Eisai Inc. and Janssen, a Johnson & Johnson Company, both announced the presentation of data from the DACO-016 trial of DACOGEN® (decitabine) at the 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO). The data demonstrate a clinical improvement in overall survival in older patients with newly diagnosed de novo or secondary acute myeloid leukemia (AML) as defined by the World Health Organization (WHO). AML is a life-threatening cancer of the blood for which there are limited treatment options. DACO-016 compared decitabine to a patient’s treatment choice with physician advice of either supportive care or low-dose cytarabine in the treatment of older patients with AML, the primary endpoint of the study was overall survival. The analysis at the protocol-specified cutoff with 396 (81.6%) deaths demonstrated an increase of greater than 50% in median overall survival in patients taking decitabine (7.7 months for decitabine patients compared to 5.0 months for patients in the comparator arm), HR=0.85, 95% CI: 0.69, 1.04, p=0.108. An updated unplanned analysis of more mature survival data with additional one year of patient follow up and 446 (92%) deaths confirmed this trend for improved overall survival (HR=0.82; 95% CI: 0.68, 0.99; nominal p=0.037). Dr. Xavier G. Thomas of the Hospital Edouard Herriot in Lyon, France, one of the lead DACO-016 investigators, comments: “Compared with the accepted standard therapies used in this study to treat older patients with AML, DACOGEN showed a clinically relevant overall survival advantage without major differences in safety.” DACO-016 was conducted in 485 patients, making it the largest AML trial to date in older patients. It was a Phase 3, randomized, open-label trial, in newly diagnosed patients ≥65 years of age with de novo or secondary AML and poor- or intermediate-risk cytogenetics. Patients were enrolled globally at 65 clinical sites. Of the 485 patients, 242 were randomized to decitabine and 243 to patient’s treatment choice of supportive care or low-dose cytarabine (majority of patients, 88% received low-dose cytarabine). Patients treated with decitabine received a 1-hour infusion, once daily for 5 consecutive days every 4 weeks. Patients treated with cytarabine received 20 mg/m2 subcutaneously once daily 10 consecutive days every 4 weeks. The median duration of treatment for patients on decitabine arm was 4.4 months, compared with 2.4 months in the cytarabine group.
Adverse events (AEs) were consistent with the known decitabine safety profile and without major differences between the treatment arms. The most commonly reported Grade 3 or 4 adverse events were thrombocytopenia (reported in 40%, 32%, and 35% and 14% of subjects in the Dacogen, treatment choice, cytarabine and supportive care groups, respectively), anemia (34%, 25%, 27% and 14% respectively), neutropenia (32%, 42%, 20% and 3% respectively) and febrile neutropenia (32%, 22%, 25% and 0% respectively).About Acute Myeloid Leukemia Acute myeloid leukemia (AML) is an aggressive, fast-growing cancer that starts inside the bone marrow with production of abnormal blood cells. It is generally a disease of older adults, with an average patient age of 64 at diagnosis, and is slightly more common among men than women. The most common symptoms of AML include tiredness, shortness of breath, bruising or bleeding easily, fever and infections. When diagnosed, treatment is to be started with minimal delay as AML usually results in death within just a few months if left untreated. AML can sometimes spread to other parts of the body including the lymph nodes, liver and spleen. In older adults, induction chemotherapy leads to a high 30-day mortality, and most patients are not candidates for or are unwilling to undergo this aggressive therapy. Therefore, treatment options are limited and overall, irrespective of therapy, median survival is merely 2.4 months. About DACOGEN (decitabine) DACOGEN is a DNA hypomethylating agent currently approved for the treatment of myelodysplastic syndromes (MDS) in more than 30 countries worldwide including key markets such as the United States, Brazil, China, India, Russia and Turkey. Eisai Inc. manages the product rights in the United States, Canada and Mexico and Janssen-Cilag International NV and other affiliates of Cilag GmbH International manage the marketing and development rights for DACOGEN in all other markets.
Dacogen is approved in selected markets 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 the phase 3 clinical trial, 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 the single-arm study, 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 DACOGEN full prescribing information, please click here. About SuperGen SuperGen is a pharmaceutical company dedicated to the discovery and development of novel cancer therapeutics in epigenetic and cell signaling modulation. The Company develops products through biochemical and clinical proof of concept to partner for further development and commercialization. SuperGen developed Dacogen and receives significant royalties on global sales. On April 6, 2011, SuperGen entered into a definitive merger agreement to acquire Astex Therapeutics Limited, a UK based biotechnology company. The transaction is subject to customary regulatory, legal and shareholder approvals. For more information about SuperGen, please visit http://www.supergen.com.