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FDA Recommends Randomized, Controlled Trial for Clofarabine To Support Use in Adult Myeloid Leukemia

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Genzyme Corporation (Nasdaq: GENZ) announced today that the FDA’s Oncologic Drugs Advisory Committee voted 9 to 3 that a randomized, controlled trial is needed to support the currently proposed label expansion for Clolar® (clofarabine) in adult myeloid leukemia (AML). The committee found that the single-arm clinical study results submitted to support the label expansion showed Clolar was an active agent in acute AML patients, but concluded that a randomized clinical trial should be necessary to better interpret Clolar’s efficacy and safety in the proposed patient population.

“I am happy that the three panel members who have significant experience in treating older adults with AML recognized the value of clofarabine in these patients and did not see the need for a randomized trial,” said Harry P. Erba, M.D., Ph.D., University of Michigan, one of the co-principal investigators of the CLASSIC II study.

“The panel indicated that it wasn’t an easy decision to vote for a randomized trial as Clolar was clearly active in these patients,” said Mark Enyedy, president of Genzyme Oncology and Multiple Sclerosis. “The requirement for a randomized control trial as a standard of evidence was a major focus of the discussion. We remain committed to the clinical development of Clolar in this patient population with high unmet medical need.”

Genzyme is conducting a randomized Phase 3 trial comparing clofarabine in combination with cytarabine to cytarabine alone in relapsed and refractory adult AML patients 55 years old or older. The trial continues to exceed patient accrual expectations, and results are expected in 2011. Clofarabine is also being investigated in clinical trials by most of the leading AML experts and major cooperative leukemia investigation groups in the United States and Europe.

The CLASSIC II study, discussed at the ODAC today, analyzed 112 adult AML patients aged 60 years and older with one or more unfavorable prognostic factors, including age 70 years or older, an antecedent hematologic disorder (AHD), poor performance status, or intermediate or unfavorable cytogenetics. As reported in peer-reviewed literature, and discussed by a separate panel of AML experts who recommended the trial, these risk factors predict poor outcomes in older patients with conventional induction therapy.

Patients in the trial had a 45.5 percent overall remission rate, including a 37.5 percent complete remission (CR) rate, and remission rates were consistent regardless of the type or number of unfavorable risk factors. The study also found that Clolar remissions were durable. Durable CR is accepted as an established surrogate for clinical benefit in patients with acute leukemias. The median duration of remission in overall responders (CR+CR with incomplete platelet recovery) was estimated as 52 weeks (12 months). Most patients who responded to treatment achieved remission after one cycle.

The safety profile of Clolar in the Phase 2 study was generally predictable and manageable. The all-cause induction 30-day mortality was 9.8 percent and was consistent regardless of the presence or number of unfavorable prognostic factors. The safety findings were consistent with those for the approved Clolar pediatric ALL indication. The most commonly occurring adverse reactions included nausea, vomiting, diarrhea, febrile neutropenia, rash, headache, fever, fatigue, hypokalemia, pneumonia, anorexia, pruritus, increased liver transaminases, neutropenia, thrombocytopenia, mucosal inflammation.

The American Cancer Society estimates that approximately 12,810 people will be diagnosed with AML in the United States in 2009. About 70 percent of these patients will die from the disease, and almost all will be adults. The median age of a patient with AML is about 67 years. As an acute disease, AML progresses rapidly and is typically fatal within weeks or months if left untreated.

About Clolar
Clolar is currently approved for pediatric acute lymphoblastic leukemia (ALL) patients who have relapsed or have refractory disease after at least two prior regimens. The drug has become the standard of care in this setting.

Clolar has Orphan Drug designation for adult and pediatric ALL, and seven years of market exclusivity in the United States for relapsed/refractory pediatric ALL. The FDA also granted six months of extended market exclusivity to Clolar under the Best Pharmaceuticals for Children Act.

Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function, which is usually reversible and dose dependent, should be anticipated and is likely to increase the risk of infection, including severe sepsis.

Administration of Clolar results in a rapid reduction of peripheral leukemia cells. Patients should be evaluated and monitored for signs and symptoms of tumor lysis syndrome and cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS), capillary leak syndrome, or organ dysfunction. Clolar should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal. The use of prophylactic steroids may be of benefit in preventing signs and symptoms of cytokine release.

The most common side effects seen after Clolar treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting, nausea, and diarrhea; hematologic effects, including anemia, leukopenia, thrombocytopenia, neutropenia, and febrile neutropenia; and infection.

Liver and kidney function should be assessed prior to and during treatment with Clolar, as the liver is a target organ for Clolar toxicity and Clolar is excreted primarily through the kidneys. Concomitant use of medications known to induce hepatic or renal toxicity should be avoided.

Clolar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant and avoid breast feeding while receiving treatment with Clolar.

Source: Genzyme

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