FL is a challenge, in part because it is generally an incurable disease requiring multiple treatments but also a disease in which relatively long survival times elevate the importance of quality of life when treatments are considered.

risk groups with different outcomes.

High tumor burden not only is an indicator for treatment, but it also is associated with shorter progression-free survival (PFS) and overall survival (OS), even in the rituximab era.11 There is no gold standard to define tumor burden, although a number of methods are in clinical use, including the Groupe D’Etude des Lymphomes Follicularies (GELF) criteria (Table 2).12,13

Prognosis and Tumor Burden The Follicular Lymphoma International Prognostic Index (FLIPI) is a clinical prognostic model developed initially for newly diagnosed advanced-stage FL,6,7 but it also has been validated in early-stage disease8 and at first relapse.9 An updated report by Federico et al examined the importance of the FLIPI prognostic score among patients given rituximab (Rituxan, Genentech/Biogen Idec)-based treatment (Table 1).10 They showed that the FLIP-2 (Follicular Lymphoma International Prognostic Index 2) yielded 3 distinct

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Treatment Approaches Traditional treatment options for low-grade NHL have included expectant observation for asymptomatic, low tumor burden disease and multiagent cytotoxic chemotherapy for patients who are symptomatic and have a high tumor burden or progressive disease.

Biologic therapy has become an integral part of therapy and includes agents that specifically target B lymphocytes, such as monoclonal anti-CD20 antibodies and radiolabeled anti-CD20 antibodies. Treatment

C LIN IC A L O N CO LO GY N EWS • JUN E 2 010

1

Table 1. Survival by Risk Group as Defined by the FLIPI-2 Risk Group

No. of Factorsa

Distribution of Patients, %

3-Year PFS, %

5-Year PFS,%

Low

0

20

91

79

Intermediate

1-2

53

69

51

High

3-5

27

51

19

FLIPI, Follicular Lymphoma International Prognostic Index; LDH, lactate dehydrogenase; PFS, progression-free survival.

Factors adversely affecting outcome include 1) age (>60 vs ≤60 y); 2) hemoglobin level (<120 vs ≥120 g/L); 3) β2-microglobulin (above normal vs normal or below); 4) largest involved lymph node (>6 vs ≤6 cm); 5) bone marrow (involved vs not involved).

a

Based on reference 10.

Table 2. Definition of Tumor Burden in FL by GELF Original GELF criteriaa • Any nodal or extranodal tumor mass >7 cm diameter • Involvement of at least 3 nodal sites, each with a diameter of >3 cm diameter • Presence of any systemic or B symptoms • Splenic enlargement with inferior margin below the umbilicus line • Compression syndrome (ureteral, orbital, gastrointestinal) • Pleural or peritoneal serous effusion (irrespective of cell content) • Leukemic phase (>5.0 x 109/L circulative malignant cells) • Cytopenia (granulocyte count <1.0 x 109/L and/or platelets <100 x 109/L).

FL, follicular lymphoma; GELF, Groupe d’Etude des Lymphomes Folliculaires a

Patients must meet only one criterion to be considered “high” tumor burden.

Based on references 26 and 27.

response to cytotoxic and biologic therapies is high initially; however, with subsequent treatments, response rate and duration decline, whereas cumulative toxicities increase and relapse is inevitable. New combinations of novel agents with biologic and cytotoxic therapies provide the opportunity to improve outcomes for patients with FL.

Initial Treatment of Advanced-Stage Disease THERAPEUTIC OPTIONS For patients with symptoms or other reasons to undergo treatment, several treatment options are

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available, including single- or multiple-agent chemotherapy with concurrent CD20 antibody therapy; CD20 antibody therapy alone in selected cases; radioimmunoconjugates; and therapy with new agents, such as bortezomib (Velcade, Millennium) and lenalidomide (Revlimid, Celgene). Autologous and allogeneic hematopoietic stem cell transplantations (HSCTs) traditionally are reserved for patients with recurrent or refractory disease, but they may be used earlier in the disease course for patients with a poorer prognosis. Additionally, many clinical trials are available for patients with FL, and all patients should be encouraged to participate in such trials.

RITUXIMAB: SINGLE-AGENT INDUCTION INDUCTION THERAPY

AND

POST-

In previously untreated patients with a low tumor burden, the overall response rate (ORR) with rituximab is 47% to 74%,14-16 with a median PFS of approximately 2 years without maintenance therapy14,16 or 3 years with abbreviated post-induction rituximab.15 Very little data exist regarding use of single-agent rituximab for patients with newly diagnosed, high tumor burden FL. The Eastern Cooperative Oncology Group (ECOG) 1496 study randomized responding patients induced with CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy to either maintenance rituximab or observation.11 The median PFS time and OS for patients receiving rituximab maintenance was significantly improved compared with those receiving no maintenance (Table 3). Patients with follicular histology, large tumor burden, and minimal residual disease appeared to gain the greatest benefit from maintenance rituximab. The 1,000 mg/m2 dose of cyclophosphamide used in ECOG 1496 may be important and may explain the somewhat lower responses and outcomes seen in other CVP-based trials.17,18 The results of 2 completed randomized trials in previously untreated patients have been eagerly awaited.

The RESORT (Rituximab Extended Schedule or Retreatment) trial, conducted by ECOG, enrolled asymptomatic low-risk patients; induction consisted of

Table 3. Selected Randomized Studies of Chemoimmunotherapy for Patients With FL Series/Author

Year

N

Arms

Conclusions

Hiddeman28 and Buske7

2005 and 2006

428

CHOP vs R-CHOP (all patients randomized to IFN vs autologous HSCT)

4-y PFS: CHOP 28% vs R-CHOP 62% (P<0.0001) 4-y OS: CHOP 81% vs R-CHOP 90% vs (P=0.039)

Forstpointner26

2006

125 (relapsed)

FCM vs R-FCM with second randomization R maintenance vs observation

Response duration significantly prolonged by R-maintenance after R-FCM

Marcus17,18

2006

321

CVP vs R-CVP

Median TTF: CVP 15 mo vs R-CVP 34 mo; OS improved for R-CVP (P=0.029)

Van Oers30

2006

465 (relapsed)

CHOP vs R-CHOP induction followed by second randomization to R maintenance vs observation

Improved PFS with R maintenance after CHOP (HR, 0.30; P<0.001) and R-CHOP (P=0.004) induction

Herold27

2007

358

MCP vs R-MCP (followed by IFN)

Median EFS (P=0.001) and median OS (P=0.0096) improved with R-MCP

Salles29

2008

358

CHVP x 12 cycles vs 6 cycles R-CHVP (both arms concurrent IFN x 18 mo)

EFS: CHVP 37% vs R-CHVP 53% (P<0.0001) Median OS: CHVP 79% vs R-CHVP 84% (P=ns)

Hochster11

2009

401

CVP vs CVP with rituximab post-induction maintenance

Improved PFS (median with rituximab 5.6 y vs 1.8 with no maintenance, P=0.0000003) and OS (88% vs 72%, P=0.03) with post-induction rituximab

CHVP, cyclophosphamide, adriamycin, etoposide, prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CI, confidence interval; CVP, cyclophosphamide, vincristine, prednisone; EFS, event-free survival; FCM, fludarabine, cyclophosphamide, mitoxantrone; FL, follicular lymphoma; HR, hazard ratio; HSCT, hematopoietic stem cell transplantation; IFN, interferon; MCP, mitoxantrone, chlorambucil, prednisone; ns, not significant; OS, overall survival; pts, patients; PFS, progression-free survival; R, rituximab; TTF, time to treatment failure; TTP, time to disease progression

4 weekly treatments with rituximab. Maintenance rituximab was compared with retreatment at the time of recurrence. Reported in abstract form, the PRIMA (Primary Rituximab and Maintenance) trial compared maintenance rituximab with observation in patients treated with rituximab plus chemotherapy. The results showed a significant improvement in PFS with rituximab maintenance administered every 8 weeks for 2 years compared with observation (2-y PFS: 82% vs 66%, respectively; P<0.0001). Rituximab maintenance was associated with an increased risk for neutropenia and infection.

Whether OS will be impacted by maintenance rituximab remains to be determined.

CHEMOTHERAPY

AND

RITUXIMAB INDUCTION THERAPY

Past clinical trials comparing multiple- and singleagent chemotherapy in patients with advanced-stage

FL have not shown improvements in the natural course of the disease.19,20 Fludarabine, identified in the 1980s as having activity in FL, has been incorporated into combination regimens that achieved high response rates, including molecular remissions; however, meaningful differences in outcome relative to other multiple-agent regimens have not been observed. 21,22 Furthermore, there is some concern that fludarabinebased treatment may make it difficult to collect stem cells from patients,23,24 and may increase the risks for transformation and myelodysplastic syndrome.25 Several randomized Phase III trials evaluating various chemotherapy combinations plus rituximab versus chemotherapy alone have been reported and updated (Table 3).7,11,17,18,26-30 The response rates and either median time-to-treatment failure (TTF) or median event-free survival (EFS) were superior in the

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chemoimmunotherapy arm for chemotherapy-naïve patients and for those who were previously treated.

Moreover, OS improvements for the chemoimmunotherapy arms (vs chemotherapy without immunotherapy) are becoming apparent.

Rummel et al recently reported the results of a randomized Phase III trial that compared induction chemotherapy using the alkylating agent bendamustine (Treanda, Cephalon) in combination with rituximab versus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) for patients with high tumor burden FL.31 The multicenter randomized Phase III study enrolled 549 patients with advancedstage, high tumor burden indolent NHL or mantle-cell lymphoma to induction treatment with either bendamustine in combination with rituximab (BR) or standard R-CHOP.31,32 Patients in the BR group received rituximab 375 mg/m2 on day 1 and bendamustine 90 mg/m2 on days 1 and 2 of each 28-day treatment cycle.

A median number of 6 cycles was given to more than 80% of those in both treatment arms. Response was similar in the 2 groups, with an ORR of 93% for BR and 91% for R-CHOP; however, the complete remission (CR) rate was improved with BR (40%) compared with R-CHOP (31%). Furthermore, BR was associated with a superior PFS compared with R-CHOP (median, 55 vs 35 mo; P=0.00012), as was time to next treatment (median, not reached vs 38 mo; P=0.00002). No differences in OS were noted. Of 513 evaluable patients, 179 had high tumor burden FL; BR was associated with significantly improved PFS among this group (not reached vs 47 mo; P=0.0281).

In terms of safety, more toxicity was seen with R-CHOP, with grade 3/4 neutropenia occurring in 47% of patients versus 11% with BR (P<0.0001), despite use of more granulocyte colony-stimulating factor in patients treated with R-CHOP (20% vs 4%). Other toxicities seen at higher rates in those treated with R-CHOP included alopecia (universal vs <2% patients; P<0.0001), paresthesias, stomatitis, infectious complications, and sepsis. Side effects more frequent with BR compared with R-CHOP were skin/erythema and allergic reaction (skin). Overall, the combination of BR improved PFS and CR rates, with a better tolerability profile. These results suggest that BR may ultimately become the new standard first-line treatment for patients with advancedstage, high tumor burden FL.

RADIOIMMUNOTHERAPY The anti-CD20 radioimmunoconjugates 131I-tositumomab (Bexxar, GlaxoSmithKline) and 90Y-ibritumomab tiuxetan (Zevalin, Biogen Idec) both deliver ionizing radiation to target cells and their neighbors. They are relatively easy to administer, safe, and effective in relapsed/refractory FL,33,34 including rituximab-refractory disease. 35 Radioimmunotherapy (RIT) also has been incorporated into the frontline management of patients with untreated indolent lymphoma through the paradigm of sequential

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therapy (RIT after multiagent induction chemotherapy). Morschhauser et al reported results of Phase III FIT (First-line Indolent Trial) examining consolidative RIT versus no consolidation in patients who achieved CR or partial remission (PR) following chemotherapy induction. 30 Patients were randomized to one dose of 90Y-ibritumomab tiuxetan or no consolidation. RIT significantly improved median PFS in all patients (36.5 vs 13.3 mo with no RIT; P<0.0001).

This gain was observed regardless of the depth of initial response to induction chemotherapy, although the benefit appeared to be greater for patients in PR versus CR. A limitation of the FIT trial was that the majority of patients did not receive rituximabbased induction chemotherapy. The extent of benefit of consolidation RIT after combined rituximab/chemotherapy therapy is not known.

As a corollary to the FIT trial, peripheral blood samples were evaluated for minimal residual disease through assessment of BCL-2 rearrangements with real-time quantitative polymerase chain reaction (PCR).36 Ninety percent of patients who received 90 Y-ibritumomab tiuxetan converted from BCL2-positive to undetectable compared with 36% of controls.

Furthermore, for patients who were BCL-2-positive and received treatment with 90Y-ibritumomab tiuxetan, the median PFS was 38 months, compared with 8 months for control (P<0.01). By contrast, there were no statistically significant differences in PFS between patients with PCR-undetectable disease at randomization who received 90Y-ibritumomab tiuxetan versus control. 131I-tositumomab also has been incorporated sequentially following chemotherapy.16,37 Further information regarding the role of up-front, sequential RIT in indolent NHL should be available soon from the large US intergroup study led by the Southwest Oncology Group (S0016). In that Phase III trial, untreated FL patients were randomly assigned to 6 cycles of R-CHOP versus 6 cycles of CHOP followed by 131I-tositumomab.

Several novel RIT-based therapeutic approaches— including concurrent use of radiation-enhancing agents, fractionation of RIT, pretargeting, and use of new humanized antibodies—are being explored to increase efficacy and mitigate toxicity.38 Novel combinations include potentially synergistic radiationsensitizing agents—eg, bortezomib,39 the synthetic 24-mer oligodeoxynucleotide CpG 7909,40 and the expanded porphyrin agent motexafin gadolinium (MGd; Xcytrin, Pharmacyclics),41 which targets redoxdependent pathways and enhances the sensitivity of tumor cells to ionizing radiation.42 In a Phase I clinical trial in which MGd was given concurrently with 90 Y-ibritumomab tiuxetan, the ORR was 57% (CR 43%), with median TTF of 10 months and median duration of 17 months.41 Moreover, in rituximab-refractory FL, the ORR was 86% (CR 64%), with a median TTF of 14 months, which compares favorably with previous data.35 These results are encouraging, but randomized

trials will be needed to prove the superiority of this combination over conventional RIT.

patients and appears to result in PFS/OS that is similar to that of myeloablative transplantation.45 The addition of rituximab to conditioning for both allogeneic and autologous HSCT has been associated with excellent outcomes in some series, but its role in transplantation for FL has to be better defined.43,46

Stem Cell Transplantation AUTOLOGOUS An expert panel convened by the American Society for Blood and Marrow Transplantation recently published an evidence-based review on the role of HSCT in the treatment of FL.43 Although high-dose therapy with autologous HSCT as a component of up-front therapy in FL consistently improves PFS/EFS, this approach is not recommended because of the high incidence of secondary myelodysplastic syndrome/acute myeloid leukemia and the lack of improvement in OS. In the salvage setting, there is a single retrospective study that addresses the question of autologous HSCT in patients with FL treated with rituximab as part of induction and/ or salvage therapy, making it difficult to make a recommendation in this setting. Nonetheless, many patients benefit from this strategy.44

Novel Agents for Relapsed And Refractory Disease VACCINATION STRATEGIES FL occasionally undergoes spontaneous regression, leading some investigators to speculate that it might be responsive to immune regulation. All cells in a lymphoid clone express the same idiotype (Id)—the variable region of the immunoglobulin molecule—making it a “tumor-specific antigen” and an ideal target for immunotherapy. Custom-made Id-specific monoclonal antibodies produced by Stanford led to durable CRs in a subset of patients with FL.47 To provide a more long-lasting immune response to the lymphoma-associated Id, Hsu et al studied vaccination with patientspecific Id manufactured using traditional monoclonal antibody technology.48 The Id protein was linked to Keyhole Limpet Hemocyanin (KLH), a highly immunogeneic carrier protein, to enhance the response to Id, and granulocye macrophage–colony-stimulating factor (GM-CSF) was injected to recruit dendritic cells to the site of injection and to encourage antigen presentation.

Patients who generated an immune response to vaccination were found to have a better survival than those who did not.48 A Phase III multi-institutional randomized trial compared vaccination in previously untreated patients who achieved a CR with combination chemotherapy to KLH plus GM-CSF alone (NCI/Biovest).49 Analysis showed that vaccination prolonged diseasefree survival (44.2 vs 30.6 mo; P=0.45) among patients who received at least one immunization and were in CR/CR unconfirmed (CRu) for 6 months after intensive

ALLOGENEIC The potentially curative allogeneic HSCT is an alternative for an increasing number of patients, given the option of reduced-intensity conditioning and the greater availability of matched unrelated donors.

Choosing between an autologous HSCT and allogeneic HSCT is a difficult decision and depends on many factors, including donor availability, donor age, patient age, and comorbidities. Because of the high treatment-related morbidity and mortality associated with allogeneic HSCT, many centers will perform an autologous HSCT first, reserving an allogeneic transplant from either a matched sibling donor or matched unrelated donor with reduced-intensity conditioning for patients who later relapse. Today, the vast majority of allogeneic HSCTs are based on reduced-intensity conditioning, which is applicable to a wider range of

Table 4. Monoclonal Antibodies for Lymphoid Malignancies Antigen Antibody

Type

Status

CD20

Rituximab (Rituxan, Biogen Idec/Genentech)

Chimeric

FDA-approved

90

Yttrium 90 murine

FDA-approved

131

Iodine 131 murine

FDA-approved

CD52

Alemtuzumab (Campath, Berlex)

Humanized

FDA-approved

CD20

Ofatumumab (HuMay-CD20, Genmab.com)

Humanized

Phase III

CD22

Epratuzumab (LymphoCide, Immunomedics/Amgen)

Humanized

Phase II/III

CD80

Galiximab (IDEC-114, Biogen Idec)

Primatized

Phase III

CD23

Lumiliximab (IDEC-152, Biogen Idec)

Primatized

Phase II

Y-ibritumomab tiuxetan (Zevalin, Biogen Idec) I-tositumomab (Bexxar, GlaxoSmithKline)

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Induction a

High-risk FL (FLIPI score 3-5 or GELF high tumor burden)

R A N D O M I Z E

Continuation

Rituximab 375 mg/m2 + bendamustine 90 mg/m2 q28d x 6 cycles

Rituximab 375 mg/m2 1 infusion q2mo x 2 y

Rituximab 375 mg/m2 + bortezomib (1.3 mg/m2, days 1, 4, 8, 11) + bendamustine 90 mg/m2 q28d x 6 cycles

Rituximab 375 mg/m2 1 infusion q2mo x 2 y

Rituximab 375 mg/m2 + bendamustine 90 mg/m2 q28d x 6 cycles

Rituximab 375 mg/m2 1 infusion q2mo x 2 y + lenalidomide 20 mg, days 1-21 q28d x 1 y

Figure. Untreated high-risk FL: E2408 study schema.

FL, follicular lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index; GELF, Groupe d’Etude des Lymphomes Folliculaires a

1:2:2 randomization; accrual: 250 patients

chemotherapy. There were no serious adverse events.

In contrast to the positive results reported preliminarily for the NCI/Biovest vaccine, 2 other large Phase III randomized trials of anti-Id vaccine have shown no benefit to vaccination. In a large Phase III trial of anti-Id vaccination following response to cyclophosphamide, vincristine, and prednisone, immune response to Id but not to KLH, correlated strongly with a favorable clinical outcome.50 These findings raise the possibility that the capacity to generate an immune response to Id is a marker of a favorable prognosis. A second antiId vaccine was studied after cytoreduction with rituximab, and again no significant difference in time to progression was observed in the entire group or any subgroup compared with patients receiving placebo and GM-CSF.51 Differences in study design likely are responsible for the differences in outcomes among the trials. New directions in vaccination include Id-pulsed dendritic cell and membrane proteolipsomal vaccines.

Alternative immunologically based approaches also are in development.

MONOCLONAL ANTIBODIES Some malignant B cells are resistant to rituximab straightaway, whereas others develop resistance over time after exposure to the antibody. There are many mechanisms of resistance, and thus there are innumerable potential strategies for the development of new targeted antibodies (Table 4).

GA101 (GlycArt/Genentech) is a novel anti-CD20 that is the first humanized and “glyco-engineered” anti-CD20 to be investigated clinically. 52 “Glyco-

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engineering” enhances antibody-dependent cellular cytotoxicity (ADCC) by increasing affinity to the ADCC receptor FCgRIIIA. GA101 binds a type II epitope on CD20 with high affinity and has greater direct cell cytotoxicity compared with type I antibodies. Complement-dependent cytotoxicity, however, is reduced.

Toxicities mostly are related to the infusion, and response rates have been high among patients with FL.53,54 Veltuzumab (Immunomedics/Nycomed) is a second-generation humanized anti-CD20 that differs from rituximab by one amino acid in one complementarity-determining region, but it has completely different framework regions. Veltuzumab has been shown to have slower “off rates” than rituximab in some lymphoma cell line studies, and it may be administered subcutaneously.55 Among patients with FL, ORRs have been high (44%), with 27% achieving CR/CRu.56 Other anti-CD20s under development include ocrelizumab (Roche), a humanized antibody with fewer infusion-related side effects and increased binding affinity to the low-affinity FcγRIIIa receptor.57 Some studies have shown that patients who are homozygous for high-affinity variants have superior disease outcome when treated with rituximab compared with those carrying low-affinity variants. In a Phase I/II trial of ocrelizumab in patients with relapsed/refractory FL, an ORR of 38% was observed, with similar response rates in patients with low-affinity and high-affinity variants.58 PRO13192 (Genentech), a third-generation, humanized anti-CD20 with enhanced ADCC and complement-dependent cytotoxicity in in vitro models, also is under investigation.59 Ofatumumab (Arzerra,

Table 5. Novel Agents for the Treatment of FL Target

Type

Agents

Proteasome

Proteasome inhibitors

Bortezomib, carfilzomib, NPI-0052

CD20

mAbs

Ofatumumab, IMMU-06, ocrelizumab, GA101

CD22 and CD74

mAbs

Epratuzumab and milatuzumab

CD19 and CD22

mAb-drug conjugates

Inotuzumab ozogamicin, SAR3419

HDAC

HDAC inhibitors

Vorinostat, PCI-24781

mTOR

Small molecule

Everolimus, temsirolimus

Bcl-2 family

Small molecule

ABT-263

B-cell receptor

Small molecule

Fostamatinib disodium, PCI-32765

JAK-2

Small molecule

SB1518

Multiple

Immunomodulatory drugs

Lenalidomide, thalidomide

FL, follicular lymphoma; HDAC, histone deacetylase; JAK, Janus kinase 2; mAb, monoclonal antibody; mTOR, mammalian target of rapamycin

GlaxoSmithKline), a fully human antibody that targets a novel epitope of the CD20 molecule that was approved in October 2009 for the treatment of chronic lymphocytic leukemia (CLL), is reported to have stronger complement-dependent cytotoxicity than rituximab.60 Although this antibody is very effective in CLL, the ORR in rituximab-resistant FL was 11%, limiting enthusiasm for this agent in this patient population.61 CD22 is a B-cellâ&#x20AC;&#x201C;associated antigen expressed on the surface of mature B cells. The humanized antiCD22 epratuzumab (Immunomedics) acts predominantly by ADCC, but some studies suggest that it acts, at least in part, by mechanisms different from rituximab. Whereas epratuzumab and rituximab target different antigens and likely effect cell kill through different signaling pathways, the combination has been studied in relapsed or refractory low-grade, CD20positive NHL.62 A high ORR (85%) was reported for FL patients with low-risk FLIPI scores, whereas those with intermediate- or high-risk scores had an ORR of 39%.

This combination with extended dosing recently has been evaluated, and results are undergoing analysis.

CD74, the invariant chain of the major histocompatibility complex class II molecule is another attractive target for the treatment of FL. Milatuzumab (Immunomedics), a humanized anti-CD74 monoclonal antibody, is rapidly internalized, and consequently has very

limited capacity for ADCC or CDC, but it may prove to be an ideal agent for conjugation with radioisotopes or cytotoxic agents.63

CONJUGATES Like the anti-leukemia agent gemtuzumab ozogamicin (Mylotarg, Wyeth), inotuzumab ozogamicin (CMC-544; Pfizer) is composed of a humanized antibody conjugated to calicheamicin, a potent cytotoxic antitumor agent. This chemoimmunoconjugate targets the B-cell antigen CD22. Responses have been seen in both FL and diffuse large B-cell lymphoma.64,65 Toxicity primarily has been self-limited thrombocytopenia.

Dang et al recently reported the results of a study of patients with relapsed/refractory FL treated with inotuzumab ozogamicin in combination with rituximab in which they found an ORR of 87%, with a median PFS of 23.6 months.66 A new immunoconjugate, SAR3419 (ImmunoGen), consisting of the humanized anti-CD19 antibody huB4 conjugated to a potent tubulin inhibitor, has shown tumor shrinkage in 68% of patients studied.67 Corneal changes resulting in blurred vision proved to be the dose-limiting toxicity.

OTHER NOVEL TARGETED AGENTS Additional agents aimed at specific molecular targets have shown promise in the treatment of FL (Table 5).

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The ubiquitinâ&#x20AC;&#x201C;proteasome pathway plays a critical role in regulating cell cycle progression, transcription-factor activation, apoptosis, and cell trafficking. Bortezomib has shown encouraging activity in relapsed or refractory lymphoma.68,69 Oâ&#x20AC;&#x2122;Connor and colleagues recently reported an ORR of 50% (22% CR) using bortezomib 1.5 mg/m2 on days 1, 4, 8, and 11,69 whereas Di Bella et al showed an ORR of 13% using bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11.68 The discrepancy between these trials is not known, but may in part be related to dosing as well as length of bortezomib therapy. Oâ&#x20AC;&#x2122;Connor et al showed that the median time to response was 12 weeks.69 Immunomodulatory drugs (IMiDs) such as thalidomide (Thalomid, Celgene) and lenalidomide (Revlimid, Celgene) have been investigated in a number of tumor types. IMiDs directly induce cell cycle arrest and also possess potent anti-angiogenic activity in vitro. Elegant preclinical studies by Gribben and colleagues showed that lenalidomide repaired several T-cell defects in FL cells, significantly enhancing the immune synapse function between tumor and T cells.70 Clinically, Witzig et al reported an ORR of 26% in relapsed/ refractory indolent lymphoma, with a 32% ORR in FL.71 Bortezomib and lenalidomide are being incorporated into frontline FL studies such as the BIONIC (Bortezomib-based Induction Or Novel IMID-based Continuation), or E2408, trial (Figure).

Other novel agents being studied in FL include histone deacetylase (HDAC) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, anti-apoptosis agents (eg, BCL-2 family inhibitors), and B-cell

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receptor (BCR)-modulating agents. HDACs have been shown to regulate cellular functions such as cell cycle progression, proliferation, survival, transcription factors, and signal transduction, and are a target of interest in lymphoma.72 Preclinical data supports the use of these agents in the treatment of lymphoma,73 and preliminary data from a Phase I study examining the panHDAC inhibitor PCI-24781 (Pharmacyclics) showed encouraging activity in FL.74 A downstream target of the PI3K/AKT pathways is the kinase mTOR. The mTOR pathway also is important for cellular functions such as initiation of transplant, protein stability, and transcription of ribosome and stress response genes. In abstract form, Smith et al showed that the rapamycin ester derivative, temsirolimus (Torisel, Wyeth) resulted in an ORR of 50% in patients with FL histology.75

Conclusion Treatment options for patients with FL have significantly improved over the past several years, in part because of the development of antibody-based and other innovative, targeted approaches as well as through the refinement of HSCT. These therapies have translated into alterations in the natural history of FL and increases in OS. Despite this optimism, FL remains an incurable disease for most patients. It is critical for oncologists and patients to be involved in clinical trials for advancements in the field to allow for continued improvements in the outcomes of patients with FL. For full reference list, go to clinicaloncology.com.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JUNE 2010

CML

Omacetaxine Promising for Patients With CML New Orleans—In patients with chronic myeloid leukemia (CML) who have stopped responding to tyrosine kinase inhibitors (TKIs), a new drug called omacetaxine (Omapro, ChemGenex) may extend survival.

This news comes from preliminary results from an ongoing Phase II/III trial, CML-202. The drug, a first-inclass cetaxine, may be a breakthrough for CML patients who have run out of other options, but its activity appears to be specific to individuals with a T315I BCR-ABL mutation.

“Omacetaxine appears to be an option for a patient population who currently has no available approved drug therapies,” said Jorge E. Cortes-Franco, MD, deputy chair, Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston. At the most recent annual meeting of the American Society of Hematology (ASH abstract 644), Dr. Cortes-Franco presented evidence of durable responses with this new drug, an agent that patients self-inject. Myelosuppression is the most common toxicity, but the drug is otherwise relatively well tolerated.

On March 22, the FDA’s Oncologic Drugs Advisory Committee voted 7 to 1 that a validated, well-characterized test to identify the T315I mutation should be reviewed by the FDA prior to approval of omacetaxine. Two different in vitro tests were used in trial CML-202 and the comparability of these tests is unknown, said the agency. On April 9, ChemGenex

met with the FDA’s Center for Devices and Radiological Health to discuss a path forward to develop a test.

Study Design The CML-202 study was not controlled, primarily because there is no current alternative therapy for CML patients who have become resistant to TKIs—imatinib (Gleevec, Novartis), dasatinib (Sprycel, Bristol-Myers Squibb) and nilotinib (Tasigna, Novartis). However, response rates and survival rates compared favorably to historical controls. Although survival is short for CML patients who are initiated on therapy in blast phase, 80% of patients in chronic-phase CML were alive at two years, and the median survival has not yet been reached in follow-up that is still ongoing.

The study enrolled patients with CML who were resistant to imatinib and had a T315I mutation. Almost 80% of the patients had failed two or more TKIs. According to Dr. Cortes-Franco, the T315I mutation is found in about 50% of patients who become resistant to imatinib and is a major reason for CML progression after initial response to TKIs. Of the 81 patients who have been evaluated to date, 49 (60%) were in chronic phase,

‘I greatly admire both the investigators and company for developing a compound from a class with a long and erratic development history, in a niche where the need is great and where other companies have not been proactive enough.’

Patients with chronic-phase CML

Thrombocytopenia

Patients with accelerated-phase CML

Anemia

Patients with blast-phase CML

Neutropenia

100

80 86

80 60 40 22 20

71

60

Patients, %

Response Rate, % of Patients

—Frank Giles, MD

20

0

Figure 1. Complete hematologic response in CML patients receiving omacetaxine.

49 40

20

0

Figure 2. Grade 3 and 4 hematologic side effects in patients on omacetaxine.

45

17 (21%) were in accelerated phase and 15 (19%) were in blast phase. The median duration of the disease was 54 months, with a range of five to 285 months. Baseline clonal evolution was identified in 25% of those in chronic phase, 38% of those in accelerated phase and 70% of those in blast phase.

Patients received an induction of 1.25 mg/m2 omacetaxine in a twice-daily subcutaneous injection for 14 days every 28 days for six cycles. Those with a hematologic response went on to a maintenance dose, which was the same as the induction dose except that it was administered for seven days over each 28-day cycle.

Patients were instructed to self-administer the injections.

Patient Response The degree of response correlated with the activity of the disease. For those in chronic phase, 86% achieved a complete hematologic response, which was observed in only 22% of those in accelerated phase and 20% of those in blast phase (Figure 1). A cytogenetic response was achieved in 41% of those in chronic phase compared with 6% of those in accelerated phase and no patients in the blast phase. A major cytogenetic response was achieved in 26% of patients in chronic phase, including a complete cytogenetic response in 18%. The median time to achieve a complete hematologic response was one month, while the median time to achieve a major cytogenetic response was approximately four months.

Although the median follow-up is only seven months, the responses have been prolonged. Eleven of the 13 patients have sustained their major cytogenetic response to date. The median duration has been five months. Importantly, the benefit appears to be largely confined to patients with chronic disease. Although the median survival in the acceleratedphase patients so far has been close to 19 months, suggesting some activity of the therapy compared with historical controls in this group, the median survival in blast-phase patients has been only 2.4 months. The investigators say, however, that the clinical activity of omacetaxine is supported by clonal monitoring which has demonstrated a reduction in mutation in 50% of treated patients, even though Dr. Cortes-Franco acknowledged that “only a handful have demonstrated a disappearance of the mutated clone.”

Except for some cases of grade 3 diarrhea, most of the side effects associated with omacetaxine in this study, including diarrhea, nausea, fatigue and fever have been relatively mild. The most common non-hematologic side effect was diarrhea in 43% of patients. Grade 3 and 4

hematologic side effects have been common including thrombocytopenia (71%), anemia (49%) and neutropenia (45%) (Figure 2). However, with dose adjustments, the incidence of these hematologic events fell substantially, and cases of febrile neutropenia were relatively uncommon.

Filling a Niche From this evidence, the investigators concluded that omacetaxine, which has received orphan drug status approval from the FDA, can extend the lives of CML patients who are no longer responding to TKIs. The efficacy of this drug in patients with the T315I mutation suggests that new strategies to address mutating CML may be a productive approach to advancing care. Researchers not involved with the study agree.

“Omacetaxine appears to represent a potentially viable therapeutic option for CML patients who develop a secondary T315I BCR-ABL mutation, which is highly resistant to the three available tyrosine kinase inhibitors,” said Richard Stone, MD, director of the Adult Leukemia Program at Dana-Farber Cancer Institute, in Boston. “The drug is myelosuppressive, so one wonders if the hematological responses are nonspecific in nature.

Would similar results have been obtained if low-dose Ara-C (and stopping the TKI which reduces the selection pressure for this mutation) was employed? Nonetheless, the fact that there is a high hematological response rate and an impressive cytogenetic response rate is encouraging. While there are more specific inhibitors of T315I BCR-ABL in development, omacetaxine could help at least some patients in the near future who develop this refractory type of CML.” According to Frank Giles, MD, chief of the Division of Hematology and Medical Oncology, University of Texas Health Science Center, San Antonio, omacetaxine is “a very important” development for patients with T315I BCR-ABL CML. Although he reported that he is among those now conducting early phase clinical studies with oral kinase inhibitors targeted at this form of CML, he does not anticipate that viable agents will be available for several years. In the meantime, omacetaxine will fill an important void.

“I greatly admire both the investigators and company for developing a compound from a class with a long and erratic development history, in a niche where the need is great and where other companies have not been proactive enough, on occasion because of their unfortunate belief that patients with T315I disease did not constitute a sufficiently large population to meet commercial aims,” Dr. Giles said.

—Ted Bosworth

21

22

PRN

CLINICAL ONCOLOGY NEWS • JUNE 2010

Clinical Trials

The WAITING ROOM

IOM REPORT

Just sign the consent form.

This clinical trial will help us determine which treatment is best.

continued from page 1

does not improve its efficiency and effectiveness, the introduction of new treatments for cancer will be delayed and patient lives will be lost unnecessarily,” commented Dr. Mendelsohn in the introduction.

The National Cancer Institute (NCI)– sponsored Clinical Trials Cooperative Group Program comprises 10 groups that involve more than 3,100 institutions and 14,000 investigators who enroll more than 25,000 patients in trials each year.

One prominent flaw identified in the IOM report is the convoluted system for designing, reviewing and initiating clinical trials—researchers must navigate a maze of excessive oversight and overlapping reviews. Often, proposals are redrafted and recycled multiple times as they bounce between academic institutions, federal agencies, institutional review boards, and industry.

Proposals may linger for years, and many trials die on the vine. The average interval between trial application and launch now stands at more than two years. Delays of that magnitude disrupt patient enrollment and frequently lead to the abandonment of trials. In fact, only 60% of NCI-sponsored Phase III clinical trials reach completion.

“Very good data show that if you don’t get a trial started within two years, it’s unlikely to accrue enough patients to answer the question you started with,” Dr. Mendelsohn said. “It’s a huge waste of time, effort and resources, and it’s unfair to patients who signed a consent

form thinking they would be contributing to medical knowledge.”

Committee member and researcher Michael Carducci, MD, knows firsthand the aggravation of shepherding trials from initial application to subject enrollment. One of his proposals for a trial of a first-line prostate cancer treatment has yet to get out of the group’s steering committee, despite having what he describes a reasonable target and multiple groups within the program willing to participate.

“I’m frustrated with this one example, but I also know people who have been trying to get their studies through since 2006 and just got the concept approved,” said Dr. Carducci, AEGON Professor in Prostate Cancer Research at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore. “Now they have to get them up and running so that the original question remains relevant.”

The report also blames inadequate

Summary of the Committee’s Goals And Recommendations Goal I. Improve the speed and efficiency of the design, launch and conduct of clinical trials 1. Review and consolidate some front-office operationsa of the Cooperative Groups on the basis of peer review.

2. Consolidate back-office operations of the Cooperative Groups and improve processes.b 3. Streamline and harmonize government oversight.

4. Improve collaboration among stakeholders.

Goal II. Incorporate innovative science and trial design into cancer clinical trials 5. Support and use biorepositories.

6. Develop and evaluate novel trial designs.

7. Develop standards for new technologies.

Goal III. Improve the means of prioritization, selection, support and completion of cancer clinical trials 8. Reevaluate the role of NCI in the clinical trials system.

9. Increase the accrual volume, diversity and speed of clinical trials.

10. Increase funding for the Cooperative Group Program.

Goal IV. Incentivize the participation of patients and physicians in clinical trials 1 1 . Support clinical investigators.

12. Cover the cost of patient care in clinical trials. a

Front-office operations refer primarily to the Cooperative Group scientific committees and statistical offices, which are responsible for activities such as trial design, prioritization and data analysis.

b

Back-office operations refer to administrative structures and activities that include such things as data collection and management, data queries and reviews, patient registration, audit functions, case report form processing, image storage and retrieval, drug distribution, credentialing of sites, funding and reimbursement for patient accrual.

by Joan Chiverton eet you, I can’t m er check-up oth an t ye e ’m in.

I hav ial that I for the tr

Unfortunately, we can’t complete the trial.

The map on the cover illustrates the chair locations of the clinical trial groups.

Philadelphia hosts four: American College of Radiology Imaging Network, Eastern Cooperative Oncology Group, Gynecologic Oncology Group and Radiation Therapy Oncology Group. The others are Cancer and ogy Leukemia Group B, Chicago; Children’s Oncology urgeons Group, Arcadia, Calif.; American College of Surgeons Oncology Group, Durham, N.C.; National Surgical Adjuvant Breast and Bowel Project, Pittsburgh; North Central Cancer Treatment Group, Rochester, Minn.; and Southwest Oncology Group, Ann Arbor, Mich.

NCI funding for the system’s stagnation. Many clinical investigators and providers shoulder up to half the cost of their work, said Dr. Mendelsohn, and almost all investigators seek supplemental funding from other sources, such as drug companies. Furthermore, academic centers don’t adequately value cooperative group trials when evaluating faculty accomplishments, which discourage participation by potential researchers.

Fixing the System The committee laid out four broad goals—and supporting recommendations—for the system to regain its footing (see sidebar). To improve system efficiency, the committee advises consolidating back-office functions, committees and even cooperative groups themselves; streamlining review and oversight processes; increasing collaboration among various participants; and standardizing data collection and analysis. It also endorsed an NCI working group recommendation of a target timeline for Phase III trials of 300 days from protocol submission to final approval. The target timeline is 200 days for Phase II trials.

“What’s needed is a great deal more working together and harmonizing,” said David Dilts, PhD, director of clinical research at the Knight Cancer Institute and professor of health care management at the Oregon Health & Science University, Portland. Dr. Dilts, an operations management expert, considers the problem from the perspective of a systems engineer. “There is a significant amount of redundancy in the system that could be removed to dramatically streamline it without sacrificing safety or efficacy,” he said.

For example, not all proposals need to pass through completely different sets of scientific reviews and institutional review boards.

Other recommendations include instituting better processes for selecting trials most likely to succeed; incorporating more scientific innovation, such as identifying biomarkers that can predict therapeutic response (thus decreasing the number of patients a trial requires); centralizing operations such as data collection, data auditing and drug distribution; increasing NCI funding; and increasing recognition and rewards from academic centers for clinical investigators.

“The NIH and NCI should place comparable value on clinical research as it does on lab research,” said Dr. Mendelsohn. “That means covering the costs adequately.” Academic centers can help by honoring clinical investigators to the same degree they do lab researchers in terms of protected time, tenure and salary support.

Much of the report’s contents have been discussed in the past, said Dr. Mendelsohn. “Now we have to put it all together in a way that everyone can look at and say, ‘Wow, there’s something that really needs to be changed.’ There are many stakeholders, including patients, clinical investigators, government agencies like the NCI and FDA, pharmaceutical companies and payers,” Dr. Mendelsohn said.

“Each one is trying to achieve a common goal of translating scientific discoveries into new treatments that will benefit cancer patients, and each one will have to do some giving in order to make this system efficient and more powerful.”

—Steve Frandzel

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.

24

SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • JUNE 2010

Anemia

Concern Revving Up Over REMS For ESAs Oncologists are struggling to comply with requirements imposed by the FDA’s Risk Evaluation and Mitigation Strategy (REMS) program for erythropoietinstimulating agents (ESAs).

The REMS places an “especially significant burden” on community oncology practices, said Patrick W. Cobb, MD, president of the Community Oncology Alliance and managing partner of the Hematology-Oncology Centers of

the Northern Rockies, a nine-physician practice in Billings, Mont. “We’ve been asked to do a lot more for decreasing reimbursement for some time and this is another thing we are required to do. ... It’s definitely an extra amount of

work on already-burdened community physicians.”

A ‘Daunting Burden’ In April 2008, the FDA required Amgen Inc., to establish and oversee a REMS program for ESAs, which include epoetin alfa (Procrit, Centocor Ortho Biotech; Epogen, Amgen) and darbepoetin alfa (Aranesp, Amgen). The program was instituted in response to studies that found ESAs caused tumors

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

to grow faster and resulted in earlier deaths in certain cancer patients.

Under the long-awaited program unveiled in February, physicians and hospitals have one year to register, undergo training and be certified in order to continue prescribing and dispensing ESAs to cancer patients. Those who fail to comply by March 2011 will be barred from accessing ESAs. The REMS program requires that health care professionals give all patients receiving ESAs the FDA-approved Medication Guide containing information about the drugs’ risks and benefits. For cancer patients, a separate REMS APPRISE program (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) requires that physicians register with Amgen; complete a specific training module on ESA usage; discuss the risks, benefits and approved usage of ESAs with each patient before beginning treatment; and document this discussion with written acknowledgment from both doctor and patient. Health care providers must re-enroll in the program every three years.

“You have to document the meeting, have the patient sign the sheet, fax or scan it into the records,” Dr. Cobb said.

“There are significant steps involved in complying with it.”

Large academic centers face additional challenges. “There are many more questions than there are answers about the ESA REMS program, especially at large academic teaching hospitals,” said Samuel Silver, MD, PhD, director of the Cancer Center Network and assistant dean for research at the University of Michigan Health System, Ann Arbor.

He noted that on-label use of ESAs for cancer has been decreasing following previous FDA-required safety warnings, and patients are increasingly being transfused or having their hemoglobin levels allowed to drop to lower levels than in the past. Nevertheless, “patients receiving on-label ESAs might get admitted to general medical service and be cared for by hospitalists, surgeons, surgical interns and residents,” Dr. Silver said. “Do all of those practitioners need to take this program? If so, the number of potential prescribers in those cases becomes huge,” he said.

“It becomes just one of a number of mandatory things that physicians have to take during their time in the hospital,” Dr. Silver continued. And while the required discussion with a patient about

SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • JUNE 2010

Anemia

ESAs might only take a few minutes, “it just adds one more thing to an already complex visit.”

Until now, most REMS requirements have been for agents and classes of agents indicated for limited patient populations, said Bridget C. Fowler, PharmD, clinical pharmacy manager at Dana-Farber Cancer Institute’s Department of Pharmacy, in Boston. “This is the first one that’s impacting pharmacists and clinicians to such an extent,”

risk management, but they are not reimbursed for those services,” said David Chen, RPh, MBA, director of Pharmacy Practice Sections at the American Society of Health-System Pharmacists (ASHP). “This is another example of unintended side effects from restrictive drug distribution systems.”

Hospital Designee Another aspect of the REMS program is that it requires hospitals dispensing ESAs

‘Hospitals are incurring all the costs of risk management, but they are not reimbursed for those services. This is another example of unintended side effects from restrictive drug distribution systems.’

—David Chen, RPh

Dr. Fowler said “Some providers may just decide not to prescribe ESAs.” According to Timothy R. Franson, MD, senior vice president at B&D Consulting in Washington, D.C., and a former regulation and drug safety specialist at Eli Lilly & Co., the REMS for ESA use represents a “daunting burden at the bedside” because it “requires health care providers and institutions to be trained, certified and held strictly accountable for implementation.” The program is further “confounded,” he said, by new enforcement powers recently granted to the FDA to assess civil monetary penalties for compliance failures. “This could be a very real concern for manufacturers and practitioners,” Dr. Franson said.

In a recent statement to its members, the American Society of Clinical Oncology stated, “Oncologists continually struggle to provide high-quality cancer care in the face of dwindling resources and growing administrative burdens. “While ASCO supports efforts to raise risk awareness and promote patient safety, we strenuously object to duplicative requirements that further diminish time and resources available for patient care.”

Some clinicians wonder whether all the extra work will actually pay off.

The benefits of requiring “burdensome administrative processes” have not yet been validated in terms of risk reduction, said Dr. Franson.

Others worry about the cost of REMS. “Hospitals are incurring all the costs of

to designate someone to “assume the authority and responsibility” to internally coordinate and oversee the institution’s program. The hospital “designee” (often the pharmacy manager) is responsible for the hospital’s compliance. This entails completing a separate training module, compiling a list of everyone at the hospital who prescribes ESAs to cancer patients, maintaining proof that each one has enrolled in APPRISE, and archiving the written acknowledgments from every cancer patient who receives ESAs. “Failure of the staff to comply with enrollment requirements will lead to suspension of access to ESAs for your hospital,” Amgen warned.

In private-practice settings, the

registration and acknowledgment forms are required to be faxed or mailed to a third-party call center that oversees and monitors compliance.

Pharmacists are particularly concerned about the bookkeeping and time management burdens APPRISE will place on them, especially because the system is paper-based. “Most hospitals and physician practices are moving toward electronic medical records.

If we want the REMS forms to be electronic, we will have to scan them into our electronic systems,” said Niesha Griffith, RPh, pharmacy director at Arthur G. James Cancer Hospital, Ohio State University, in Columbus.

Additional time-consuming activities are likely if a medication order arrives without the necessary paperwork.

“While it may take only 10 minutes for

Dr. Fowler said. “The pharmacists will have to go through one central person who is the designee, and that’s not terribly user-friendly,” she explained.

According to Mr. Chen, APPRISE “puts the pharmacist in the middle of collecting and validating the information; it’s putting the pharmacist in the role of a compliance officer instead of a clinician,” he added. “We are starting to see pharmacy practice being driven by the risk of noncompliance to regulations versus building medication use systems that manage the risks for all patients in the institutions.”

Ms. Griffith concurred. “I am not sure the hospital pharmacy director is best to sign for the hospital enrollment because they don’t have any authority over the physicians who are expected to comply.

We cannot make them enroll, but then we are not permitted to give them the drugs if they don’t. It puts us in a very tenuous position.”

The hospital’s responsibility, she added, shouldn’t rest solely with pharmacy. “You have to engage risk management [lawyers], Medication Safety and Quality Committees, the P&T [pharmacy and therapeutics] Committee, as well as medical and nursing staffs that will be impacted by the program,” Ms. Griffith said. “It’s not just pharmacy—it’s a multidisciplinary issue.”

The REMS is the latest in a series of restrictions imposed by federal agencies on ESAs. In March 2007, the FDA ordered black box warnings to be added to labeling for ESAs and subsequently limited initiation to patients with hemo-

The program is further confounded by new enforcement powers recently granted to the FDA to assess civil monetary penalties for compliance failures.

the physician to print out the form and talk with the patient, when the order is sent to the hospital, if the sheet doesn’t accompany the order, the amount of time it will take to track it down will be much more than 10 minutes,” said Mr. Chen. And although individual pharmacists are not required to register and be APPRISE-certified, they also will not have access to the hospital’s master list to verify which physicians are registered,

globin levels of 10 g/dL or lower. In July 2007, the Centers for Medicare & Medicaid Services (CMS) issued a national coverage determination (NDC) denying ESA reimbursement for any anemia of cancer unrelated to chemotherapy. CMS also tied initiation to hemoglobin levels lower than 10 g/dL (hematocrit <30%) and for a maximum of eight weeks.

—Ted Agres

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25

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

SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • JUNE 2010

Pain

Cost Analysis for End-Stage Cancer Pain:

Intrathecal Therapy More Affordable Than Opioids A cost analysis of implanted intrathecal therapy versus long-acting opioids for patients with end-stage cancer pain has shown that intrathecal pumps are less costly than comprehensive medical management over a patient’s last year of life.

Although intrathecal (IT) therapy for pain dates back at least five decades, experts say that the approach is still widely underused in pain management for cancer patients, primarily because of concerns about significant up-front costs.

“I think it’s underused and used way too late in the [treatment] algorithm,” said Tim Deer, MD, president and chief executive officer of the Center for Pain Relief in Charleston, W.Va., and clinical professor of anesthesiology and pain medicine at West Virginia University, in Morgantown.

Previous research by Dr. Deer and others demonstrates that IT therapy has some advantages over opioid management from a quality-of-life (QoL) perspective for patients with terminal cancer pain (J Clin Oncol 2002;20:4040-4049, PMID: 12351602). When used for palliative care, patients report less fatigue and somnolence with IT pumps, as well as better overall QoL, said Dr. Deer.

“Not only is it better for them, but it’s also better for their caregivers,” he said.

“Systemic opioid therapy for these patients requires such huge doses, that yes, you can create a patient who has dramatically reduced pain, but they are so mentally clouded and not with it that they can’t communicate with their families in their final months of life,” said Robert Hurley, MD, PhD, associate professor of anesthesiology and chief of pain medicine at the University of Florida in Gainesville, and senior author of the new study.

Despite the QoL benefits of IT therapy for cancer pain, cost and reimbursement issues have hindered widespread use. In a survey Dr. Deer published in Pain Medicine in 2009 (10:304-309, PMID: 19254334), more than 90% of respondents who used IT therapy in their practices (n=87) reported that “reimbursement rates for filling, refilling and programming patient pumps are not adequate to cover practice costs.”

“Some physicians don’t offer the therapy because they just can’t afford to,” Dr. Deer said. “Patient access has been reduced in the past few years secondary to cuts in reimbursement and it’s unfortunate, because in many cases it would greatly enhance the patient’s life.”

A major problem, Dr. Hurley said,

is that the cost of IT therapy is poorly studied and there is little concrete data on when IT therapy should be initiated.

Last year, Dr. Hurley and a colleague, Meredith Adams, MD, a fellow in pain medicine at Johns Hopkins University in Baltimore, informally surveyed fellows and attending physicians at several major academic institutions, asking them how long it takes for the cost of opioids for palliative cancer pain to cross-over, or equal, the high up-front cost of IT pumps. There was wide variability in the responses, Dr. Hurley said; however, ultimately most physicians settled on three months. When asked why, many said they were trained that

way, based primarily on old data on the costs of IT therapy.

“The big problem was the way people were quoting [old] literature,” Dr. Hurley said. “Even though it’s old baseline data, it also was being entirely misrepresented in people’s recollections.”

Current Study To compare the costs of IT and systemic opioid therapies, Drs. Hurley and Adams retrospectively collected 2009 reimbursement data from the Centers for Medicare & Medicaid Services on IT pumps for the last year of life in patients with metastatic cancer. This included costs of professional and facility fees, medication and pump reprogramming. They then developed four therapeutic models based on national standards of practice, which varied in expense based on the type of pretherapeutic trial (e.g., outpatient vs. inpatient trial) and whether hydromorphone or ziconotide (Prialt, Elan) was used in the IT pump.

The least expensive model—a “single-

‘A lot of [physicians] think, “It’s a very expensive therapy and this patient is going to pass away in one or two months,” and it becomes very hard to get an insurance company to understand the high up-front cost will actually save them in the long run.’

—Robert Hurley, MD, PhD

shot,” outpatient trial followed by IT hydromorphone—averaged $36,000 in the last year of life for cancer patients.

The most expensive—an inpatient trial followed by IT ziconotide—cost approximately $66,000 for the same patient population.

According to published research, the total health care costs in the last year of life for patients with metastatic cancer on long-acting opioids ranged from $76,446 to $90,935, depending on the type of opioid used (Manag Care Interface 2004;17:28-34, PMID: 15108758).

The overall cost of long-acting opioids comes not from the cost of drugs, however, Dr. Hurley said, but from hospital readmissions. Many terminal cancer patients are readmitted to hospitals with a primary diagnosis of refractory pain, which for end-of-life cancer patients usually means admission to an intermediate care or intensive care unit.

“That is where the cross-over point becomes very clear,” Dr. Hurley said. “If you have multiple admissions throughout a year, you will very rapidly pay for intrathecal care, provided it keeps them [patients] from getting admitted.” Dr. Hurley added that only prospective studies will be able to address questions about hospital admissions for patients with IT pumps, but at his institution and at Johns Hopkins, use of IT pumps has been shown to prevent cancer patients from being readmitted with a primary diagnosis of pain.

Ultimately, Dr. Hurley said this cost study is only the first of several that he hopes will provide clear data on when to initiate IT therapy.

“The No. 1 barrier has been cost, and this is why we have gone after this,” he said. “A lot of [physicians] think, ‘It’s a very expensive therapy and this patient is going to pass away in one or two months,’ and it becomes very hard to get an insurance company to understand the high up-front cost will actually save them in the long run.

“This is purely the cold hard facts of looking at the money side,” he added.

“This is an attempt to show, at least, if you were simply a bean counter, could you be convinced that [IT] therapy is at least cheaper to provide. Stage 2 [of the research] will actually be the cost– benefit analysis.”

Results of the study were presented at the annual meeting of the American Society of Regional Anesthesia and Pain Medicine in San Antonio (abstract ID 2).

—Gabriel Miller

31

32

FDA NEWS

Tarceva Approved for Maintenance Therapy For Lung Cancer

CLINICAL ONCOLOGY NEWS • JUNE 2010

patients receiving erlotinib were rashlike events and diarrhea.

This approval is erlotinib’s second indication in locally advanced or metastatic NSCLC. Erlotinib was originally approved in November 2004 for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

Cellular Immunotherapy Approved for Advanced Prostate Cancer

T T

he FDA has approved erlotinib (Tarceva, Genentech) for maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

In a randomized double-blind, placebocontrolled, multinational trial, 889 patients with locally advanced or metastatic NSCLC whose disease did not progress during first-line platinum-based chemotherapy were randomized (1:1) to receive either erlotinib (150 mg) or placebo orally once daily until disease progression or unacceptable toxicity. The primary end point was whether adding erlotinib to platinum-based chemotherapy improved progression-free survival (PFS) compared with placebo in either all patients or in patients with endothelial growth factor receptor (EGFR) immunohistochemistry (IHC)-positive tumors.

Overall survival (OS) was a secondary end point in the trial but was designated as the regulatory end point for approval of this indication.

Patient demographics and disease characteristics were balanced between the two groups. Approximately 70% of patients’ tumors were EGFR-positive. The hazard ratio for PFS was 0.71 (95% confidence interval [CI], 0.62-0.82; P<0.0001).

The hazard ratio for OS was 0.81 (95% CI, 0.70-0.95; P=0.0088). The PFS and OS hazard ratios in patients with EGFR IHCpositive tumors were 0.69 (95% CI, 0.580.82) and 0.77 (95% CI, 0.64-0.93), respectively. The PFS and OS hazard ratios in patients with IHC-negative tumors were 0.77 (95% CI, 0.51-1.14) and 0.91 (95% CI, 0.59-1.38), respectively. Following disease progression, a greater proportion of patients in the placebo group (57%) received second-line treatment for NSCLC compared with the erlotinib group (47%). Of the 259 patients in the placebo group who received secondline treatment, 37 (14%) received either erlotinib or gefitinib (Iressa, AstraZeneca) at first progression, 80 (31%) received docetaxel, and 37 (14%) received pemetrexed. In total, 59% of patients in the placebo group who received treatment at the time of tumor progression received FDA-approved second-line NSCLC drugs.

The safety results for patients treated with erlotinib were consistent with the known safety profile previously described in product labeling. The most common (>20%) adverse reactions in

he FDA has approved sipuleucel-T (Provenge, Dendreon), an autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic, castrationresistant prostate cancer (CRPC).

Provenge is designed to induce an immune response against prostatic acid phosphatase, an antigen expressed in most prostate cancers, and is the first in a new therapeutic class known as autologous cellular immunotherapies.

A product shot of Provenge during the manufacturing process

Approval was based on the Phase III IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) trial (D9902B), a multicenter, randomized, double-blind, placebo-controlled study that evaluated 512 men with asymptomatic or minimally symptomatic, metastatic CRPC. Provenge increased median overall survival by 4.1 months; median overall survival for patients receiving Provenge treatments was 25.8 months compared with 21.7 months for those who did not receive the treatment. Overall, Provenge reduced the risk for death by 22.5% compared with the control therapy (hazard ratio, 0.775).

Almost all of the patients who received Provenge had some type of adverse reaction. Common adverse reactions reported included chills, fatigue, fever, back pain, nausea, joint ache and headache. The majority of adverse reactions were mild or moderate. Serious

adverse reactions, reported in approximately one-fourth of the patients receiving Provenge, included acute infusion reactions and stroke. Cerebrovascular events, including hemorrhagic and ischemic strokes, occurred in 3.5% of patients in the Provenge group compared with 2.6% of patients in the control group.

Dendreon says it intends to make Provenge available through approximately 50 centers, all of which were approved Provenge clinical trial sites, and expects to increase capacity over the next year.

More Abuse-Resistant Formulation of Opioid Gets the Green Light

T

he FDA has approved a new formulation of the controlled-release drug oxycodone (OxyContin, Purdue Pharma) that has been designed to help discourage misuse and abuse of the medication.

OxyContin slowly releases the potent opioid oxycodone to treat patients who require a long-term, continuous, opioid analgesic for management of moderate to severe pain. Because of its controlledrelease properties, each tablet contains a large quantity of oxycodone, which allows patients to take the drug less often. However, the previous formulation enabled individuals intent on abusing the drug to release high levels of oxycodone all at once, which can result in a fatal overdose and contributes to high rates of OxyContin abuse.

The reformulated OxyContin is intended to prevent the opioid medication from being cut, broken, chewed, crushed or dissolved to release more medication.

The new formulation may be an improvement that may result in less risk for overdose due to tampering, and will likely result in less abuse by snorting or injection; but it still can be abused or misused by simply ingesting larger doses than are recommended.

“Although this new formulation of OxyContin may provide only an incremental advantage over the current version of the drug, it is still a step in the right direction,” said Bob Rappaport, MD, director of the Division of Anesthesia and Analgesia Products in the FDA’s Center for Drug Evaluation and Research. “As with all opioids, safety is an important consideration,” he said.

“Prescribers and patients need to know that its tamper-resistant properties are limited and need to carefully weigh the benefits and risks of using this medication to treat pain.”

According to the U.S. Substance

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Abuse and Mental Health Services Administration’s National Survey on Drug Use and Health, approximately 500,000 people used OxyContin nonmedically for the first time in 2008.

The manufacturer of OxyContin will be required to conduct a postmarketing study to collect data on the extent to which the new formulation reduces abuse and misuse of this opioid. The FDA is also requiring a Risk Evaluation and Mitigation Strategy (REMS) that will include the issuance of a Medication Guide to patients and a requirement for prescriber education regarding the appropriate use of opioid analgesics in the treatment of pain.

Agency Takes Steps to Reduce External Infusion Pump Risks

T

o address the safety problems associated with external infusion pumps, the FDA has launched a comprehensive “infusion pump improvement initiative” that includes proposed strict regulations for manufacturers and practice suggestions for pharmacists and clinicians.

As part of its initiative, the FDA is moving to establish additional premarket requirements for infusion pumps, in part through the issuance of a new draft guidance and letter to infusion pump manufacturers. The initiative, said Jeffrey Shuren, MD, director of FDA’s Center for Devices and Radiological Health, represents a “major shift” in its approach to medical device safety.

From 2005 to 2009, FDA received more than 56,000 reports of problems associated with infusion pumps involving 710 deaths, more than 19,000 serious injuries and nearly 35,000 malfunctions.

Some of the deaths were due to accidental overdose from clinician error or device malfunction, according to the agency.

The most common problems involved software, human factors (user error), broken components, and alarm and battery failures. One example is the problem of “key bounce,” in which a number entered into a keypad is recorded more than once, resulting in overmedication.

Many of these problems are due to design defects that are “foreseeable and preventable,” according to Dr. Shuren.

Under the draft regulations, FDA will require manufacturers to provide detailed design and engineering information in their premarket submissions, including steps taken to mitigate risks in design, manufacture, maintenance and use. Manufacturers must also test their pumps in hospital and home settings to uncover real-life environmental and user issues, instead of relying on simulated testing. And for the first time, FDA could inspect manufacturing plants prior to approval.

Representatives of major pump manufacturers, including Baxter Healthcare, Medtronic and CareFusion, said their companies were still reviewing the proposed regulations but supported FDA efforts to improve safety.

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.

34

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • JUNE 2010

Health Care Costs

INITIATIVES continued from page 1

how treatments really work for patients.

Community providers have an important role to play in this process and can benefit from the outcome.

Reality Check The future of health care depends on dealing with realities. The United States’ success rate in treating chronic disease lags behind that of other industrialized nations, and yet it touts itself as having the best health care. At the pace of health

care cost escalation in the United States, the system cannot provide all treatment options to every patient. There just isn’t enough money. Average individual and family incomes have not grown in proportion to health care costs, and typical employers’ profits can’t keep pace with rising insurance premiums, let alone take on full health care costs.

People often say that reform will involve the government in decision making and they support the free market system driving health care decisions, in which if you can pay, you get the care you need. The problem is that most people don’t recognize that they

can’t afford to have a serious illness.

Individuals don’t pay—they count on insurance. Many people don’t see the inequalities or problems with insurance coverage until they or someone they love gets sick. Often, it is only then that they realize that they can’t afford the services they need.

So, what is the solution? Some thought leaders have advocated for a health care system in which the unhealthy pay more, because of the perception that poor health is caused by a lack of willpower to make health-promoting choices. The fairness and logistics of how this would work, however, are rather questionable.

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

A Tool for Change The Pritchard Group is an advocate of designing a system based on comparative effectiveness research that provides consumers with appropriate information that they can use to work with their providers to make quality care choices.

It is not a one-step process to get from today’s insurance-driven, high-liability model to a provider-driven, patientchoice one, and community oncologists need to be involved. Some influential scholars may argue to refocus health care on large “institutes of excellence” with maintenance roles played by community providers. A system in which decision making is driven solely by academicians without community input, however, will not produce the best outcomes.

Prostate cancer has been identified as a good candidate for an initial comparative effectiveness project for several reasons.

Providers including oncologists must actively engage in the health care dialogue in substantive ways to create influence. They must provide input into comparative effectiveness initiatives that study medical interventions by outcome and total cost and rank them, so that doctors and patients have a tool to chart a course of treatment. This system promotes innovation and will identify patients who would best respond to treatment X versus treatment Y. Oncologists can begin by agreeing on data collection tools for specific tumor sites and pairing treatment outcomes (both clinical and quality of life) with a one-year price tag. Data could be collected over five years or more and all providers would collect the same data. Programs around the country would have access to the same collected data that they can then share with patients. Treatment choice would remain with the patients who would base their decision on real data from providers. This system allows providers to follow their passion for providing the best patient care, and it creates a shared decision-making process that patients will value. It leaves the decision-making process in the doctor– patient realm, and it reduces liability risk because the information is more obvious to the patient.

Oncologists can jumpstart the comparative effectiveness movement by setting a course to collect data, by not settling for standardized process programs, and by emphasizing that value is not about saving money but rather about saving patients. Innovation can be used to drive cost down as outcomes are proven.

Prostate cancer has been identified

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • JUNE 2010

Drug Financing

How To Sift Through 340B Resources Katheryne Richardson, PharmD Senior Quality and Compliance Specialist

Table 1. 340B-Focused Organizations

Danielle Mathers

Organizationa

Description

Communications Manager

340B Prime Vendor Program (PVP) https:// www.340bpvp.com/ public/about/

The organization is responsible for the negotiation of pharmaceutical pricing below the 340B price as well as improving access to affordable medications by establishing a distribution network for pharmaceuticals to covered entities. The program is free and voluntary to facilities that are already 340B-eligible.

Safety Net Hospitals for Pharmaceutical Access (SNHPA) http://www.snhpa. org/public/index.cfm

SNHPA monitors, educates and serves as an advocate on federal legislative and regulatory issues related to 340B pricing and other pharmacy matters affecting safety net providers.

Pharmacy organizations

Some examples include the American Pharmacists Association (APhA), the American Society of HealthSystem Pharmacists (ASHP), the Academy of Managed Care Pharmacy (AMCP), the National Community Pharmacists Association (NCPA) and the National Association of Chain Drug Stores (NACDS).

Health care/policy organizations

Some examples include the National Conference of State Legislatures (NCSL), the National Association of Community Health Centers (NACHC), State and Regional Primary Care Associations, the National Governors Association (NGA), the National Rural Health Association (NRHA), the American College of Healthcare Executives (ACHE), the National Council for Prescription Drug Programs (NCPDP), the National Alliance of State and Territorial AIDS Directors (NASTAD), the National Family Planning & Reproductive Health Association (NFPRHA), the Child Health Corporation of America (CHCA), the National Association of Children’s Hospitals and Related Institutions (NACHRI) and the National Association of Children’s Hospitals (NACH).

Health Resources and Services Administration, Pharmacy Services Support Center

T

here are various sources of information on the 340B Drug Pricing Program, and it can be hard to decipher what information is good and what information is not. This article outlines some of the organizations and resources available to help you with the 340B program.

The Pharmacy Services Support Center The Health Resources and Services Administration (HRSA) Pharmacy Services Support Center (PSSC) is the government-approved resource for all 340B information. PSSC operates through a contract between HRSA and the American Pharmacists Association (APhA).

PSSC was created to help federally funded clinics and other health care safety net providers develop clinically and costeffective pharmacy services. Central to this endeavor is optimal use of the 340B Drug Pricing Program, which is run by the Office of Pharmacy Affairs (OPA) in the HRSA Healthcare Systems Bureau.

PSSC provides free information, education and technical assistance to increase patient access to affordable drugs and pharmacy services.

Reach out to the PSSC call center (800) 628-6297 for any questions concerning 340B. This free resource is available to help with all of your 340B inquiries. Staff, trained in the various issues relating to the 340B program, is on hand to answer questions or direct your calls to the appropriate people. The call center operates 9 a.m. to 4:30 p.m. (Eastern Time). Or e-mail PSSC anytime at

PSSC@aphanet.org.

In addition to the call center, PSSC manages a free technical assistance (TA) program, PharmTA, in partnership with OPA. This resource provides 340B-eligible entities solutions

a

Government programs

Each government program that is involved with eligible entities closely works with the Office of Pharmacy Affairs on 340B-related issues. Some examples include the HRSA Office of Pharmacy Affairs, the HRSA Bureau of Primary Healthcare, the HRSA Office of Rural Health Policy/Rural Assistance Center (RAC), the Indian Health Service, Centers for Disease Control and Prevention, and the FDA.

Other

The primary mission of these organizations is not 340B-specific, but they do stay engaged in 340B issues.

HRSA PSSC does not endorse or hold a position on any of the above stakeholders’ specific practices pertaining to 340B guidance.

directly from expert pharmacist consultants. An objective-based work plan guides the process, and TA is delivered

via phone, e-mail or site visit. Call (800) 628-6297 or e-mail PSSC@aphanet.org to request this service.

The 340B Journey PSSC developed the 340B Journey, an extranet, as a place to put all of the most reliable 340B information. The 340B Journey is a collection of resources—links, documents, photos, videos, tools and presentations. PSSC has sifted through all of the 340B information available on the Internet and vetted that information so that only the best and most accurate 340B resources were posted on the site.

The site is organized into the following sections: Tip of the week: This section changes on a weekly basis and contains general information that offers quick assistance to users.

Quick search: The quick search tool allows users to search the site for key terms. This tool also searches the entire APhA library for relevant information. see 340B, page 36

Medical Records

INITIATIVES continued from page 34

as a good candidate for an initial comparative effectiveness project for several reasons. Many successful treatment options are available and therapy costs vary greatly. For example, surgery costs roughly $26,000, intensity-modulated radiation therapy approximates $50,000, and proton beam therapy can

amount to $100,000. Secondly, outcomes are about more than cancer-free status—data show that quality of life is a critical component of men’s satisfaction with their treatment. Third, welldefined data recording devices exist.

And finally, most prostate cancer programs do not track data and a central data bank for information sharing does not exist.

It is possible to work on overcoming these obstacles. Oncologists can begin

Clinical Oncology and other organizations are working in that area now. They can also require that quality-of-life data be collected post-treatment and create several database repositories for comparison. Oncologists can share data that no payer has access to. We can begin with prostate cancer.

—Mary Lou Bowers, MBA by agreeing on the data that need to be collected, and the American Society of

President & CEO of The Pritchard Group, LLC, Rockville, Md. www.thepritchardgroup.net

35

36

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • JUNE 2010

Drug Financing

Table 2. 340B Member Organizationsa

340B

Service Providers

continued from page 35

Getting started: This section contains comprehensive information for all entities in the 340B program. Folders are titled with all of the different entity types; users simply click on the folder of choice to find all of the information they need to enroll and implement the 340B program at the eligible site. Any entity-specific information also is listed in this section.

Policy and education: Users can find relevant PowerPoint presentations, 340B educational modules and the most current policy information. PSSC’s Policy Blast, a newsletter containing policy developments specific to the 340B program, can be found here.

Patient safety and quality initiatives: This section includes all of the latest information and resources relating to the HRSA Patient Safety and Clinical Pharmacy Services Collaborative and other federal and private sector programs relating to improving patient safety.

Resources: This section contains Access for All articles, recommended journal lists, PSSC presentations, links to other Web sites, PSSC’s tools and a page for consumers.

340B spotlight: Scrolling lists of breaking news and upcoming 340B meetings are presented in this section.

Links: This section highlights PSSC’s social networking group on LinkedIn, the 340B resource network.

All sections of this site are fully searchable and the information can be easily e-mailed or printed. This resource is continually updated as the PSSC staff discovers new resources available to assist the safety net community. So check back frequently for new updates.

To access the 340B Journey, go to the PSSC Web site (http://pssc.aphanet. org) and click on the luggage tag.

Distribution

Data Management (Services/ Systems)

Consulting

340B Partners Pharmacy, LLC ✔

AmerisourceBergen

✔

✔

✔

✔

✔

✔ ✔

✔

✔

✔ ✔

Centric Health Resources ✔

Coordinated Care Network CVS Caremark

✔

Physician Dispensing

✔

Capture Rx Cardinal

Pharmacy Dispensing Services

✔

APS Pharmacy A-S Medication Solutions

Disease Management (Services/ Software)

✔

AmeriChoice

✔

✔

✔

✔

✔

✔

✔

✔

Dispensing Solutions Inc eAudit Solutions

✔

eRx

✔

EquiScript

✔

Global Pharmaceutical Solutions

✔

✔

Good Health Systems Inc

✔

Hudson Headwaters

✔

Huron

✔ ✔

Innovation Associates Integrated Informatics McKesson

✔

Morris & Dickson

✔

✔

✔

✔

✔

✔

Net-Rx

✔

✔

✔

✔

✔

✔

Pharmacy Services Support Center

a

✔

✔

Ramsell Public Health Rx

✔

✔

RxStrategies

✔

✔

S/T Health Group Consulting, Inc

✔

✔

Sentry Data Systems

✔

✔

Speed Script

✔

✔

SunRx

✔

Talyst

✔

WellPartner

✔

Wilkinson Benefit Consultants

✔

✔

Pharmacy HealthCare Solutions

ScriptPro

✔

✔

NEC Networks, LLC

Qs1

✔

✔

Navigant

PDX, Inc.

✔

✔

National Direct Home Pharmacy

In the 340B environment, there are organizations that represent the voices of members and/or provide solutions to issues that impact 340B stakeholders.

These include 340B-focused and other organizations. Table 1 offers additional information; however, it does not detail each organization due to space limitations. Any omission is unintentional.

Over the last several years, the 340B marketplace has expanded exponentially. There are a variety of vendors and consultants that offer 340B-related services (Table 2), ranging from assistance with 340B compliance to data management and capture. Many of the organizations that appear in Table 1 also offer 340B services, but are not repeated in Table 2. The descriptions in Table 2 have been kept intentionally brief

Pharmacy Operations (Software/ Hardware)

American Health Care

340B Organizations

Service Providers

Category of 340B Service

✔

✔ ✔

HRSA PSSC does not endorse or hold a position on any of the above stakeholders’ specific practices pertaining to 340B guidance.

Category Key: Distribution: drug distribution and reverse distribution services (there are at least 13 regional/specialty distributors that were not included in this table due to space constraints; some are detailed on the Prime Vendor Program’s Web site under Agreements, Distributors); Pharmacy Operations (Software/Hardware): pharmacy dispensing software, interactive voice response systems, pharmacy automation systems, telepharmacy, central fill; Data Management (Services/Systems): split billing, pharmacy benefit management, contract pharmacy data services, overcharge recovery services; Consulting: 340B compliance, operational improvement assistance, program evaluation, legal advice; Disease Management (Services/Software): software, provision/administration of disease management services; Pharmacy Dispensing Services: contract pharmacy services; due to space constraints, only organizations that were easily identifiable via Internet searching appear here; there are a large number of potential contract pharmacies; Physician Dispensing: in-clinic medication, systems that allow dispensing by a non-pharmacist.

due to space limitations, and the contents represent the results of an Internet search conducted in December

2009. Thus, the table may not include every possible vendor; any omission is unintentional.

For more information on resources available, contact PSSC at (800) 6286297 or PSSC@aphanet.org.

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • JUNE 2010

37

Medical Records

T

he American Medical Association (AMA) and other organizations have filed a lawsuit in federal court seeking to prevent the Federal Trade Commission (FTC) from extending the Red Flags Rule to physicians. The rule requires creditors to implement safeguards against identity theft. The suit charges that the FTC’s rule exceeds the powers delegated to it by Congress and that its application to physicians is “arbitrary, capricious and contrary to the law.” Other organizations joining the AMA in its legal battle include the American Osteopathic Association (AOA) and state medical societies.

“This unjustified federal regulation of medicine treats physician practices like banks, credit card companies and mortgage lenders,” said Cecil B. Wilson, MD, AMA president-elect, in a press statement. “The extensive bureaucratic burden of complying with the Red Flags Rule outweighs any benefit to the public.”

The HIPAA of 1996 made protecting the privacy of patients a top priority for hospitals, health care providers, insurance companies and other entities. Now, the FTC, which promulgated the rule, hopes the Red Flags Rule will combat a potentially even greater threat to patients: identity theft.

At the heart of the FTC’s Identity Theft Red Flags Rule program is the agency’s assertion that physicians, by accepting credit cards and deferring payments, are “creditors” or “financial institutions,” and therefore are covered

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under banking regulations regarding consumer privacy. The program mandates that medical practices must create and institute programs that are appropriate to their size and operation, with the goal of identifying and detecting patterns, practices and activities that indicate the possible breach of privacy of patient data. The FTC calls such breaches “red flags.”

Identity thieves increasingly are focused on stealing medical records, which contain not only Social Security and credit card numbers, billing addresses and dates of birth, but also insurance and personal health information. Thieves can use this information

not only to obtain goods, open accounts and more, but also to seek medical care in the victim’s name, ultimately corrupting the victim’s true medical history and records and sometimes receiving care for which the victim is billed. According to the FTC, 4.5% of the annual 8.3 million victims of identity theft had their medical information plundered.

Many individuals say that physicians already are responsible ethically and legally for ensuring the confidentiality and security of patient medical information and that it is unnecessary to add to the existing web of federal security regulations they must follow.

“The final Red Flags Rule provided no indication from the FTC that physicians fell within the definition of creditor. The FTC’s decision to apply the rule to physicians is both misguided and inconsistent with its regulatory power,” commented Larry A. Wickless, DO, president of the AOA. The lawsuit follows two years of communications to the FTC from the AMA and AOA regarding the unintended consequences of the rule. On Jan. 27, the AMA and AOA joined other groups to petition the FTC to exclude physicians from the Red Flags Rule. The FTC responded on March 25 saying it could not accommodate the request.

Unmet needs.

Unmet needs met.

That’s our focus at EMD Serono.

EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany, has a global commitment to developing new therapeutic options for people living with cancer. We are focused on developing novel cancer therapies that combine approaches targeting the tumor cell, tumor environment and immune system to optimize treatment outcomes.

We’ve developed leading medicines for multiple sclerosis, fertility, growth hormone deficiency and HIV-associated

wasting. We’re one of the world’s leading biopharmaceutical companies. And our values are reflected not only in our products, but in our programs of patient education and support, such as MS LifeLines®, Fertility LifeLines™, SeroCareSM and Connections for Growth®.

The people of EMD Serono are focused on significant unmet medical needs. Meeting them. And helping people live more fully.

Embracing life. Enhancing life. That is the spirit of EMD Serono. www.emdserono.com

©2010 EMD Serono, Inc.

Doctors Sue Over Identity Theft Regulations

CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS • JUNE 2010

New Phase II and III Clinical Trials

Hematologic

Solid Tumors

Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to May 11, 2010. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Supportive

38

Protocol Type

Age

Protocol ID

Trial Sites

Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple-Negative Breast Cancer, Phase I/II

18 to 90

10-005

NJ, NY

Study of a Novel Indibulin Dosing Schedule for the Treatment of Metastatic Breast Cancer, Phase I/II

18 and over

IBL2001

NY

Hormone Therapy and Combination Chemotherapy Before and After Surgery in Treating Women With Hormone ReceptorPositive Breast Cancer That Can be Removed by Surgery, Phase II

18 and over

CDR0000564756

WA

Cone Beam Computed Tomography for Breast Imaging, Phase II

35 and over

KCT-003

NY

Cyclophosphamide and Paclitaxel With or Without Trastuzumab in Treating Women With Stage I or Stage II Breast Cancer Who Have Undergone Surgery, Phase II

19 and over

371-09

NB

Eribulin Mesylate in Combination With Intermittent Erlotinib in Patients With Previously Treated, Advanced Non-Small Cell Lung Cancer (NSCLC), Phase II

18 and over

E7389-G000-205

AL, CA, CO, DC, FL, KS, MI, MO, NV, OR, TX, VA, WA

Study of Erlotinib With or Without Investigational Drug (CS-7017) in Subjects With Advanced NSCLC, Phase II

18 and over

CS7017-A-U204

OH

Study of Paclitaxel, Carboplatin and YM155 (Survivin Suppressor) in Subjects With Solid Tumors (Phase I) and Advanced NSCLC (Phase II)

18 and over

100051

MD

Study of PXD101 (Belinostat) in Combination With Cisplatin, Doxorubicin and Cyclophosphamide in the First-Line Treatment of Advanced or Recurrent Thymic Malignancies, Phase I/II

18 and over

100077

IN, MD, NY

Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma, Phase II

18 and over

UPCC 03510

PA

Docetaxel, Cisplatin, Fluorouracil, Bevacizumab, and Radiation Therapy in Treating Patients With Advanced Nasopharyngeal Carcinoma, Phase II

18 and over

SU-030520091958

CA

Clinical and Translational Study of STA-9090 (colon cancer), Phase II

18 and over

10-029

NY

Study of Selumetinib (AZD6244) (ARRY-142886) in Combination With Irinotecan in Previously Treated Patients With Colorectal Cancer, Phase II

18 and over

D9010C00009

CA

Study of E7080 in Subjects With Advanced Endometrial Cancer and Disease Progression, Phase II

18 and over

E7080-G000-204

AZ, IL, MN, OR, TX, VA, WA

Re-irradiation With Fractionated Stereotactic Radiosurgery Plus Cetuximab in Patients With Recurrent Squamous Cell Carcinoma of the Head and Neck, Phase II

18 and over

UPCI 06-093

PA

Everolimus Versus Placebo in Head and Neck Cancer, Phase II

18 and over

09-266-B

IL

TPI 287 in Patients With Recurrent Glioblastoma Multiforme, Phase II

18 and over

2009-0759

TX

A Panobinostat Presurgery (glioblastoma), Phase II

18 and over

00020612

NC

Bevacizumab, Irinotecan and Temozolomide for Relapsed or Refractory Neuroblastoma, Phase II

Any age

10-015

NY

A Trial of ABT-888 in Combination With Temozolomide Versus Pegylated Liposomal Doxorubicin Alone in Ovarian Cancer, Phase II

18 and over

M10-757

CA, IL, NC, NM, OH, OK, PA, WI

An Assessment of an Attenuated Live Listeria Vaccine in Cervical Intraepithelial Neoplasia 2+, Phase II

18 to 45

Lm-LLO-E7-07

FL

Velcade and Sorafenib in Unresected or Metastatic Renal Cell Carcinoma, Phase II

18 and over

INST 0812

NM

Dacarbazine and Recombinant Interferon Alfa-2b in Treating Patients With Primary Uveal Melanoma With Genetic Imbalance, Phase II

Not specified

CASE2609

OH

Study of Brentuximab Vedotin (SGN-35) for Prevention of Hodgkin Lymphoma Progression (The AETHERA Trial), Phase III

18 and over

SGN35-005

CA, CO, IL, MI, NY, OR, PA, SC, TX, VA

Study to Evaluate the Efficacy and Safety of Treatment With Bendamustine in Combination With Ofatumumab in Previously Untreated Patients With Indolent B-Cell Non-Hodgkin’s Lymphoma, Phase II

18 and over

C18083/2048

FL

Does Maitake Mushroom Extract Enhance Hematopoiesis in Low-Risk, Untreated Myelodysplastic Patients, Phase II

18 and over

09-094

NY

Eltrombopag in Elderly Acute Myelogenous Leukemia, Phase I/II

60 and over

UPCC 17409

PA

Study of 0.1% Uracil Ointment for the Prevention of Hand-Foot Syndrome, Phase I/II

18 and over

OIC-1UO-C001

AL, IN, KS, OH

Comprehensive Patient-Reported Outcomes Management for Oncology Practice, Phase I/II

18 and over

HC4ext

AZ, WA

Contingency Management for Smoking in Substance Abusers, Phase II

18 and over

08-081-2

CT

Naltrexone for At-Risk and Problem Drinking in Smoking Cessation Treatment, Phase II

18 and over

NIAAA-17181-1

RI

Topiramate to Aid Smoking Cessation in Alcohol-Dependent Men, Phase II

18 to 65

NEUA-003-08S

OH

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A Guide to Cancer Genetics in Clinical Practice Sue Clark

This book covers the basic concepts of cancer genetics. The common inherited cancer syndromes are each dealt with in greater depth, with the current management outlined.This book is aimed at all clinicians who may encounter these conditions in their practice. It aims to facilitate identification of high-risk individuals and families, to inform interaction with geneticists and other subspecialists, to provide a basis for patient management and to stimulate interest in these fascinating conditions.

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Atlas of Diagnostic Oncology Arthur T. Skarin

Atlas of Diagnostic Oncology, Fourth Edition, by Arthur T. Skarin, MD, FACP, FCCP, provides the guidance you need to diagnose a full range of neoplastic conditions with greater accuracy for better patient outcomes. An unrivaled collection of more than 2,500 images and drawings— combined with succinct, clinically focused text—equips you with essential information on pathology, diagnostic studies, staging and clinical manifestations. New discussions on modern diagnostic PET imaging of cancer, and expanded coverage on the side effects of chemotherapy, bring you up to date on the issues impacting research and treatment.

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Cancer and its Management

4

Cancer Pain: Assessment and Management

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Dahlin’s Bone Tumors: General Aspects and Data on 10,165 Cases

Jeffrey Tobias; Daniel Hochhauser

This book is an excellent practical text that presents information on all the major cancers in a clear, concise, and coherent way. Each chapter covers screening, pathology, clinical features, diagnosis, staging, management, and prognosis of a specific cancer.

This problem-oriented approach makes the book ideal for use in the clinical setting.

Eduardo D. Bruera; Russell K. Portenoy

Drs. Eduardo D. Bruera and Russell K. Portenoy have completely revised and updated the widely respected Cancer Pain: Assessment and Management for the second edition of this unanimously praised book. This is a comprehensive, clinically oriented review of all aspects of the complex and multidimensional problem of cancer pain, including many new chapters.

K. Krishnan Unni; Carrie Y. Inwards

The classic text on Mayo Clinic’s experience with bone tumors, Dahlin’s Bone Tumors presents a succinct, profusely illustrated summary of the largest single collection of well-diagnosed bone tumors anywhere in the world. This updated sixth edition contains a strong blend of archival material and new cases, and incorporates the latest knowledge about the grading and staging of these tumors.

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Early Diagnosis and Treatment of Cancer Series: Head and Neck Cancers: Expert Consult - Online and Print Wayne M. Koch, MD

Each volume in this series is packed with practical, authoritative information designed to cover the full range of diagnostic procedures, including pathologic, radiologic, bronchoscopic and surgical aspects. You’ll be able to determine the safest, shortest, leastinvasive way to reach an accurate diagnosis; stage the disease; and choose the best initial treatment for early stages. Based on current evidence in the literature, authors provide clinical, hands-on tools to help you make informed decisions on precisely what tests and imaging studies are needed to diagnose and stage each type of cancer.

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Early Diagnosis and Treatment of Cancer Series: Ovarian Cancer

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ESMO Handbook of Cancer Prevention

Robert Bristow; Deborah Armstrong

Each volume in the Early Detection and Treatment of Cancer Series is packed with practical, authoritative information designed to cover the full range of diagnostic procedures, including pathologic, radiologic, bronchoscopic and surgical aspects. You’ll be able to determine the safest, shortest, least-invasive way to reach an accurate diagnosis; stage the disease; and choose the best initial treatment for early stages.

Dirk Schrijvers; Hans-Jörg Senn; Håkan Mellstedt; Ursula Kapp; Branko Zakotnik

This handbook summarizes the fast-moving world of research into the genetics and prevention of cancer. An international selection of experts here present the points of most relevance for oncologists and those involved professionally with screening and chemotherapy programs.

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Kuerer’s Breast Surgical Oncology

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How to Work Less and Make More

Henry M. Kuerer

Written by an internationally recognized multidisciplinary team of authors, Kuerer’s Breast Surgical Oncology is the first text specifically dedicated to breast surgical oncology. Turn to any page, and you’ll find cutting-edge, evidence-based information and insights — supplemented by a full-color presentation and a companion DVD — all designed to help provide a solid foundation for current and future best practices.

David B. Mandell, JD, MBA

In this lecture, the author educates doctors on how they can become a “CEO” of their practice and career— focusing on the legal, financial and business issues that physicians so often ignore. Specific topics include how to shield both practice and personal assets from medical malpractice, employment and other types of lawsuits, designing the medical practice for maximum financial value to the doctor, and more.

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