Phase 1/ 2 Study of Sapacitabine and Decitabine Administered Sequentially in Elderly Patients with Newly Diagnosed AML,

Sapacitabine is a novel nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading to production of double strand DNA breaks and/or G2 cell cycle arrest. It is orally administered and has demonstrated promising activity in patients with acute myeloid leukemia (AML). In AML cell lines, the active metabolite of sapacitabine, CNDAC, is synergistic with hypomethylating agents with the synergy being more apparent if cells are treated with hypomethylating agents first. We are conducting a phase 1/ 2 study to evaluate the safety and efficacy of administering sapacitabine in alternating cycles with decitabine in elderly patients with newly diagnosed AML. Methods: Decitabine 20 mg/m² was administered intravenously daily × 5 days of a 4-week cycle (odd cycles) alternating with sapacitabine 300 mg po b.i.d. × 3 days/week × 2 weeks of a 4-week cycle (even cycles). After these doses were shown to be safe in the phase 1 part, patients were treated in the Phase 2 part to reach a planned sample size of approximately 24 patients. The primary efficacy endpoint is response rate (CR, CRp, PR, or major HI). The regimen will be considered active if response rate is ≥30%. Eligible patients must be ≥70 years with untreated AML unsuitable for or unwilling to receive standard induction chemotherapy; patients who received hypomethylating agents for prior MDS or MPD are excluded. Results: As of August 2011, 25 patients were treated with the above regimen and 23 had ≥ 60 days of follow-up. Median age is 76 years (range, 72–90). No DLTs were observed. Four patients achieved CR, 3 PR and 2 major HIs in platelets. Median time to response is 2 cycles (range 2– 6). Fifteen patients have received ≥4 cycles of treatment. Three patients died within 60-days and the deaths were unrelated to study drugs by investigator assessment. Common adverse events (regardless of causality) included weakness, anorexia, nausea, constipation, diarrhea, dyspnea, edema, pneumonia, febrile neutropenia, neutropenia, thrombocytopenia, anemia, and hypocalcemia, mostly moderate in intensity. Conclusion: The sequential combination of decitabine and sapacitabine is safe and active in elderly AML.

Off Label Use: Decitabine for the treatment of elderly AML. Wetzler:Cyclacel Limited: Research Funding. Chiao:Cyclacel Limited: Employment, Equity Ownership.