Statement Regarding FDA Oncologic Drugs Advisory Committee (ODAC) Opinion on

On February 9, 2012, the U.S. Food and Drug Administration's (FDA's) Oncologic Drugs Advisory Committee (ODAC) voted 10 to 3 with one abstention that the data in the company's supplemental New Drug Application (sNDA) for DACOGEN® (decitabine) for injection did not support a favorable benefit-risk profile for the potential treatment of acute myeloid leukemia (AML) in adults 65 years of age or older who are not considered candidates for induction chemotherapy.

The FDA has the option of seeking the advice of its advisory committees when it is reviewing a new drug application, although it is not obliged to follow the committee's recommendation. The advisory committee reviewed data from the open-label Phase III clinical trial (DACO-016) comparing DACOGEN versus patient's choice with physician's advice of either supportive care or low-dose cytarabine in patients 65 years and older with newly diagnosed de novo or secondary acute myeloid leukemia (AML) and with poor-or intermediate-risk cytogenetics. It is one of the largest randomized controlled studies in older patients with AML conducted to date. Acute myeloid leukemia (AML) is a life-threatening cancer of the blood for which there are few treatment options.

DACOGEN is approved for treatment of patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS of all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia), and Intermediate-1, Intermediate-2 and High-Risk International Prognostic Scoring System (IPSS) groups.

Important Safety Information
Treatment with DACOGEN is associated with neutropenia and thrombocytopenia. Complete blood and platelet counts should be performed as needed to monitor response and toxicity but at a minimum prior to each dosing cycle. After administration of the recommended dosage for the first cycle, treatment for subsequent cycles should be adjusted if indicated by dose adjustment guidelines. Clinicians should consider the need for early institution of growth factors and/or antimicrobial agents for the prevention or treatment of infections in patients with MDS. DACOGEN may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with DACOGEN and for 1 month following completion of treatment. Women of childbearing potential should be counseled to use effective contraception during this time. Men should be advised not to father a child while receiving treatment with DACOGEN and for 2 months following completion of treatment. DACOGEN may cause fetal harm. Men with female partners of childbearing potential should use effective contraception during this time.

In a phase 3 clinical trial in MDS patients, the highest incidence of Grade 3 or Grade 4 adverse events in the DACOGEN arm was neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%), and leukopenia (22%). Bone marrow suppression was the most frequent cause of dose reduction, delay, and discontinuation. Six patients had fatal events associated with their underlying disease and myelosuppression (anemia, neutropenia, and thrombocytopenia) that were considered at least possibly related to drug treatment. Of the 83 DACOGEN-treated patients, 8 permanently discontinued therapy for adverse events compared to 1 of 81 patients in the supportive care arm.

In a single-arm study in MDS patients, the highest incidence of Grade 3 or Grade 4 adverse events was neutropenia (37%), thrombocytopenia (24%), and anemia (22%). Seventy-eight percent of patients had dose delays, the median duration of this delay was 7 days. Hematologic toxicities and infections were the most frequent causes of dose delays and discontinuation. Eight patients had fatal events due to infection and/or bleeding that were considered at least possibly related to drug treatment. Nineteen of 99 patients permanently discontinued therapy for adverse events.

Other commonly occurring reactions include fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.

If hematologic recovery from a previous DACOGEN treatment cycle requires more than 6 weeks when administering the 3-day dosing, then the next DACOGEN cycle should be delayed and dosing temporarily reduced. When administering the 5-day dosing, the DACOGEN cycle should be delayed until there is hematologic recovery. If the following nonhematologic toxicities are present, DACOGEN treatment should not be restarted until the toxicity is resolved: (1) serum creatinine ≥2 mg/dL; (2) SGPt, total bilirubin ≥2 × ULN; and (3) active or uncontrolled infection.

Because there are no data on use of DACOGEN in patients with renal or hepatic dysfunction, DACOGEN should be used with caution in these patients.

For full prescribing information, please see http://us.eisai.com/pdf_files/Dacogen_PI.pdf.



DACOGEN® is a registered trademark used by Eisai Inc. under license from Astex Pharmaceuticals, Inc., Dublin, CA, U.S.A.
 

Type Press Release

Date Released February 10, 2012

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