General Information

Dacogen is a nucleoside analog, designed to disrupt DNA synthesis. This disruptive activity promotes cytotoxic DNA hypomethylation and apoptotic cell death in rapidly dividing cells.

Dacogen is specifically indicated for the treatment of multiple types of myelodysplastic syndromes, including previously treated and untreated, de novo and secondary myelodysplastic syndromes (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, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.

Dacogen is supplied as a a sterile lyophilized white to almost white powder, for reconstitution in sterile water and dilution for intravenous injection. Recommended initial dosing is 15 mg/m2 via continuous 3-hour intravenous infusion, once every 8 hours for 3 days. Treatment cycles should be repeated every 6 weeks, for a minimum of 4 cycles, barring serious adverse reaction. If adverse reaction (including insufficient hematologic recovery occurs 6 weeks after a dosing cycle) occurs, subsequent cycles can be delayed until recovery is achieved. Treatment should be discontinued if evidence of disease progression is observed.

Mechanism of Action

Dacogen is an analogue of the nucleoside 2’-deoxycytidine. It is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. DNA hypomethylation is achieved at concentrations below those required to significantly inhibit DNA synthesis, which may promote restoration of function to genes associated with control of cellular differentiation and proliferation. Cytotoxicity in rapidly dividing cells may also result from covalent adducts between DNA methyltransferase and decitabine incorporated into DNA.

Side Effects

Adverse events associated with the use of Dacogen may include, but are not limited to, the following:

• Thrombocytopenia
• Anemia
• Pyrexia
• Cough
• Petechiae
• Nausea
• Constipation
• Diarrhea
• Hyperglycemia
• Febrile Neutropenia

As anticipated, use of Dacogen is associated with incidence of bone marrow suppression, including neutropenia and thrombocytopenia. The most frequently observed serious (Grade 3) or severe (Grade 4) adverse events observed in pivotal trials were neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%). Bone marrow suppression was the most frequent cause of dose reduction, delay or discontinuation. 6 subjects experienced fatal events associated with myelosuppression. Careful monitoring of complete blood and platelet counts should be maintained throughout treatment cycles, with dose adjustment, delay, or discontinuation as appropriate.

Clinical Trial Results

Approval of Dacogen was based on 3 clinical trials: one pivotal phase III trial and a pair of phase II trials.

Phase III Trial
This randomized open-label, multicenter, controlled study enrolled 170 patients with MDS meeting FAB classification criteria and International IPSS High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. 89 subjects were randomized to receive Dacogen plus best-supportive-care, and 81 received best-supportive-care alone. 12 patients (9 Dacogen, 3 supportive care) were excluded from the study after randomization due to revised diagnosis of acute myeloid leukemia. Dacogen was administered at a dose of 15 mg/m2 via 3-hour infusion every 8 hours for 3 consecutive days every 6 weeks. Supportive care included blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. Trial data met one of the study's co-primary endpoints subjects receiving Dacogen achieved an overall response rate (complete response rate + partial response rate) of 17% (9% complete response, 8% partial response) in the intent to treat population, compared to 0% for supportive care; median duration of response for Dacogen was 288 days. Dacogen did not significantly improve median time to progression to acute myeloid leukemia or death.

Phase II Trials
These open-label, single-arm, multi-center studies were designed to investigate the safety and efficacy of Dacogen in MDS patients. Subjects received 15 mg/m2 of the drug via 4 hour infusion on the usual 8 hours/3 day/6 weeks dose cycle schedule. Results from the studies were consistent with those observed in the phase III trial, with overall response rates of 26% (n=66) and 24% (n=98).