Regulatory Decision Summary for Dacogen

The clinical trial program for Dacogen included two different dosing schedules in inpatient and outpatient settings that were supported by a randomized controlled Phase 3 pivotal trial (D-0007) and a single arm Phase 2 study (DACO-020), respectively. These studies enrolled adult myelodysplastic syndromes (MDS) patients meeting French-American-British (FAB) classification criteria (1997) and International Prognostic Scoring System (IPSS) intermediate risk INT-1, INT-2 and high-risk scores.

The pivotal Phase 3 D007 trial provided support for the Option 1: Inpatient 3-day dosing regimen, comparing standard care (SC) treatment alone (N = 81) to SC treatment plus decitabine (N = 89) in adult patients with MDS with any French-American-British (FAB) subtype and International Prognostic Scoring System (IPSS) score ≥ intermediate-1 (INT-1). Decitabine was infused intravenously at 15 milligram/square meter (mg/m²) over a 3-hour period, every 8 hours, for 3 consecutive days; this cycle was repeated every 6 weeks. Co-primary endpoints were Overall Response Rate (ORR), defined as Complete Response (CR) plus Partial Response (PR), and time to Acute myeloid leukemia (AML) transformation or death. Statistical significance of either co-primary endpoint was considered to confirm that the response observed with decitabine was superior to that observed with SC. The intention-to-treat (ITT) analysis demonstrated that the ORR in patients received Dacogen was 17% (15/89) compared to 0% (0/81) in the SC treatment arm, (p <0.001). There were eight patients (8.9 %) with CR and seven patients (7.9%) with PR in patients treated with Dacogen. Responses were durable with a median duration of 288 days (range 116-288 days). Median time to response was 93 days (55-272 days). However the time to AML or death in the ITT analysis did not reach statistical significance as compared with patients treated with the SC treatment alone (12.1 vs. 7.8 months).

The single arm Phase 2 DACO-020 study provided support for the Option 2: Outpatient 5-Day dosing regimen in 99 patients with MDS with any FAB subtype and IPSS score ≥INT-1. Patients received decitabine at a dose of 20 mg/m² by IV infusion over 1-hour daily, on days 1-5 of week 1 every 4 weeks (1 cycle). The ITT analysis showed an ORR of 16% (16/99), including 15 subjects with CR, which was consistent with that from Study D-0007. Responses were durable with a median duration of 443 days. The time to AML progression was not investigated in this study.

Adverse reactions (AR) were similar in patients treated with the above two options. The most common ARs relate to myelosuppression (neutropenia, thrombocytopenia, anemia, and febrile neutropenia). However, the incidence of these ARs including Grade 3 and Grade 4 serious ARs were lower in patients treated with the Option 2 (5-day out patient dosing regimen) as compared with Option 1 (3-day inpatient dosing regimen). The product label contains clear instructions on dose adjustments to manage ARs.

With both treatment options, there was an increased risk of febrile neutropenia and increased requirements for transfusion in the first two treatment cycles. Dose-related, but transient cytopenias, were reported early in the treatment regimen following the initial Dacogen infusions. Serious infection-related ARs such as septic shock, sepsis, and pneumonia were reported in patients receiving Dacogen. Higher frequencies of ARs were reported in patients ≥70 years of age compared to patients aged 65-69 years. Lack of efficacy was reported from clinical studies in children with AML receiving Dacogen in sequential/combination with other drugs. Dacogen is not recommended in pregnant and nursing woman. Decitabine is mutagenic and therefore men and women of child bearing potential should be counselled regarding the use of effective contraception. The product label of Dacogen contains boxed warnings on toxicities (i.e., neutropenia and thrombocytopenia; as well as the potential for fetal harm if administered in pregnant women, or in women or men with child bearing potential). Data for Dacogen use in pediatrics, hepatic and renal impairment, as well as in patients with uncontrolled cardiac disorders are not available. It is recommended in the Risk Management Plan (RMP) for Dacogen that use in severe renal impairment, use in hepatic impairment, and use in severe cardiac disease be tracked and discussed in PSURs/PBRERs to be submitted by the MAH for 3 years following marketing authorization.

The benefit risk balance of Dacogen in the treatment of adult MDS patients meeting FAB classification criteria and IPSS intermediate risk INT-1, INT-2 and high-risk scores following the two dosing options is deemed to be favourable.