Background: 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 is 1-year survival. Secondary endpoints include the rate of CR, CRp, PR, major hematological improvement (HI) or stable disease and their corresponding durations. 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. The planned sample size is 60 patients (20 patients in each arm). Methods: Eligible patients must be ≥ 60 years with intermediate-2 or higher risk MDS previously treated with hypomethylating agents and 6 - < 20% blasts in bone marrow, 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). The number of cycles is not limited. Results: As of January 2012, 61 patients were enrolled and 56 had ≥ 30 days of follow-up. Mean follow-up was 173 days. Median age was 71. Two or 3 cytopenias were present in 42 patients and 14 have received both azacitidine and decitabine. Baseline bone marrow had 6-10% blasts in 31 patients and 11-19% blasts in 25 patients. Median number of cycles was 2 and 18 patients received ≥ 4 cycles. To date, 8 patients have responded (2 CRs, 2 CRp, and 4 major HIs): 15% (Arm G), 16% (Arm H) and 12% (Arm I). Time to response is 1-3 cycles. Additionally, 6 patients achieved stable disease lasting longer than 16 weeks. More than 50% of patients have lived 16 weeks or longer. Three deaths occurred within 30 days of randomization and 1 death was considered to be related to sapacitabine. Common adverse events (all grades, regardless of causality) included fatigue, nausea, diarrhea, constipation, edema, dyspnea, pyrexia, pneumonia, febrile neutropenia, anemia, neutropenia and thrombocytopenia, most of which were mild to moderate. Conclusions: Sapacitabine appears to be safe and active across all 3 dose regimens. Updated data will be presented at the meeting.