A Randomized Phase II Study Of Sapacitabine In MDS Refractory To Hypomethylating Agents

Sapacitabine is an orally administered nucleoside analogue which causes single-strand DNA breaks and induces G2 cell cycle arrest. A multi-center, randomized phase 2 study was conducted to evaluate 3 dose regimens in older patients with MDS refractory to hypomethylating agents. The primary endpoint was 1-year survival. Secondary endpoints included the rate of CR, CRp, PR, major hematological improvement (HI) or stable disease and their corresponding durations. The study used a selection design to identify a dose regimen which produced a better 1-year survival rate in the event that all three dose regimens were active. The planned sample size was 60 patients (20 patients in each arm).

Eligible patients were ≥ 60 years with intermediate-2 or higher risk MDS and 6 - < 20% blasts in bone marrow after receiving hypomethylating agents, ECOG 0-2, adequate renal and hepatic functions. Patients were randomized 1:1:1 to receive sapacitabine every 4 weeks at 200 mg b.i.d. x 7 days (Arm G), 300 mg q.d. x 7 days (Arm H), or 100 mg q.d. x 5 days per week x 2 weeks (Arm I). Treatment was continued indefinitely until unacceptable toxicity or disease progression.

Sixty three patients were randomized and treated (21 patients per arm). Median follow-up was 23.6 months. Median age was 73. Prior therapy also included lenalidomide (n=8), clofarabine (n=1) and fludarabine-based regimen for bone marrow transplant (n=2). Thirteen patients had high risk and all others had intermediate-2 risk. Baseline bone marrow had 10-19% blasts in 40 patients. Median number of cycles was 3 (range: 1- >21) and 30 patients received ≥ 4 cycles. To date, 9 patients have responded (2 CRs, 2 CRp, and 5 major HIs): 19% (Arm G), 10% (Arm H) and 14% (Arm I). Time to response is 1- 3 cycles. Additionally, 21 patients achieved stable disease lasting longer than 16 weeks. Median overall survival was 8.6 months: 9.7 months (Arm G), 9.7 months (Arm H) and 7.6 months (Arm I). One –year survival is 38% (Arm G), 24% (Arm H), and 33% (Arm I). Thirty-day death rate was 5% on each of the arms. Common adverse events regardless of causalities included fatigue, nausea, diarrhea, constipation, pneumonia, edema, pyrexia, epistaxis, febrile neutropenia, anemia, neutropenia and thrombocytopenia, most of which were mild to moderate.

Sapacitabine appears to be safe and active across all 3 dose regimens. The median survival in all three arms appears to exceed the median survival in published reports of the outcome of MDS patients after treatment failure of hypomethylating agents (Jabbour Cancer 2010, Prebet JCO 2011: median survival 4.3 – 5.6 months). The dose regimen of 200 mg b.i.d. x 7 days (Arm G) has better 1-year survival rate and the highest response rate.

Garcia-Manero1:Cyclacel: Research Funding. Wetzler:Cyclacel: data safety monitoring of another study Other, Research Funding. Seiter:Cyclacel: Research Funding. Chiao:Cyclacel: Employment, Equity Ownership, Patents & Royalties. Kantarjian:Cyclacel: Research Funding.