Clinical Oncology News - May 2009 - Digital Exclusive Edition

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Advances in Cancer Care CLINICALONCOLOGY.COM • MAY 2009

FDA NEWS

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• Everolimus approved for advanced kidney cancer.

• Bevacizumab granted accelerated approval for glioblastoma.

• System for treating skin manifestations of CTCL approved.

HEMATOLOGIC DISEASE

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Dexamethasone reduces relapses in childhood acute lymphoblastic leukemia.

SOLID TUMORS

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Higher dose of fulvestrant may improve outcomes in patients with breast cancer.

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For locally advanced breast cancer, neoadjuvant trastuzumab to become standard of care.

CLINICAL TRIALS

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

S PE C I AL O FF ERS

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Information on how to order our popular pocket guides and wall charts such as Cancer Therapeutic Regimens.

PET Is Powerful Tool for Staging Bladder Cancer

Chemo-Related Cardiotoxicity Not Managed Appropriately

Orlando, Fla.—Positron emission tomography (PET) scanning is more accurate than computed tomography (CT) or magnetic resonance imaging (MRI) alone for determining the extent of disease in patients with bladder cancer, according to a new study.

Data, presented at the 2009 Genitourinary Cancers Symposium (abstract 239), revealed that fluorodeoxyglucosepositron emission tomography (FDGPET) has excellent sensitivity and specificity in detection of metastatic bladder cancer and can provide additional diagnostic information that may significantly enhance clinical management. PET scans found more disease than CT or MRI in 40% of cases when recurrence was suspected and scans helped avoid see BLADDER, page 16

C. difficile Infection On the Rise in Cancer Patients Washington—Clostridium difficile infections (CDIs) are on the rise in cancer patients, prolonging hospital stays and increasing morbidity and mortality rates, according to a new study.

The study also suggests that clinicians should consider therapies other than metronidazole, the standard therapy, for patients with severe CDI. “This problem is on the rise, and it is becoming a bigger problem across the country. It is going to affect our cancer patients, and we are probably going to see a worse outcome in this immunocompromised population,” said study investigator Roy Chemaly, MD, MPH, associate professor of medicine and

WWW.CMEZONE.COM

see CLOSTRIDIUM, page 6

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See page 13.

Orlando, Fla.—Patients with cancer who develop chemotherapy-related left ventricular (LV) dysfunction often are not appropriately treated or referred for a cardiology consultation, especially if they have asymptomatic LV dysfunction.

Only half of symptomatic patients were referred to a cardiologist for their LV dysfunction, according to a retrospective

analysis reported at the 58th annual meeting of the American College of Cardiology (ACC; abstract 1033-202). “There is a very large disconnect, unfortunately, between oncologists and cardiologists,” said Ronald Witteles, MD, senior author of the study and assistant professor of medicine at Stanford University in Palo Alto, Calif. see VENTRICULAR, page 6

POLICY & MANAGEMENT

Multidisciplinary, Nurse Navigator Program Excels in GI Cancer Care San Francisco—Patients with gastrointestinal cancer seen within a multidisciplinary care program required significantly fewer clinic visits before beginning treatment and received quicker access to treatments. This is the finding from a novel program that involves a nurse navigator at the Vermont Cancer Center in Burlington. A more structured approach to the management of patients with pancreatic, esophageal, gastric, liver and biliary tract cancers has allowed for more timely evaluation and treatment in a highly coordinated

fashion, thanks mainly to the efforts of a nurse navigator.

The program was described at the 2009 American Society of Clinical Oncology Gastrointestinal Cancers Symposium by Nicole Messier, RN, nurse navigator, and the surgeon who pushed for the development of the program, Laurence E. McCahill, MD, physician-researcher and surgical oncologist, both of the Upper GI Multidisciplinary Clinic at Vermont Cancer Center. Ms. Messier, who has experience in see MULTIDISCIPLINARY, page 3

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POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • MAY 2009

Coordinating Patient Care

MULTIDISCIPLINARY continued from page 1

both inpatient oncology nursing as well as general surgical oncology nursing, said that before the program existed, “it was not uncommon to see patients who were diagnosed six weeks earlier just coming in to discuss surgery. It took weeks to complete imaging studies and all appropriate consultations because so many different people were involved.

‘After I receive referrals from the primary physician, I hand the patient over to the nurse navigator who arranges everything else.’

—Richard Zubarik, MD

“We saw that the nurse navigator program was working well for the breast cancer program,” she continued, “and Dr. McCahill asked, ‘Why can’t we do that for our GI cancer patients?’ ” Dr. McCahill is also associate professor of surgery at the University of Vermont in Burlington.

The Institute of Medicine has reported that the delivery of cancer care in this country often is quite poor. In some parts of Europe, by contrast, a more focused, multidisciplinary approach that revolves around a coordinating nurse has been shown to facilitate assessment and evidence-based treatment, Dr. McCahill said. “In the public health system in the United Kingdom, patients must be seen within two weeks of their diagnosis,” he noted. “At Vermont Cancer Center, we are trying to move toward that model.”

The Upper GI Multidisciplinary Clinic at the Vermont Cancer Center has three key components: 1) a multidisciplinary clinic comprised of gastroenterologists,

pathologists, radiologists and surgical oncologists; 2) treatment planning conferences (instead of traditional “tumor boards”) that are held three times per month immediately before clinic and are attended by all physician staff; and 3) a dedicated nurse navigator whose subspecialty is cancer.

The Linchpin: The Nurse Navigator The use of nurse navigators, who help patients “navigate” their treatment course, has been shown in some studies not only to enhance patient care but also to improve survival. In this case, Ms. Messier is responsible for coordinating all aspects of patient care.

She starts by obtaining the patient’s history and medical records, which she uses for the initial staging of the disease. She schedules diagnostic tests, books appointments (attempting to have patients complete several visits with different doctors in one day) and organizes the treatment planning conference—all before a physician has seen the patient.

She serves as a liaison with the patient at all steps of the journey, transitions the postoperative patient to outpatient care and coordinates postoperative visits.

“Initial testing and consults are accomplished within two weeks of my first contact with the patient and treatment is initiated within 30 days. We are trying to tighten this up even more,” Ms. Messier said.

Richard Zubarik, MD, chief of endoscopy at the Vermont Cancer Center and associate professor of medicine at the University of Vermont, said the new program not only has streamlined patient care, moving it from an “ad hoc situation,” but it also has “improved communication and collaboration between the physicians involved in the care.

“I am on the front end of putting the

Table. New Multidisciplinary Program for Upper GI Cancer at Vermont Cancer Center Decreased Delays and Increased Efficiency Outcome

Group 1a (n=78)

Group 2b (n=55)

P Value

Diagnostic Efficiency Staging evaluation (days) Days to last pretreatment visit Days to first cancer treatment

7.9 21.1 25.2

11.3 24.3 32.3

0.07 0.39 0.05

Multidisciplinary Evaluation Treatment planning conference

96%

0%

64% 2.6

20% 5.8

Coordination of Care Met with all physicians in single day Number of pretreatment hospital/ clinic visits a b

Patients referred during the first six months of the new multidisciplinary program.

Patients treated before implementation of the new program.

— <0.001

patients into the system,” Dr. Zubarik continued. “After I receive referrals from the primary physician, I hand the patient over to the nurse navigator who arranges everything else. Because of her, at the planning conference, we will have all the data we need when we discuss the case.”

He also said the nurse navigator relieves physicians of the responsibility of updating the referring physician. Dr. Zubarik believes the collaboration and continued dialogue among team members has helped him recruit patients to his clinical trials.

Ms. Messier realizes that her efforts and the collaboration that occurs during the planning conference have made everyone’s work easier. “Before, physicians were always paging each other about the patients. It was very inefficient,” she observed.

Jordan D. Berlin, MD, clinical director of GI oncology at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., commented on the program. “This is a great concept. In fact, we are planning to develop this kind of program at Vanderbilt. For major institutions, patients often come for a second opinion and have already had tests done. Getting the correct data on them is important, which nurse navigators can do. They can also ensure that patients see the right subspecialist first, which in GI oncology is not always the case. Patients are often scheduled to see the medical oncologist when what they really need is the surgeon.”

Ed Chu, MD, chief of the Section of Medical Oncology and deputy director of clinical research at Yale Cancer in New Haven, Conn, also thinks highly of the program. “These navigator programs are really great for patients, as it does help patients work through the system to go from clinic to clinic and to help coordinate the various appointments and scheduling of tests,” he said. “In particular, these programs are helpful for the minority, underserved population.”

Patients Like It, Numbers Prove It Dr. McCahill evaluated the impact of this new approach on the efficiency of health care by comparing patients referred during the first six months of the new program with those treated before the new system was implemented. The majority of patients had pancreatic cancer (followed by esophageal cancer and gastric cancer), and approximately half of the patients had stage I or II disease.

Patients seen within the multidisciplinary program experienced significantly shorter times between their first visit and initiation of treatment, required significantly fewer hospital or clinic visits before beginning treatment and were significantly more likely to receive a multidisciplinary evaluation (Table).

Dr. McCahill noted that the number of

Physician-researcher Laurence McCahill, MD, and nurse navigator Nicole Messier, RN, are part of a multidisciplinary program at the Vermont Cancer Center in Burlington that has streamlined and greatly improved care for patients with upper gastrointestinal cancer.

patients with upper GI cancers referred for care at his center has grown considerably since the new program was initiated.

“I think patients sense that we have coordinated care here,” he said. “And once they come here, they really like the fact that they are not coming in for nearly six visits before treatment, but more like three visits. That is a really big change.”

“A lot of our patients travel over two and a half hours to come here,” Ms. Messier added, “so this is very important to them.”

At Vermont Cancer Center, similar multidisciplinary programs have been established for breast and lung cancers; however, “we are the only ones measuring everything we do,” Dr. McCahill explained, adding that he anticipates this component will become part of an emerging mandate to meet benchmarks of quality cancer care.

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • MAY 2009

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Community Oncology

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

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Oncology Nursing

Russell K. Portenoy, MD Charles F. von Gunten, MD

Gynecologic Cancer Maurie Markman, MD

Breast Cancer Andrew Seidman, MD

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Guide to Cancer Therapeutic Regimens 2009 Pocket Guide The use of cancer therapeutic agents in combination is well established. The knowledge of cell kinetics and the pharmacology of antitumor agents have allowed the clinician to use combination therapy to maximize tumor cell kill with minimal or acceptable toxicity to the patient.

Guide to Cancer Therapeutic Regimens 2009 Wall Chart—Part 1 Part 1: Solid Tumor Cancers This wall chart lists common combination regimens and doses used in solid cancers.

Guide to Cancer Therapeutic Regimens 2009 Wall Chart—Part 2 Part 2: Hematologic Cancers This wall chart lists common combination regimens and doses used in hematologic cancers.

Oral Mucositis: Causative Regimens and Pathways for Treatment Mucositis can be best described as a distinct and complex pathobiologic entity resulting in mucosal barrier injuries that is a consequence and frequent complication of chemotherapy and radiation therapy in patients with cancer.

Cancer Support 2009 This guide outlines characteristics of hazardous drugs, detrimental effects of occupational exposure, methods of determining exposure and common routes of exposure. It also highlights the technologies available to reduce risks and national guidelines for ensuring safe compounding, transport, delivery, administration and disposal of hazardous drugs by using personal protective equipment.

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Current Strategies for the Treatment of Acute Promyelocytic Leukemia 2007 Acute promyelocytic leukemia (APL) was first described as a distinct clinical entity in 1957. Since the introduction of all-trans retinoic acid (ATRA [Vesanoid, Roche]) in the early 1990s and its administration with anthracycline-based chemotherapy, APL has become curable in the majority of patients.

Guide for the Administration and Use of Targeted Cancer Agents 2007/2008 The National Cancer Institute defines targeted therapy as “a type of treatment that uses drugs or other substances, such as monoclonal antibodies, to identify and attack specific cancer cells without harming normal cells.” Although other variations of the definition exist, collectively they define a change in the drug development process.

Therapeutic Strategies for Patients With Chronic Lymphocytic Leukemia In the past 10 years, progress in the understanding of the biologic basis of chronic lymphocytic leukemia, the introduction of novel prognostic factors to complement the clinical staging systems, the use of monoclonal antibodies and the development of better measures of response assessment have led to a revised approach to this most common of the adult leukemias.

The Medical Treatment of Metastatic Breast Cancer Breast cancer is a global health burden with more than 1 million new cases diagnosed worldwide and more than 250,000 new cases diagnosed in the United States each year. The rationales for several common management strategies are reviewed.

Treating the Patient With Metastatic Non–Small-Cell Lung Cancer Lung cancer is a major health problem worldwide. In recent years, new chemotherapeutic compounds and biologic agents have been developed and approved by the FDA for the treatment of metastatic non–small–cell lung cancer.

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FDA NEWS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • MAY 2009

Everolimus Approved for Advanced Kidney Cancer

System for Treating Skin Manifestations of CTCL Approved

T

he FDA has approved the Cellex Photopheresis System (Therakos) for the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL) that are unresponsive to other forms of treatment. The integrated system uses extracorporeal photopheresis, an innovative cellular therapy, to relieve the symptoms of CTCL.

he FDA has approved everolimus (Afinitor, Novartis) for the treatment of patients with advanced kidney cancer whose disease has progressed after treatment with sunitinib (Sutent, Pfizer) or sorafenib (Nexavar, Bayer).

The approval is based on data that showed everolimus, when compared with placebo, more than doubled the time without tumor growth or death in patients with advanced kidney cancer (4.9 vs. 1.9 months) and reduced the risk for disease progression or death by 67% (hazard ratio, 0.33; 95% confidence interval, 0.25-0.43; P<0.0001). Furthermore, data revealed that after 10 months of treatment with the drug, approximately 25% of patients still had no tumor growth.

The most frequent adverse reactions in the trial (occurring in at least 20% of patients) included inflammation in the mouth, loss of strength, diarrhea, poor appetite, fluid buildup in the extremities, shortness of breath, coughing, nausea, vomiting, rash and fever. Laboratory tests of blood samples determined that at least half of all patients experienced anemia, low white blood counts, high cholesterol and high triglycerides and high blood sugar.

Everolimus works by blocking the mammalian target of rapamycin or mTOR.

Bevacizumab Granted Accelerated Approval for Glioblastoma

T

The new system features several improvements designed to enhance the patient treatment experience, such as shorter treatment times and reduced extracorporeal blood volume, making it possible to treat lower-weight patients and others previously not considered for this therapy. The benefits of reduced risk for infection and reinfusion errors are maintained in the Cellex Photopheresis System from the current Therakos UVAR XTS Photopheresis System. Specific features of the new system include an automated, closed-system design that provides users the ability to switch between double- and single-needle treatment, if necessary.

IV Form of Temodar Approved

T

he FDA has approved the intravenous (IV) formulation of temozolomide (Temodar, Schering-Plough) as an alternative to the already approved oral form of the drug.

Temozolomide is approved for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. It has also been approved for refractory anaplastic astrocytoma (i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine).

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he FDA, following the recommendation of its Oncologic Drugs Advisory Committee, has granted accelerated approval of bevacizumab (Avastin, Genentech) for previously treated glioblastoma. The approval is based on an improvement in objective response rate.

No data are available from randomized controlled trials demonstrating an improvement in survival or diseaserelated symptoms.

The approval was based on data from the AVF3708g trial conducted in 167 patients. The trial was an open-label, multicenter study that evaluated bevacizumab alone or in combination with irinotecan in previously treated glioblastoma. The trial revealed that in 28% of the 85 patients treated with bevacizumab alone, tumors shrank to at least half their original size. In those whose tumors shrank, half experienced a response of at least 5.6 months and 43% lived six months without their disease progressing. Half of the patients lived at least 9.3 months after starting treatment with bevacizumab and 38% survived longer than one year.

All patients in the trial had previously progressed on prior temozolomide and radiation. No new safety signals were observed in the trial and the safety profile was consistent with bevacizumab experience in other tumor types.

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SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • MAY 2009

Diarrhea

CLOSTRIDIUM continued from page 1

director of infection control at M.D. Anderson Cancer Center, Houston. “So, as we see more and more of this infection, we need to know how best to handle these patients. We need to educate our physicians that if you see a severe C. difficile infection, you should probably start oral vancomycin from the getgo and you may get a better outcome based on studies done in noncancer patients.”

The new study was presented at the joint annual meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America by researchers at M.D. Anderson Cancer Center (presentation K513).

The number of new cases of CDI in hospitals has significantly increased over the past 10 years. C. difficile was responsible for more than 15,000 deaths in 2007 alone, according to the U.S. Centers for Disease Control and Prevention. Between April and September 2007, the number of CDI cases at M.D. Anderson Cancer Center increased suddenly, most likely as a consequence of the introduction of a more virulent strain of C. difficile into the institution. In just the past five years, outbreaks of severe CDI with this new strain (BI/NAPI/027) have occurred and been associated with increased mortality because of a lackluster standard therapy—metronidazole.

Between Jan. 1, 2007, and Dec. 31, 2007, there were a total of 322 cases of CDI at a rate of 0.86 per 1000 patient days at M.D. Anderson Cancer Center. The center witnessed an increase in the rate of CDI from 0.38 in February to 0.72 in March with a peak rate of 1.92 in May 2007.

Study Design To get a better grasp of the problem, researchers retrospectively evaluated 50 cases of CDI that occurred in patients with cancer between May 1 and June 15, 2007, at M.D. Anderson. Investigators collected data on demographics and clinical manifestations, in addition to microbiologic records. They also evaluated surgical intervention; use of proton pump inhibitors, other antacids, and antibiotics; ICU admissions; and concomitant infections. Patients were classified as having severe CDI if they had at least one of the symptoms of fever, abdominal pain and severe diarrhea along with colitis on computed tomography, abnormal total white cell count, abnormal serum albumin level, hypotension due to dehydration, paralytic ileus and toxic megacolon or sepsis.

Patients in the study had a mean age of 65.5 years (range, 35-81 years), 42 were male and 27 (54%) had a hematologic malignancy. The remaining patients had solid tumors, including seven (14%) involving the gastrointestinal tract and nine (18%) involving the genitourinary tract. CDI was severe in 17 patients (34%), and patients with severe infection were more likely than those with mild or moderate infection to be transferred to the ICU (24% vs. 3%; P=0.04). Patients with severe CDI were also more likely to die of their infection (24% vs. 3%; P=0.04).

The researchers found trends toward a higher APACHE (Acute Physiology and Chronic Health

immediately for C. difficile toxins and, if the result is positive, be treated immediately and isolated to protect other hospitalized patients. A thorough understanding of the clinical manifestations and outcome of CDI in this patient population is extremely important to optimize therapy and lower the associated morbidity and mortality.

According to Dr. Chemaly, multiple randomized trials in patients without cancer have demonstrated that for severe CDI, oral vancomycin works better than metronidazole, so he believes that patients who have cancer with severe CDI should be started on vancomycin when the condition is diagnosed. “There is no data in cancer

‘C. difficile is a growing problem both in hospitalized and in community patients.

I have found vancomycin to be a superior though more costly treatment.

There are laboratory and clinical data to back up my experience.’

—David Prelutsky, MD

Evaluation) II score in patients at the onset of infection (P=0.07) and an increased length of hospital stay (P=0.09). The average stay for patients with mild or moderate CDI was 8.3 days, whereas it was 15.02 days for those with severe CDI. The vast majority (96%) of patients were treated initially with metronidazole, and this therapy failed in 19% of them. The overall rate of mortality with CDI as a contributory or attributable cause was 10% (five patients). Among these five patients, four were given oral metronidazole only and one was switched to oral vancomycin after not responding to metronidazole.

Overall, 48 patients were given metronidazole as initial therapy, and 28 (58%) of these responded completely to the therapy without any complication. Nine patients (19%) had to be switched to oral vancomycin because of nonresponse. Of the remaining 11 patients who were treated with metronidazole, seven (15%) responded, but then developed complications such as vancomycin-resistant enterococci. Four (8%) of the 48 patients died while on metronidazole therapy alone, and three of these four had severe CDI.

Take-Home Message

patients yet, but we are extrapolating from the other studies. Based on our results regarding higher mortality rate in patients with severe CDI while on metronidazole, we believe that oral vancomycin would be a better choice than oral metronidazole to treat our cancer patients,” Dr. Chemaly said. “Most of the patients were treated with oral metronidazole for CDI in our study as this is still the first-line choice.”

David Prelutsky, MD, a clinical assistant professor of medicine at Washington University School of Medicine, St. Louis, Mo., said that this study is important because severe cases of CDI are now increasing nationwide. He also said that the study highlights the importance of good infection control at hospitals across the country.

“C. difficile is a growing problem both in hospitalized and in community patients. I have found vancomycin to be a superior though more costly treatment. There are laboratory and clinical data to back up my experience,” Dr. Prelutsky said. “I initiate suspected cases on vancomycin, especially if they have other severe comorbidities. We need to be more vigilant with our infection control measures to prevent this problem.”

The study investigators say that patients with cancer who have diarrhea should be screened

—John Schieszer

Cardiotoxicity

VENTRICULAR continued from page 1

“This is not meant as a criticism of anyone, but oncologists are as comfortable with cardiology issues as cardiologists are with oncology issues, which is not very comfortable.”

Oncologists and cardiologists need to collaborate in caring for these patients so that they can continue on chemotherapy without experiencing further cardiac damage, explained lead author, Geoffrey Yoon, MD, a resident at Stanford.

Left Ventricular Dysfunction Anthracyclines and trastuzumab (Herceptin, Genentech) commonly used to treat breast cancer can cause LV dysfunction, which can progress to heart failure.

Tyrosine kinase inhibitors (TKIs), such as trastuzumab, bevacizumab (Avastin, Genentech), alemtuzumab (Campath, Berlex), sunitinib (Sutent, Pfizer), lapatinib (Tykerb, GlaxoSmithKline), imatinib (Gleevec, Novartis), dasatinib (Sprycel, Bristol-Myers Squibb), and nilotinib (Tasigna, Novartis) also are associated with cardiotoxicity.

The study focused on all patients (N=88) taking anthracyclines or

trastuzumab at Stanford University between Oct. 1, 2005 and Oct. 31, 2007, who were entered in a large pharmacy database. Mean age of participants was 52 years (range, 33-67 years); 41 were male and 47 were female. Of the 88 participants, approximately 33% had hypertension, 26% hypercholesterolemia, 17% diabetes, 10% cardiomyopathy and 7% coronary artery disease.

All members of the study group were on chemotherapy and each had echocardiograms to measure LV ejection fraction (EF) at baseline, during and after chemotherapy. An extensive chart review of these patients showed that the mean

EF was 60% at baseline (normal EF is >55%). At baseline, 13% had a belownormal EF. During or after chemotherapy, 41% had EFs that fell below normal.

Of the 88 patients, 75% were asymptomatic, and 25% had symptoms of dyspnea, orthopnea or edema, which can also mimic adverse events of chemotherapy.

Guideline-recommended therapy for asymptomatic LV dysfunction includes β-blockers, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Of patients who developed below-normal EFs, only 56% received β-blockers, and 47% were treated with an ACEI or an

SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • MAY 2009

Cardiotoxicity 15

14.6-fold

increased by 5.1-fold (Figure).

Other studies have shown that bevacizumab also doubles the risk for thromboembolic events.

Increase in Risk

12 9-fold

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Implications for Oncologists 5.7-fold

6

3

0 Breast Cancer

Renal Cell Cancer

Colon Cancer

Figure. Patients’ increased risk for highgrade hypertension after treatment with bevacizumab.

ARB. Only 50% of symptomatic patients and 37% of asymptomatic patients were referred to a cardiologist for consultation regarding their LV dysfunction.

Dr. Yoon suggested implementation of screening protocols for patients with cancer who are undergoing chemotherapy that poses a risk for cardiotoxicity. Even though it is well known that anthracyclines are cardiotoxic, clinicians do not routinely conduct cardiac screening on patients taking anthracyclines.

Both Drs. Yoon and Witteles emphasized that physicians should ensure that chemotherapy is as safe as possible in order to minimize cardiotoxicity.

Drs. Yoon and Witteles noted that cardiac monitoring should be continued after chemotherapy is stopped even if cardiac function returns to normal.

High-Grade Hypertension With Bevacizumab Another presentation at the ACC (abstract 1001-303) revealed that patients with cancer who were treated with bevacizumab had a fivefold increase in highgrade hypertension. “This side effect of bevacizumab is well known, but the risk has not been clear,” said Bhargava Pulipati, MD, of Stony Brook University Medical Center, in Stony Brook, N.Y. The retrospective study was based on data from 13,104 patients with various solid tumors who participated in 20 prospective randomized trials of chemotherapy with and without bevacizumab. Bevacizumab was associated with all-grade hypertension in 23.6% of patients; 7.9% had high-grade hypertension (grade 3 or 4 [life-threatening]). Risk for high-grade hypertension was unchanged with high or low doses of the drug, but tumor type had variable associations with risk for high-grade hypertension. Breast cancer was associated with a 14.6-fold increased risk for high-grade hypertension; renal cell cancer with a ninefold increased risk; colorectal cancer with a 5.7-fold increased risk; and overall, the relative risk was

According to Steven Jones, MD, medical director of U.S. Oncology Research in Houston, oncologists do not adequately appreciate the cardiotoxicity of common cancer drugs, particularly in older patients in whom effects may not be seen for many years. The problem is compounded by newer regimens with recently approved biologic therapies that aggravate cardiotoxicity, he added.

“Anthracyclines and trastuzumab are still commonly prescribed, even though there are non-anthracycline regimens for many patients with early breast cancer, such as TC [docetaxel/cyclophosphamide] for HER2-negative disease and TCH [docetaxel/cyclophosphamide/ trastuzumab] for HER2-positive disease,” Dr. Jones said.

“Baseline monitoring of cardiac function by echo [echocardiogram] or MUGA [Multi-Gated Acquisition scan] is critical before starting therapy. If there is any question about cardiac function, the patient should be referred to a cardiologist before starting therapy and during

therapy if a significant drop in ejection fraction occurs,” Dr. Jones said.

Acknowledging the side effects of these potentially lifesaving drugs, he commented: “We may be curing many more women with early breast cancer, but we have to be cognizant of the potential price our patients are paying in terms of cardiac reserve and function. Many cardiologists do not have the interest in this topic, so my advice is to talk to your cardiology colleagues, identify those who do have the interest, and refer patients to them on a regular basis.”

—Alice Goodman

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research

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CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • MAY 2009

Acute Lymphoblastic Leukemia

Dexamethasone Reduces Relapses in Childhood ALL San Francisco—In a multicenter randomized trial, adding dexamethasone to induction therapy in children with acute lymphoblastic leukemia (ALL) produced a “remarkable reduction” in relapse when compared with adding prednisone.

Although the results were impressive, study investigators did not recommend that the results should dictate a change in practice. One reason was that the 10 mg/m2 per day of dexamethasone produced an increase in the risk for treatment-related death. Another reason was that the study could not confirm an overall survival advantage even though it confirmed a significant improvement in event-free survival.

“The clinical applicability of these results depends on the experience of the treatment center in managing steroid-related adverse events,” said Martin Schrappe, MD, an oncologist in the Department of Pediatrics, University of Kiel, Germany. After a median followup of 4.4 years, the cumulative six-year incidence of relapse was reduced by slightly more than one-third.

According to Dr. Schrappe, however, the advantage of dexamethasone may not warrant the risks, particularly because dexamethasone may still be used effectively as a rescue therapy if prednisone fails.

In the study, known as the AIEOP-BFM ALL 2000 trial, 3,655 patients from participating centers in four countries in Europe were randomized to 10 mg/m2

‘The clinical applicability of these results depends on the experience of the treatment center in managing steroidrelated adverse events.’

—Martin Schrappe, MD

Patients randomized to prednisone Patients randomized to dexamethasone

20 18

15

% of Patients

10

11

10

5

0 P<0.01

Figure. Incidence of relapse at six years.

of dexamethasone or 60 mg/m2 prednisone given daily from day 8 to day 29 of an induction cycle. The other components of the induction regimen, which was otherwise identical in the two arms, were 1.5 mg/m2 vincristine and 30 mg/m2 daunorubicin both given on days 8, 15, 22 and 29 of the cycle, as well as 5,000 IU/m2 l-asparaginase given intravenously every three days from day 12 and intraventricular methotrexate, which was given three times during the cycle.

“The concept behind this study was that if dexamethasone is effective when used in delayed intensification [also called reinduction phase], which is basically the repetition of the initial induction therapy, why not evaluate it as an up-front strategy,” said Dr. Schrappe.

He presented the results of this study at the 2008 annual meeting of the American Society of Hematology (abstract 7).

The cumulative incidence of relapse at six years was 18% for those randomized to prednisone and 11% for those randomized to dexamethasone (P<0.001; Figure). The event-free survival at six years was 84.1% versus 79.1%, respectively (P=0.0083). The advantage of dexamethasone was consistent across several types of relapses, including relapses in the bone marrow (8% vs. 12%) and central nervous system (CNS; 2% vs. 4%).

These relative advantages, however, were diluted by the toxicity. This not only included a higher risk for severe infections on dexamethasone but a greater risk for treatment-related deaths. In patients older than age 10, the rate of death was 4.5% among those randomized to dexamethasone versus 2.4% for those randomized to prednisone (P=0.13). In younger patients, treatment-related death rates were 1.4% and 0.5% (P=0.01), respectively.

Due to the precarious risk–benefit advantage of dexamethasone, Dr. Schrappe was cautious in his interpretation of the results. Moreover, several observations were made that complicated efforts to draw conclusions. For example, in vivo, prednisone sensitivity testing suggested that the advantage of dexamethasone was greatest in those who were sensitive to prednisone, indicating that dexamethasone did not overcome prednisone resistance. In a post hoc analysis, dexamethasone did not appear to provide any clinical advantage over prednisone in those who demonstrated poor prednisone sensitivity.

Another notable result was the difference in relapse, despite similar rates of minimal residual disease (MRD) on day 33 of the study. When those who achieved MRD negativity (47.9% of those receiving dexamethasone vs.

45% receiving prednisone) were compared, those who received dexamethasone were significantly less likely to have a subsequent relapse (P=0.012).

In this analysis, patients randomized to prednisone had more late relapses than those randomized to dexamethasone. Although Dr. Schrappe expressed surprise that a relatively modest change in the induction regimen

would alter the risk for late relapse, he noted that this may be an important difference to consider in comparing the regimens, because late relapses “can be rescued better than early relapses,” making crude relapse rates a potentially misleading point of comparison.

One variable not explored in this study is the difference between centers in relative ability to avoid or effectively manage adverse events associated with dexamethasone.

Dr. Schrappe suggested that experienced centers able to minimize the toxicity of dexamethasone may be able to improve the relative risk–benefit ratio that would favor dexamethasone use, but a second trial comparing steroids that used a lower dose of dexamethasone (6 mg/d) also found dexamethasone to produce a higher rate of infections than prednisone, 60 mg per day. The difference was particularly pronounced among patients who received prolonged l-asparaginase (29.1% vs. 21.8%).

Contending that the “optimal dosage of either of these glucocorticoids remains to be determined,” the author, Yves Bertrand, MD, of this second comparison with 1,703 patients, also expressed concern about an increased risk with an uncertain gain from using dexamethasone. Dr. Bertrand is a pediatric hematologist at the Centre Hospitalier Universitaire, Lyon, France.

Although CNS recurrences were less common on dexamethasone at the end of five years (2.9% vs. 4.9%), non-CNS recurrences were similar (10.9% vs. 9.4%) and death rates were slightly higher (2.7% vs. 2.1%).

“There has been some evidence that dexamethasone is more effective than prednisone for reducing relapses in the treatment of ALL in a pediatric population, but now we have two large randomized comparisons,” Dr. Bertrand said. Even with several thousands of patients, “I do not think we have a clear answer.”

—Ted Bosworth

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • MAY 2009

11

Breast

Higher Dose of Fulvestrant May Improve Outcomes San Antonio—A higher-than-approved dose of fulvestrant—500 mg—may offer better disease control than anastrozole when given as first-line therapy to patients with advanced hormone receptor–positive (HR+) breast cancer, according to results of a Phase II trial.

At the time the data were presented, the median time to progression (TTP) was 12.5 months in patients taking anastrozole (Arimidex, AstraZeneca) and had not yet been reached in those taking fulvestrant (Faslodex, AstraZeneca).

This corresponded to a 60% longer TTP for fulvestrant. The results of FIRST (Fulvestrant First-line Study Comparing Endocrine Treatments) were presented at the recent San Antonio Breast Cancer Symposium (abstract 6126).

At the time the data were presented, the median time to progression was 12.5 months in patients taking anastrozole and had not yet been reached in those taking fulvestrant. This corresponded to a 60% longer time to progression for fulvestrant.

The study also revealed that high-dose fulvestrant was similar to anastrozole for the primary end point of clinical benefit (including overall response rate, complete response rate and partial response rate); 72.5% of women taking fulvestrant derived clinical benefit, compared with 67% of those on anastrozole (P=0.386).

“Although responses to high-dose fulvestrant are not more frequent than with anastrozole, at this dose of fulvestrant, responses might be more durable. This possibility will be explored further in the Phase III CONFIRM [Comparison of Faslodex in Recurrent Metastatic Breast Cancer] trial [which will compare high-dose fulvestrant with approved-dose fulvestrant in advanced breast cancer],” said lead author, Matthew Ellis, MB, PhD, a medical oncologist at the Siteman Cancer Center, Washington University in St. Louis, Mo. Fulvestrant at the approved dose of 250 mg has been found to be at least as effective as anastrozole as second-line therapy for advanced cancer following anti-estrogen therapy. The new data, if confirmed in a larger trial, show that the drug may have an additional trick up its sleeve when given at a higher dose. “These improved clinical outcomes with the 500mg dose indicate that we may have found a way to make a good drug even better,” said senior author of the study, John Robertson, MD, an oncologist at Nottingham

City Hospital, in the United Kingdom.

Study Details FIRST was a randomized, open-label trial in postmenopausal women with

locally advanced or metastatic disease who had received no prior endocrine therapy. The study randomized 102 women to 500 mg of fulvestrant [two 250-mg injections on days 0, 14 and 28, and every 28 days thereafter] and 103 women to 1 mg of anastrozole per month as first-line treatment. Treatment was continued until progression of disease or an adverse

event requiring discontinuation.

The median age of the patients was 66 years in the fulvestrant group and 68 years in the anastrozole group. The tumors of all patients were HR+ and about 18% were HER2-positive according to immunohistochemistry. Of the enrolled patients, 71.6% in the fulvestrant group and 77.7% in the anastrozole group had not received prior endocrine see FULVESTRANT, page 13

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Original activity not based on a previous live program New Directions in Metastatic Renal Cell Carcinoma

Based on live programs at HOPA/ISOPP 2008 in Anaheim Integrating the Epothilones into Clinical Practice: Focus On Breast Cancer Optimizing Patient Adherence to Self-Administered Chemotherapy: Best Practices for Hematology/ Oncology Pharmacists

Targeted Drug Therapies for the Treatment of Non–SmallCell Lung Cancer Updates in Cancer Supportive Care: VTE, Tumor Lysis Syndrome, and Chemotherapy-Induced Nausea and Vomiting What’s New in the Management of Multiple Myeloma?

Based on a live program at HOPA 2007 in Denver Taking Aim at Multiple Targets: Oncology Pharmacist Perspectives on TKIs

SOLID TUMORS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • MAY 2009

Breast Cancer

For Locally Advanced Breast Cancer …

Neoadjuvant Herceptin To Become Standard of Care San Antonio—Adding trastuzumab (Herceptin, Genentech) to neoadjuvant chemotherapy extends event-free survival (EFS) in women with locally advanced HER2-positive breast cancer, according to final results of the Phase III NOAH (NeOAdjuvant Herceptin) trial.

“The results of this study imply that starting chemotherapy with one year of Herceptin should become the standard of care for women with locally advanced HER2-positive breast cancer,” said Luca Gianni, MD, from the Istituto Nazionale Tumori Milano, in Milan, Italy. Dr. Gianni presented the study at the CTRCAACR San Antonio Breast Cancer Symposium (abstract 31).

Trastuzumab is currently approved as adjuvant therapy for women with HER2-positive breast cancer and as treatment for metastatic HER2positive breast cancer. The neoadjuvant setting is a new use for this drug, and the positive results of NOAH support a new indication for regulatory approval, according to the investigators.

Locally advanced breast cancer (including inflammatory breast cancer) is a particularly aggressive form of cancer with a poor prognosis, accounting for about 6% of all cases of breast cancer, according to Dr. Gianni. Median survival is three to six years compared with 10 years or longer for other types of breast cancer. He said that new treatment approaches are needed to improve outcomes in these patients.

Study Details NOAH showed that the addition of trastuzumab to chemotherapy containing an anthracycline and taxane prior to surgery significantly improved EFS (the primary end point of the trial) compared with preoperative chemotherapy alone. At three years of followup, 70% of women who received trastuzumab were alive and free of breast cancer-related events compared with 53% of women treated with chemotherapy alone, representing a 46% reduction in risk for events (P=0.006). Although a trend toward improved survival was observed in the HER2-positive patients treated with trastuzumab, longer follow-up will be needed to confirm an overall survival benefit, Dr. Gianni said.

The study is the largest randomized Phase III trial to evaluate the benefits of neoadjuvant trastuzumab in combination with chemotherapy versus chemotherapy alone in locally advanced HER2-positive breast cancer. The study randomized 228 women with HER2-positive cancer to trastuzumab plus chemotherapy compared with chemotherapy alone; all women had surgery followed by radiotherapy, and then those in the trastuzumab arm continued this drug for up to one year. A parallel observational cohort of 99 women with HER2-negative disease was treated with chemotherapy alone. Chemotherapy alone was active in both HER2-positive and HER2-negative patients, Dr. Gianni said.

The addition of trastuzumab almost doubled the pathological complete response (pCR) rate in HER2-positive women: 43% who received trastuzumab achieved a pCR compared with 23% who did not receive the drug (P=0.002; Figure). Similar results for pCR were observed between the HER2-positive chemotherapyalone arm and the HER2-negative arm. Subgroup analysis of HER2-positive patients showed that all subgroups had improved EFS with trastuzumab, including patients with and without inflammatory breast cancer, patients who were hormone-receptor positive and those who were hormonereceptor negative, and those with or without pCR. The neoadjuvant trastuzumab-containing regimen was well tolerated, with acceptable cardiac toxicity, Dr. Gianni said.

The grade 3/4 adverse event rate was below 2% for all trastuzumab-treated patients. In HER2-positive patients who did not receive trastuzumab, the most frequent grade 3 and 4 adverse events were neutropenia (4.4%), diarrhea (3.5%), stomatitis (3.5%) and arthralgia (2.7%).

Consistent With Other Trials The overall results of NOAH are consistent with other trials showing that trastuzumab plus chemotherapy improves overall EFS, said Matthew Ellis, MB, BChir, PhD, professor of medicine and head of medical oncology at Washington University School of Medicine in St. Louis, Mo. “There is adequate, albeit indirect, evidence that when you give Herceptin before surgery, you get a similar degree of benefit as when Herceptin is given after surgery,” Dr. Ellis said. “In my mind, there is no major concern regarding the sequencing of surgery and Herceptin.”

NOAH, however, does not address the standard of care regarding the actual chemotherapy regimen given along with trastuzumab in this setting. “The ‘alphabet soup’ regimen given in NOAH would not be considered the standard of care in the United States,” Dr. Ellis continued. “It is complex, fairly toxic, and it’s not clear that all the drugs included in that regimen are really necessary.”

Adding trastuzumab is already the standard of care for HER2-positive patients, but the favored preoperative regimen is open to question, particularly as to whether to overlap the anthracycline and trastuzumab. Two large trials will address these issues. The ACOSOG (American College of Surgery) Z1041 trial will directly address whether trastuzumab should overlap with an anthracycline in the neoadjuvant setting,

Patients who received trastuzumab Patients who did not receive trastuzumab

50 43

40

% of Patients

12

30 23

20

10

0 P=0.002

Figure. Comparison of pathological complete response.

‘The results of this study imply that starting chemotherapy with one year of Herceptin should become the standard of care for women with locally advanced HER2-positive breast cancer.’

—Luca Gianni, MD

as was done in the NOAH trial, or whether it should be given after the anthracycline. One arm will receive trastuzumab continued throughout weekly paclitaxel followed by four cycles of an FEC-75 regimen, and the other arm will receive FEC-75 regimen first and then trastuzumab starting along with weekly paclitaxel.

“The ACOSOG trial is powered to determine pCR and will help define how to use Herceptin in the preoperative setting,” Dr. Ellis stated.

The Cancer and Leukemia Group B also is planning a trial that touches on another important issue, he continued. All patients will receive paclitaxel and then will be randomized to receive Herceptin, lapatinib (Tykerb, GlaxoSmithKline), or the combination of the two prior to surgery. This trial will show whether combining Herceptin with another agent that targets HER2 provides additional benefit in terms of the pCR rate, he said.

The NOAH trial was conducted in collaboration with the Spanish Grupo SOLTI and was cosponsored by F. Hoffman-LaRoche and the Michaelangelo Foundation.

—Alice Goodman

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE

SOLID TUMORS

13

Breast

FULVESTRANT continued from page 11

therapy; 27.5% and 22.3%, respectively, had received adjuvant endocrine treatment for early disease at least 12 months before randomization.

A greater percentage of patients in the fulvestrant group (41.2%) than in the anastrozole group (35%) achieved stable disease at 24 weeks or more. At the time

injection site was 5.9%, similar to the 4.6% rate reported with the approved dose.

Both arms had a high rate of treatment discontinuation. In the fulvestrant group, 64 patients discontinued treatment (28 because of disease progression), and in the anastrozole group, 43 discontinued treatment (38 because of disease progression).

According to William J. Gradishar, MD, professor of medicine and director of breast medical oncology at Robert

â&#x20AC;&#x2DC;The study highlights the importance of identifying the optimal dose and schedule of fulvestrant. Early preclinical experiments predicted higher-dose fulvestrant may be more effective, and now a series of clinical experiences supports this observation, with greater benefit conferred to patients with higher doses of the drug.â&#x20AC;&#x2122; â&#x20AC;&#x201D;William J. Gradishar, MD

of the San Antonio Breast Cancer Symposium, median TTP had not yet been reached for fulvestrant and was 12.5 months for anastrozole (hazard ratio, 0.6266; 95% confidence interval, 0.39290.9991; P=0.0496).

Safety and Tolerability Both drugs were generally well tolerated, with similar adverse event profiles. A small number of patients experienced at least one adverse event: 11.9% with highdose fulvestrant and 9.7% with anastrozole. Three patients in each group discontinued therapy because of an adverse event.

Although each patient received twice as many injections with the high-dose fulvestrant regimen, the rate of pain at the

H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, higherdose fulvestrant, unlike chemotherapy, improves the clinical benefit to patients without increasing side effects. â&#x20AC;&#x153;The study highlights the importance of identifying the optimal dose and schedule of fulvestrant,â&#x20AC;? said Dr. Gradishar, who was not involved with the study. â&#x20AC;&#x153;Early preclinical experiments predicted that higher-dose fulvestrant may be more effective, and now a series of clinical experiences supports this observation, with greater benefit conferred to patients with higher doses of the drug.â&#x20AC;?

Director of the Prostate Cancer Research Center (PCRC) Division of Hematology/Oncology Department of Medicine Cedars-Sinai is pleased to announce an outstanding Medical Oncology leadership opportunity in our Prostate Cancer Program. The successful candidate for the position will be an innovative leader with a background that spans a robust medical oncology clinical practice and an active laboratory. An outstanding group of peer program leaders add to the potential for a world class program. Focus of the position includes: x

Leading the development, coordination, and administration of the PCRC

x Maintaining an active research program in prostate cancer, creating new opportunities for basic and clinical prostate cancer research, publications in peer reviewed journals/publications; cancer research grant submittals to various federal and state granting agencies and pharmaceutical companies, and actively participating in philanthropic endeavors to enhance the Center. x Overseeing and maintaining quality control at the Center in order to provide the highest standard of care to both the inpatient and outpatient populations, and to attract physicians of exceptional ability to the Medical Center. x

Establishing training and procedural criteria and standards for performing prostate cancer clinical research.

x Responsible for the development and strengthening of an active teaching program in urologic malignancies within the Division, with activities that would include educational programs such as teaching rounds, formal rounds and lectures to medical students, house staff, fellows and other attending staff. x Works closely with the Directors of the Hematology/Oncology Fellowship Program and the Medicine Residency Program to optimize the knowledge and experience of students, house staff, and fellows in urologic malignancies, and is involved in the recruitment of research and clinical fellows Ideal candidates will demonstrate the following qualifications: 9 9 9 9 9 9 9 9

Medical Degree from an accredited medical school Board Certification (or eligibility) in General Internal Medicine and in the subspecialty of Hematology/Oncology.

Eligible for an unrestricted California license as Physician Successful application for CSMC Medical Staff Membership Demonstrated evidence of focus in prostate cancer A published author of high value peer reviewed articles Demonstrated ability to serve as principal investigator for peer reviewed funding A track record of excellence in teaching, patient care and administration

Cedars-Sinai, a tertiary acute care academic medical center is proud to be on the list of â&#x20AC;&#x153;Americaâ&#x20AC;&#x2122;s Best Hospitalsâ&#x20AC;? as ranked by US News and World Report. If you are interested in this opportunity to join a flourishing clinical, teaching and research environment, please send your curriculum vitae to: Search Committee Chairman, Dr. Steven Piantadosi c/o Patricia Carson 8700 Beverly Boulevard, 5th Floor, South Tower, 5724 ~ Los Angeles, California 90048 Email: carsonp@cshs.org CEDARS-SINAI ENCOURAGES AND WELCOMES DIVERSITY IN THE WORKPLACE. AA/EOE

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CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • MAY 2009

New Phase II and III Clinical Trials Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to April 12, 2009. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Solid tumors

14

Protocol Type

Age

Protocol ID

Trial Sites

Monthly SOM230C for Recurrent or Progressive Meningioma, Phase II

18 and over

08-266

MA

Study of LBH589 (Panobinostat) to Treat Malignant Brain Tumors, Phase II

18 and over

LIBTC-2008-1

NY

Pilot Study of Reduced-Intensity Conditioning Comprising Fludarabine Phosphate, Busulfan, and Anti-Thymocyte Globulin Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients With High-Risk Relapsed or Refractory Neuroblastoma, Phase II

1 to 18

NCH-08-0234

OH

Study to Compare the Overall Survival of Patients Receiving INGN 201 (Study Drug) With Patients Receiving Methotrexate [for patients with recurrent squamous cell cancer of the head and neck (SCCHN)], Phase III

18 and over

T301

CO, KY, MD, SC, TX

Effectiveness and Safety of INGN 201 in Combination With Chemotherapy Versus Chemotherapy Alone [for patients with recurrent squamous cell cancer of the head and neck (SCCHN)], Phase III

18 and over

T302

AR, CO, FL, KY, MD, SC, TX

Randomized Study of Vandetanib and Bortezomib in Patients With Recurrent, Metastatic, or Primary Unresectable Medullary Thyroid Cancer or Other Solid Tumors, Phase I, II

18 and over

NCI-09-C-0089

MD

Study of Standard Chemotherapy Plus BSI-201 (a PARP inhibitor) in the Neoadjuvant Treatment of Triple Negative Breast Cancer, Phase II

18 and over

20080206

CA

Vitamin D in Postmenopausal Women at High Risk for Breast Cancer, Phase II

21 and over

Protocol Dated 121308

NY

Bendamustine With Irinotecan Followed by Etoposide/Carboplatin for Patients With Extensive Stage Small Cell Lung Cancer, Phase I, II

18 to 79

F080929010

AL

Randomized Study of Adjuvant Chemotherapy Versus Observation in Patients With Stage I Non-Small Cell Lung Cancer, Phase III

18 and over

CALGB-30506

NC

Dasatinib in Advanced Non-Small Cell Lung Cancer (NSCL) With Ex Vivo and In Vivo Assessment of Tumor Target Modulation, Phase II

18 and over

MCC-15656

FL

Study of REOLYSIN in Combination With Paclitaxel and Carboplatin for Non-Small Cell Lung Cancer With KRAS or EGFR Activation, Phase II

18 and over

REO 016

OH

Randomized, Multi-Center, Open-Label Study of Docetaxel Versus Docetaxel/PR104 in Non-Small Cell Lung Cancer (NSCLC), Phase II

18 and over

R104-2003

CA, IA, IL, IN, KS, KY, LA, MD, MI, NC, OH, TX

Study of Neoadjuvant Gemcitabine Hydrochloride, Cisplatin, and Bevacizumab Followed by Surgery and Adjuvant Cisplatin and Etoposide in Patients With Stage IIIA Nonsquamous Cell Non-Small Cell Lung Cancer, Phase II

18 to 70

NCI-09-C-0107

MD

Sunitinib Non-Small Cell Lung Cancer Patients Over 70, Phase II

70 and over

06-135

FL, MN, NC, OR, SC, TX, VA, WA

Tarceva With Whole Brain Radiation Therapy—Brain Mets From Non-Small Cell Lung Cancer, Phase II

18 to 70

2008-0170

TX

Eloxatin Plus Gemcitabine Chemotherapy for Mesothelioma, Phase II

18 and over

Protocol— Final 2004-05-14

NY

Trimodal Lung-Sparing Treatment of Pleural Mesothelioma, Phase II

18 to 75

Protocol Amdt 6 dated 092508

NY

Study of Capecitabine and Temozolomide for Progressive, Differentiated, Metastatic Neuroendocrine Cancers, Phase II

18 to 80

CAP/TEM for Neuroendocrine CA

NY

Study of ARRY-334543 and Gemcitabine in Patients With Advanced Cancer and Pancreatic Cancer, Phase I, II

18 and over

ARRAY-543-206

AZ, TN

Study of Pemetrexed for Second-Line Pancreas Cancer, Phase II

18 and over

IIT2007022

DC

Study for Inoperable Non-Metastatic Pancreatic CA (Stage IVA) With Neoadjuvant GTX, and Radiation With Gemzar, Phase II

18 to 70

GTX IVA

NY

Trial Combination Irinotecan, Oxaliplatin and Cetuximab for Locally Advanced or Metastatic Pancreatic Cancer, Phase II

18 and over

INST 0802

NM

Safety and Toxicity Study of Sorafenib in Patients With Kidney Cancer, Phase II

18 and over

SU-02272009-1898

CA

Study of 2G-1 T-Cell Receptor-Transduced Peripheral Blood Lymphocytes or Tumor Infiltrating Lymphocytes and Aldesleukin After a Nonmyeloablative Preparative Chemotherapy Regimen in Patients With Metastatic Renal Cell Carcinoma, Phase I, II

18 and over

NCI-09-C-0092

MD

Hepatic Arterial Infusion With Floxuridine and Dexamethasone Combination With Chemotherapy With/Without Bevacizumab for Hepatic Metastases From Colorectal Cancer, Phase II

18 and over

04-086

NJ, NY

Study of Intrahepatic Arterial Cisplatin or Carboplatin in Combination With Sorafenib Tosylate in Patients With Unresectable Hepatocellular Carcinoma, Phase II

18 and over

SCCC-2007101

FL

Solid tumors Hematologic Malignancies

15

CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE â&#x20AC;˘ MAY 2009

Protocol Type

Age

Protocol ID

Trial Sites

Sorafenib or Placebo in Combination With TACE for Intermediate Stage Hepatocellular Carcinoma (SPACE), Phase II

18 and over

12918

GA

Randomized Phase Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma, Phase I, II

18 and over

PR104-2002

CA, IL, IN, NY

Randomized Study of Bevacizumab and Erlotinib Hydrochloride Versus Sorafenib Tosylate as First-Line Treatment in Patients With Advanced Hepatocellular Carcinoma, Phase II

Over 18

MUSC-101282

CA, FL, SC, TX

GTX Regimen for Biliary Cancers, Phase II

18 to 70

AAAB3329

NY

Effect of 2-h Infusion of ON 01910.Na in Ovarian Cancer Patients, Phase II

18 and over

Onconova 04-12

IN

Letrozole in Women With Advanced Estrogen/Progesterone Receptor-Positive Uterine Leiomyosarcoma, Phase II

18 and over

08-341

MA

MLN8237 for Treatment of Patients With Ovarian, Fallopian Tube, or Peritoneal Carcinoma, Phase II

18 and over

C14006

NJ

Pre-Operation Chemo and Antibody Therapy Followed by Surgical Resection and Adjuvant Chemoradiation for Gastric Cancer, Phase II

18 and over

04-72 (H12637)

NY

Irinotecan/Cisplatin, Potentially Curative Surgery With or Without Floxuridine, Followed by Capecitabine for Stomach and Gastro-Esophageal Junction (GEJ) Cancers, Phase II

18 and over

07-837

CA, NY

Study to Evaluate NKTR-102 Versus Irinotecan in Patients With Second-Line, Irinotecan-NaĂŻve, KRAS Mutant, Colorectal Cancer, Phase II, III

18 and over

08-PIR-03

IL

Hypofractionated Radiotherapy for Localized Prostate Cancer (With CyberKnife or With IMRT), Phase II

18 and over

SU-11022007-792

CA

CyberKnife Radiosurgery for Locally Recurrent Prostate Cancer, Phase II

18 and over

CK Recurrent Prostate SD

CA

Neoadjuvant Dasatinib Plus LHRH Analogue Therapy in High-Risk Localized Prostate Cancer, Phase II

18 and over

HOG GU07-124

IN

Exogenous Testosterone Plus Dutasteride for the Treatment of Castrate Metastatic Prostate Cancer, Phase II

Over 18

09-008

NY

Docetaxel and Imatinib Mesylate (Gleevec) in Hormone Refractory Prostate Cancer, Phase I, II

18 and over

NYU 04-47 (H12554)

NY

Gemcitabine, Cisplatin, and Sunitinib (GC-S) as Neoadjuvant Chemotherapy in Patients With Muscle-Invasive Bladder Cancer, Phase II

18 and over

08-159

NJ, NY

Neoadjuvant Cisplatin, Gemcitabine, Sunitinib Malate + Radical Cystectomy for Transitional Cell Carcinoma (TCC) of the Bladder, Phase II

18 and over

HOG GU07-123

IN

Study of Riluzole in Patients With Unresectable Stage III or IV Melanoma, Phase II

18 and over

CINJ-090802

NJ

Study of Cellular Adoptive Immunotherapy Comprising Autologous NY-ESO-1-Melanoma-Specific CD8+ T Cells With or Without Ipilimumab in Patients With Metastatic Melanoma, Phase I, II

18 and over

FHCRC-2225.00

WA

Study of Short-Term Cultured Autologous Tumor-Infiltrating Lymphocytes in Combination With High-Dose Aldesleukin After a Nonmyeloablative Lymphocyte-Depleting Conditioning Regimen Comprising Cyclophosphamide and Fludarabine Phosphate in Patients With Metastatic Melanoma, Phase II

18 and over

STLMC-L-0839

WI

Alimta Plus Gemcitabine for Advanced Sarcoma, Phase II

18 and over

GemAltima Protocol v2

NY

Pilot Study of Neoadjuvant Sorafenib Tosylate and Ifosfamide in Patients With Resectable High-Grade Soft Tissue or Bone Sarcoma, Phase II

18 and over

UCLA-0704086

CA

Sunitinib in Soft Tissue Sarcoma, Phase II

18 and over

Sunitinib in Sarcoma

NY

Radiofrequency Ablation (RFA) of Tumors Acquired in Childhood, Phase II

Under 21

RFAII

WA

Study of Risk-Adapted Induction Chemotherapy, Risk-Adapted Consolidation Combination Chemotherapy Including Arsenic Trioxide, and Maintenance Combination Chemotherapy in Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia, Phase III

2 to 21

COG-AAML0631

CA

SCH 727965 in Patients With Mantle Cell Lymphoma or B-Cell Chronic Lymphocytic Leukemia (Study P04715), Phase II

18 and over

P04715

NJ

Evaluate Rituximab in Obtaining PCR-Negative Leukapheresis Product in Patients With Relapsed Follicular Lymphoma, Phase II

18 and over

11571

KS

Open-Label Trial of SGN-35 for Systemic Anaplastic Large Cell Lymphoma, Phase II

12 and over

SG035-0004

CO, MN, MO

Study of Rituximab With Combination Chemotherapy in Patients With Previously Untreated Mantle Cell Lymphoma, Phase II

18 to 64

SCCC-2008043

FL

Pilot Study of Bortezomib in Combination With Intensive Reinduction Chemotherapy in Young Patients With Relapsed Acute Lymphoblastic Leukemia or Acute Lymphoblastic Lymphoma, Phase II

1 to 31

COG-AALL07P1

CA, FL, NY

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

18 and over

UMN-2008LS043

MN

Evaluating the Safety and Effectiveness of a Bone Marrow Transplant From Partially Matched Donors and Using Low-Dose Chemotherapy in People With Leukemia or Lymphoma (BMT CTN #0603), Phase II

1 to 70

605

CA, FL, GA, MD, NE, PA, SC, TN, TX, WA

Evaluating the Safety and Effectiveness of an Umbilical Cord Blood Stem Cell Transplant That Uses Low-Dose Chemotherapy in People With Leukemia or Lymphoma (BMT CTN #0604), Phase II

1 to 70

606

CA, FL, IA, MA, MN, OH, VA

Lenalidomide Following Fludarabine/Rituximab (FR) in Untreated Chronic Lymphocytic Leukemia (CLL), Phase II

18 and over

RV-CLL-PI-089

DC

Hematologic Malignancies

CLINICAL TRIALS

Support

16

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • MAY 2009

Protocol Type

Age

Protocol ID

Trial Sites

Mismatched Donor Lymphocyte Infusions for Relapsed Disease Following Allogeneic Stem Cell Transplantation, Phase II

8 to 75

090087

MD

Study of Stem Cell Transplant for Leukemia and Myelodysplastic Syndromes Using Clofarabine and Busulfan Regimen, Phase II

18 and over

006-150

TX

Study of Pre- and Post-Transplant Rituximab in Patients Undergoing Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation for Relapsed or Refractory CD20+ B-Cell Malignancies, Phase II

Any age

FHCRC-2226.00

WA

Study of the Novel Proteasome Inhibitor Bortezomib in Combination With Rituximab, Cyclophosphamide and Prednisone in Patients With Relapsed/Refractory Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL), Phase I, II

18 and over

ILS-2

NY

Study of Repeat Intranodal Injection of Memgen’s Cancer Vaccine, Ad-ISF35, in Subjects With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Phase II

18 and over

UCSD-080497

CA

Augmented Berlin-Frankfurt-Munster (BFM) Therapy for Adolescent/Young Adults With Acute Lymphoblastic Leukemia or Acute Lymphoblastic Lymphoma, Phase II

12 to 40

2006-0375

TX

Recalcitrant Pruritis in Cutaneous T-Cell Lymphoma, Phase I, II

18 and over

0705M09523

MN

Safety Study of Lenalidomide Maintenance Therapy Post Allogeneic HCT for High-Risk Multiple Myeloma, Phase II

18 to 70

07-REV

CA, MA, NY

PHA-739358 for the Treatment of Multiple Myeloma, Phase II

18 to 75

AURA-6202-011

AZ, IL

Trial of High-Dose Lenalidomide in Patients With Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) With Trilineage Dysplasia (AML-TLD), Phase II

Over 18

J0882

MD

Study of 48-Hour Infusion of ON 01910.Na in Patients With MDS, Phase I, II

Over 18

Onconova 04-15

NY

STA-9090 for Treatment of AML, CML, MDS and Myeloproliferative Disorders, Phase I, II

18 and over

9090-03

MA, TX

Efficacy and Safety of 5-Day Dosing of ON 01910.Na in Intermediate-1,-2, or High-Risk Myelodysplastic Syndrome (MDS), Phase I, II

18 and over

Onconova 04-11

NY

LBH589 and Bevacizumab in Patients With Recurrent High-Grade Glioma, Phase I, II

18 and over

08-342

MA

Pilot Study of Bortezomib, Bendamustine and Rituximab on Non-Hodgkin’s Lymphoma, Phase II

18 and over

ULYM07054

NE, NY

Study of Bortezomib and Gemcitabine Hydrochloride in Patients With Relapsed B-Cell Non-Hodgkin Lymphoma, Phase I, II

18 and over

CHNMC-04115

CA

A Pivotal Open-Label Trial of SGN-35 for Hodgkin Lymphoma, Phase II

12 and over

SG035-0003

CA, CO, DC, IL, MN, MO, NY, OH, TX

Proton Therapy for Hodgkin Lymphoma, Phase II

6 and over

UFPTI 0806-HL01

FL

Multi-Center Study of Entinostat (SNDX-275) in Patients With Relapsed or Refractory Hodgkin’s Lymphoma, Phase II

18 and over

SNDX-275-0501

TX

Evaluation of Sunitinib Malate in Patients With Von Hippel-Lindau Syndrome (VHL) Who Have VHL Lesions to Follow, Phase II

18 and over

2005-0463

TX

Sitagliptin Umbilical Cord Blood Transplant Study, Phase II

18 to 55

0812-15; IUCRO-0223

IN

Thiotepa-Clofarabine-Busulfan With Allogeneic Stem Cell Transplant for High-Risk Malignancies, Phase II

Under 60

2008-0363

TX

TCAD vs. Monotherapy for Influenza A in Immunocompromised Patients, Phase I, II

1 and over

6895

WA

Study of a Computerized Smoking Cessation Clinical Decision Support System in Assisting Physicians Who Counsel Patients Who Smoke Cigarettes, Phase II

18 and over

VCC-08186

VT

BLADDER continued from page 1

other tests being ordered in 70% of cases. Clinicians changed their original planned management in 68% of the cases following PET scans.

“Our findings suggest that PET scanning has the potential to be a cost-effective imaging tool in patients with suspected or existing metastatic bladder disease,” said lead study author Andrea Apolo, MD, a medical oncology fellow at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. “Given the enhanced ability to detect disease compared with CT or MRI alone, PET warrants inclusion as a standard of care when there is a high suspicion of metastatic disease.”

In the study, patients with bladder cancer had PET scans for staging, treatment

response or evaluation of suspected metastasis. A total of 57 patients (aged 54-91 years) underwent PET scans; 21% for initial staging (n=12 patients), 7% for treatment response (n=four patients) and 72% for evaluation of suspected recurrence (n=41 patients), after routine CT or MRI. Investigators conducted a patientbased analysis and a separate organ-specific, lesion-based analysis, and they validated the accuracy of their PET findings by either a lesion biopsy or subsequent CT or MRI. Pre- and post-PET scan questionnaires determined how scans impacted patient management.

The investigators found that 46 patients had evaluable PET scans that were subsequently followed by either biopsy (n=22 patients) or follow-up scan (n=24 patients). Dr. Apolo said that in 24 of 30 patients, the PET scan correctly diagnosed malignant disease. This resulted in a sensitivity of 80% (95% confidence

interval [CI], 71%-100%). Additionally, the researchers found that the PET scan was negative in 15 of 16 patients without malignant lesions, achieving a specificity rate of 94% (95% CI, 71%-100%).

A total of 133 individual lesions were evaluable as part of the organ-specific lesion analysis. Each lesion was validated by either biopsy (n=22) or subsequent imaging (n=111). The researchers concluded that overall PET sensitivity was 88% (95% CI, 77%-94%) and specificity was 91% (95% CI, 76%-97%). The organ-specific analysis by researchers for sensitivity/specificity was found to be 100%/80% for adrenal, 93%/100% for bone, 83%/100% for liver, 100%/100% for kidney, 89%/80% for lymph node and 100%/100% for soft tissue.

“We found that physicians changed their management based on the PET findings two-thirds of the time. PET gave a more accurate picture of the actual

extent of disease in patients with bladder cancer, potentially helping guide clinicians as to the most appropriate management plan,” Dr. Apolo said. “The takehome message is that PET scans offer a great adjuvant tool to a baseline CT or MRI in assessing metastatic disease and warrants further study as a management tool in bladder cancer.”

Martin Gleave, MD, professor of urologic sciences at the University of British Columbia, Vancouver, Canada, said the study is important. “This report supports a growing body of information that PET adds additional information above and beyond CT and MRI and can be used judiciously in select patients,” he said. “What really is needed in imaging is an imaging scan that not only detects metastasis but provides us with treatment response indicators as well.”

—John Schieszer

Vectibix® (panitumumab) Injection for Intravenous Use Brief Summary of Prescribing Information.

For complete prescribing information consult official package insert.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. [see Warnings and Precautions and Adverse Reactions]. Although not reported with Vectibix®, fatal infusion reactions have occurred with other monoclonal antibody products. [see Dosage and Administration].

INDICATIONS AND USAGE Vectibix® is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Preparation and Administration].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions.

Dose Modifications for Infusion Reactions [see Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

• Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions.

Dose Modifications for Dermatologic Toxicity [see Adverse Reactions] • Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix®.

• If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix®, treatment may be resumed at 50% of the original dose.

– If toxicities recur, permanently discontinue Vectibix®.

– If toxicities do not recur, subsequent doses of Vectibix® may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached.

Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus.

Preparation Prepare the solution for infusion, using aseptic technique, as follows: • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Although Vectibix® should be colorless, the solution may contain a small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates (which will be removed by filtration; see below). Do not shake. Do not administer Vectibix® if discoloration is observed.

• Withdraw the necessary amount of Vectibix® for a dose of 6 mg/kg.

• Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL. • Mix diluted solution by gentle inversion. Do not shake.

Administration • Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter.

• Vectibix® must be administered via infusion pump.

– Flush line before and after Vectibix® administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Vectibix® with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab.

– Infuse over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. Doses higher than 1000 mg should be infused over 90 minutes.

Use the diluted infusion solution of Vectibix® within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Discard any unused portion remaining in the vial.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Dermatologic Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported. Withhold Vectibix® for severe or life-threatening dermatologic toxicity [see Boxed Warning, Adverse Reactions, and Dosage and Administration].

Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3–4).

Across all clinical studies, severe infusion reactions occurred with the administration of Vectibix® in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension [see Boxed Warning and Adverse Reactions]. Although fatal infusion reactions have not been reported with Vectibix®, fatalities have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix® [see Dosage and Administration].

Increased Toxicity With Combination Chemotherapy Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix®-treated patients included rash/dermatitis/acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs <1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 4%) and included fatal events in three (<1%) Vectibix®-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Pulmonary Fibrosis Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patients is uncertain.

One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix® in combination with chemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix®. The second case was characterized by cough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix® as monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix® in combination with chemotherapy. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

Electrolyte Depletion/Monitoring In Study 1, median magnesium levels decreased by 0.1 mmol/L in the panitumumab arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®.

In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed.

Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

EGF Receptor Testing Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix® therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage, and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit.

Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix® and for full instructions on assay performance.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning and Warnings and Precautions] • Infusion Reactions [see Boxed Warning and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix® were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis.

Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy [see Warnings and Precautions].

The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients with a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix® Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* Body System All Grades Grade 3–4 All Grades Grade 3–4 % % % % Body as a Whole Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Acneiform Dermatitis 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0.

Dermatologic, Mucosal, and Ocular Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to: conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced a NCI-CTC grade 3 event of mucosal inflammation.The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions].

Median time to the development of dermatologic, nail, or ocular toxicity was 14 days; the time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported.

Infusion Reactions Infusional toxicity was defined as any event described at any time during the clinical study as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration].

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity.The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%).

For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10 of the 613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies.

No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not.

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

DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with Vectibix®.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring.

[See Reproductive and Developmental Toxicology]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers It is not known whether panitumumab is excreted into human milk; however human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients.

Geriatric Use Of 229 patients with mCRC who received Vectibix® in Study 1, 96 (42%) were ≥age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix® between these patients and younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17 -estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment.A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified.The effects of panitumumab on male fertility have not been studied. However, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight).

Animal Toxicology and/or Pharmacology Weekly administration of panitumumab to cynomolgus monkeys for 4 to 26 weeks resulted in dermatologic findings, including dermatitis, pustule formation and exfoliative rash, and deaths secondary to bacterial infection and sepsis at doses of 1.25 to 5-fold higher (based on body weight) than the recommended human dose.

Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20–50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).

PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning and Warnings and Precautions], • Persistent or recurrent coughing, wheezing, or dyspnea [see Warnings and Precautions], • Pregnancy or nursing [see Use in Specific Populations].

Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations].

This brief summary is based on the Vectibix® prescribing information v4, 6/2008.

Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, as well as other patents or patents pending. © 2006–2008 Amgen Inc.All rights reserved.

Important Safety Information Including Boxed WARNINGS: Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy.

WARNING:DERMATOLOGICTOXICITYandINFUSIONREACTIONS

DermatologicToxicity:Dermatologictoxicitiesoccurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤grade 2 within1month,permanentlydiscontinueVectibix®.The clinical manifestations included, but were not limited to,dermatitisacneiform,pruritus,erythema,rash,skin exfoliation, paronychia, dry skin, and skin fissures.

Subsequenttothedevelopmentofseveredermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported.

The first fully human* anti-EGFR monoclonal antibody

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm,andhypotension.Althoughnotreported with Vectibix®, fatal infusion reactions have occurred withothermonoclonalantibodyproducts.Stopinfusion if a severe infusion reaction occurs. Depending on the severityand/orpersistenceofthereaction,permanently discontinue Vectibix®.

* Correlation with safety andefficacyisunknown

Vectibix®isindicatedasasingleagentforthetreatmentofEGFR-expressing,metastaticcolorectalcarcinoma (mCRC)withdiseaseprogressiononorfollowingfluoropyrimidine-,oxaliplatin-,andirinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-freesurvival(PFS).Currently,nodatademonstrateanimprovementindisease-relatedsymptomsor increased survival with Vectibix®.

Basedonindependentreviewofdiseaseprogression, a statistically significant prolongation in PFS was observed with Vectibix®1 100%

Convenient dosing1 Q2Wdosing,typicallyadministered over 60 minutes (doses >1000 mg administered over 90 minutes), with no loading dose required† 3 available vial sizes: 400 mg (20 mL), 200 mg (10 mL), 100 mg (5 mL)

Kaplan-Meier Estimate of PFS Time

90%

Proportion Event Free

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of Vectibix® to thecombinationofbevacizumabandchemotherapyresulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions.

In a single-arm study of 19 patients receiving Vectibix® in combinationwithIFL,theincidenceofNCI-CTCgrade3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Pulmonary fibrosis occurred in less than 1% (2/1467) of patientsenrolledinclinicalstudiesofVectibix®.Following the initial fatality, patients with a history of interstitial pneumonitis,pulmonaryfibrosis,evidenceofinterstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in such patientsisuncertain.PermanentlydiscontinueVectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

In the randomized, controlled clinical trial, median magnesiumlevelsdecreasedby0.1mmol/LintheVectibix® arm.Additionally,hypomagnesemia(NCI-CTCgrade3or4) requiringelectrolyterepletionoccurredin2%ofpatients 6 weeks or longer after the initiation of Vectibix®. In some patients,bothhypomagnesemiaandhypocalcemiaoccurred.

Patients’electrolytesshouldbeperiodicallymonitoredduring andfor8weeksafterthecompletionofVectibix® therapy, and appropriate treatment instituted, as needed.

Exposuretosunlightcanexacerbatedermatologictoxicity.It isrecommendedthatpatientswearsunscreenandhatsand limit sun exposure while receiving Vectibix®.

Dermatologic, mucosal, and ocular toxicities were also reported.

Adequatecontraceptioninbothmalesandfemalesmustbe used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy.

ThemostcommonadverseeventsofVectibix®areskinrash withvariablepresentations,hypomagnesemia,paronychia, fatigue,abdominalpain,nausea,anddiarrhea,including diarrhea resulting in dehydration. The most serious adverseeventsofVectibix®arepulmonaryfibrosis,severe dermatologictoxicitycomplicatedbyinfectioussequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

80%

Vectibix® + BSC‡ (n=231) (Mean PFS: 96 days)

70%

BSC‡ Alone (n=232) (Mean PFS: 60 days)

60%

P < 0.0001

50%

†

40% 30% 20%

Dose modifications may be needed if toxicity occurs; appropriate medical resources for the treatment of severe infusion reactions should be available.

Reference: 1. Vectibix® (panitumumab) prescribing information. Amgen.

10% 0% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks

‡

best supportive care

Nodifferenceinoverallsurvivalobservedbetweenstudyarms ©2008 Amgen. All rights reserved.

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