A Multicenter Phase I/II Study of Obatoclax Mesylate Administered as a 3- or 24-Hour Infusion in Older Patients with Previously Untreated Acute Myeloid Leukemia

PURPOSE: An open-label phase I/II study of single-agent obatoclax determined a maximum tolerated dose (MTD) and schedule, safety, and efficacy in older patients (≥70 yr) with untreated acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: Phase I evaluated the safety of obatoclax infused for 3 hours on 3 consecutive days (3 h×3 d) in 2-week cycles. Initial obatoclax dose was 30 mg/day (3 h×3 d; n = 3). Obatoclax was increased to 45 mg/day (3 h×3 d) if ≤1 patient had a dose-limiting toxicity (DLT) and decreased to 20 mg/day (3 h×3 d) if DLT occurred in ≥2 patients. In the phase II study, 12 patients were randomized to receive obatoclax at the dose identified during phase I (3 h×3 d) or 60 mg/day administered by continuous infusion over 24 hours for 3 days (24 h×3 d) to determine the morphologic complete response rate. RESULTS: In phase I, two of three patients receiving obatoclax 30 mg/day (3 h×3 d) experienced grade 3 neurologic DLTs (confusion, ataxia, and somnolence). Obatoclax was decreased to 20 mg/day (3 h×3 d). In phase II, no clinically relevant safety differences were observed between the 20 mg/day (3 h×3 d; n = 7) and 60 mg/day (24 h×3 d; n = 5) arms. Neurologic and psychiatric adverse events were most common and were generally transient and reversible. Complete response was not achieved in any patient. CONCLUSIONS: Obatoclax 20 mg/day was the MTD (3 h×3 d) in older patients with AML. In the schedules tested, single-agent obatoclax was not associated with an objective response. Evaluation in additional subgroups or in combination with other chemotherapy modalities may be considered for future study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00684918