A Randomized Phase 2 Study of Sapacitabine, An Oral Nucleoside Analogue, in Older Patients with Myelodysplastic Syndrome (MDS) Refractory to Hypomethylating Agents.

Sapacitabine is a novel nucleoside analogue with a unique ability to cause irreparable single-strand DNA breaks and induce G2 cell cycle arrest. It is orally administered and has demonstrated promising anti-leukemic activity against relapsed or refractory AML and MDS in a phase 1 trial. We are conducting a multi-center, open-label, randomized phase 2 study to evaluate 3 dose regimens of this drug in older patients with MDS refractory to hypomethylating agents. The primary objective is to evaluate 1-year survival rate. The study uses a selection design to identify a dose regimen which produces a better 1-year survival rate in the event that all three dose regimens are active. There is an early stopping rule for excessive toxicity. The planned sample size consists of 60 patients or 20 patients in each arm.

Eligible patients must be ≥60 years with MDS and an IPSS score of intermediate -2 or high - risk who have been previously treated with hypomethylating agents, ECOG 0-2, creatinine '1.5 x ULN, total bilirubin or direct bilirubin '1.5 x ULN and ALT '2.5 x ULN or '5 x ULN if the liver is involved by leukemic blasts. Patients were randomized 1:1:1 to receive one of the 3 dose regimens: 200 mg b.i.d. x 7 days every 3-4 weeks (Arm A), 300 mg b.i.d. x 7 days every 3-4 weeks (Arm B), or 400 mg b.i.d. x 3 days per week x 2 weeks every 3-4 weeks (Arm C). There is no limit on the maximum number of cycles. The primary efficacy endpoint is 1-year survival. Secondary efficacy endpoints include the rate of CR, CRp, PR, CRi or hematological improvement (HI) and their corresponding response durations.

As of August 2009, 39 older patients with MDS refractory to hypomethylating agents have been treated and had ≥ 30 days of follow-up. There are 13 patients on each arm. Median age was 73 and 79% of patients were 70 years or older. Baseline bone marrow contained 5-10% blasts in 20 patients (51%), 11-20% blasts in 16 patients (41%) and 21-30% blasts in 2 patients (5%). The median number of cycles was 2 and 33% of patients received ≥ 4 cycles. Overall response rate is 23% (1 CR and 8 major HIs): 23% (Arm A), 38% (Arm B) and 8% (Arm C). Median time to response is 1-2 cycles (range 1-5). One death occurred within 30 days of randomization and the death was considered to be unrelated to sapacitabine. According to interim safety data, common adverse events (all grades, regardless of causality) included fatigue, nausea, diarrhea, constipation, anemia, neutropenia and alopecia, most of which were mild to moderate in intensity.

Sapacitabine appears to be safe across all 3 dose regimens. Based on interim data, the highest overall response rate was observed on the 7-day high dose regimen (Arm B). Updated data will be presented at the meeting.

Chiao:Cyclacel: Employment.