Journal Article

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

Goard, Carolyn, Borthakur, Gautam, Raza, Azra, Carter, Thomas H., Claxton, David, Tallman, Martin S., Schimmer, Aaron D., Erba, Harry, DeAngelo, Daniel J.

2014

Overview

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). 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. 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. 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. ClinicalTrials.gov NCT00684918.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acute myeloid leukemia / Aged / Aged, 80 and over / Apoptosis / Ataxia / Blast Crisis - drug therapy / Blast Crisis - pathology / Cancer therapies / Chemotherapy / Demography / Drug Administration Schedule / Experimental design / Female / Humans / Inhibitor drugs / Leukemia / Leukemia, Myeloid, Acute - blood / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - pathology / Lung cancer / Lymphoma / Male / Medical prognosis / Medicine and Health Sciences / Myeloid leukemia / Neutrophils - pathology / Patients / Platelet Count / Pyrroles - administration & dosage / Pyrroles - adverse effects / Pyrroles - therapeutic use / Reagents / Safety / Schedules / Subgroups / Targeted cancer therapy / Toxicity / Treatment Outcome