A Randomized Phase 2 Study of Sapacitabine, An Oral Nucleoside Analogue, in Elderly Patients with AML Previously Untreated or in First Relapse.

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 elderly AML. 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. The planned sample size consists of 60 patients or 20 patients in each arm. The study also uses a Bayesian continuous monitoring rule to stop accrual in one or more arms of the study in the event that a dose regimen does not have a sufficient number of responses.

Eligible patients must be ≥70 years with AML previously untreated or in first relapse, 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.

Between December 2007 and October 2008, 60 elderly patients with AML were enrolled and treated. Median age was 77 and 35% of patients were 80 years or older. Fifty-one patients had previously untreated AML and 9 patients had AML in 1^st relapse. The majority of the patients (87%) had intermediate/unfavorable risk karyotypes and 45% of AML were preceded by an antecedent hematological disease (AHD). As of August 2009, 9 patients are still on study. The median number of cycles was 3 and 18 patients (30%) received ≥ 6 cycles. Four patients (7%) discontinued treatment for unacceptable toxicity. The overall response rate is 45% on Arm A (10% CR, 35% PR/major HI), 25% on Arm B (10% CR/CRp, 15% PR/major HI), 35% on Arm C (25% CR, 10% major HI). Median time to response is 3 cycles (range 1-9). Eight deaths of all causes occurred within 30 days of randomization and one death was considered to be possibly related to sapacitabine. According to interim safety data, common adverse events (all grades, regardless of causality) included fatigue, nausea, diarrhea, anemia, febrile neutropenia, thrombocytopenia and peripheral edema, most of which were mild to moderate in intensity.

Sapacitabine is safe and active across all 3 dose regiments with the highest CR rate observed on the 3-day dose regimen (Arm C). Mature 1-year survival data will be presented at the meeting.

Kantarjian:Cyclacel, Inc.: Research Funding. Garcia-Manero:Cyclacel, Inc.: Research Funding. Chiao:Cyclacel, Inc.: Employment, Equity Ownership.