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PLoS One. 2014 Oct 6;9(10):e108694. doi: 10.1371/journal.pone.0108694. eCollection 2014.

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.

Author information

1
Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
2
Columbia University Medical Center, New York, New York, United States of America.
3
The University of Iowa, Iowa City, Iowa, United States of America.
4
Penn State, Hershey, Pennsylvania, United States of America.
5
University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
6
Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
7
Leukemia Service, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York, United States of America.
8
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Abstract

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.

PMID:
25285531
PMCID:
PMC4186779
DOI:
10.1371/journal.pone.0108694
[Indexed for MEDLINE]
Free PMC Article

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