Phase I Study of Sapacitabine, an Oral Nucleoside Analogue, in Patients with Advanced Leukemias or Myelodysplastic Syndromes (MDS).

Background: Sapacitabine, a 2′-deoxycytidine nucleoside analogue with unique ability to cause irreparable single-strand DNA breaks and as a result induce G2 cell cycle arrest, is undergoing clinical evaluation for the treatment of cancer. The recommended Phase II dose (RD) in patients with advanced solid tumors was 75 mg twice daily (b.i.d.) x 7 days orally every 21 days. The major DLT was myelosuppression. Here, we present the initial results of a Phase I study of sapacitabine in patients with advanced leukemias or MDS. The primary objective was to define the MTDs of two dosing schedules, b.i.d. x 7 days orally every 21 days or b.i.d. x 3 days per week for 2 weeks every 21 days. The secondary objectives were to characterize the PK/PD effects of sapacitabine and its major metabolite CNDAC.

Methods: Eligible patients had relapsed/refractory leukemias or MDS, or untreated disease if not willing to proceed with conventional systemic chemotherapy, adequate organ functions and performance status of 0–2. At least 3 patients were enrolled at each dose level. The MTD was the highest dose level at which ≤2/6 patients experienced a DLT during the first treatment cycle.

Results: Forty-seven patients received sapacitabine, including 35 treated with the 7-day schedule and 12 treated with the 3-day per week schedule. Median age was 65 (range: 36 – 91). The majority of patients had AML (n=36) or MDS (n=4). Median number of prior chemotherapies was 2 (range: 0 – 6). Cytogenetic abnormalities were present in 27; 30 had relapsed disease or were refractory to cytarabine or high-dose cytarabine regimens. MTD was reached at 375 mg b.i.d. on the 7-day schedule, and 475 mg b.i.d. on the 3-day per week x 2 schedule. DLTs consist of abdominal pain/small bowel obstruction (n=1), neutropenic colitis (n=2) and diarrhea (n=3). One patient died from complications of neutropenic colitis. Common non-hematologic adverse events (all grades, regardless of causality) included fatigue, nausea, vomiting, diarrhea, anorexia, cough, dyspnea, and abdominal pain, most of which were mild to moderate in intensity. PK and PD data are being analyzed. To date, 11 patients of 42 evaluable (9 AML, 2 MDS) had a reduction in bone marrow blast counts to ≤ 5% including 2 CRs, 2CRs with incomplete recovery of platelets, 1 CR of extramedullary disease, and 1 PR of extramedullary disease. 5/11 had relapse-resistance disease on prior cytarabine.

Conclusion: The MTD of sapacitabine is 375 mg b.i.d. by the 7-day schedule and 475 mg b.i.d. by the 3-day per week schedule. The predominant DLT is gastrointestinal toxicity. Sapacitabine is well tolerated and has promising antileukemic activity in patients with relapsed or refractory AML and MDS.