Phase I dose finding studies of obatoclax (GX15-070), a small molecule Pan-BCL-2 family antagonist, in patients with advanced solid tumors or lymphoma

Jimmy J. Hwang, John Kuruvilla, David Mendelson, Michael J. Pishvaian, J. F. Deeken, Lillian L. Siu, Mark S. Berger, Jean Viallet, John L. Marshall

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Two phase I, single-agent studies were conducted to determine the dose and regimen of obatoclax, an antagonist of all BCL-2 antiapoptotic proteins, for evaluation in phase II trials. The two studies, GX001 and GX005, evaluated the safety and tolerability of weekly 1-hour and 3-hour infusions of obatoclax, respectively. Experimental Design: Eligible patients in both studies were adults with solid tumor or lymphoma and performance status 0-1 for whom standard therapies were not appropriate. In the GX001 study an accelerated dose titration design was initially used with subsequent cohorts of three to six patients with 40% dose increments between levels. In the GX005 study three to six patients entered at each dose level with 40% dose increments between levels. Results: Thirty-five patients were enrolled in studies GX001 (n = 8) and GX005 (n = 27). Clinically significant central nervous system (CNS) toxicity was observed using the 1-hour infusion schedule. The obatoclax maximum tolerated dose (MTD) in GX001 was 1.25 mg/m2 due to these infusional CNS events. The 3-hour infusion schedule studied in GX005 had improved tolerability, and the obatoclax MTD was 20 mg/m2. One patient in GX005 with relapsed non-Hodgkin's lymphoma achieved partial response of 2 months' duration, and one patient with relapsed non-Hodgkin's lymphoma had stable disease for 18 months. Conclusions: The 1-hour infusion schedule of obatoclax was associated with neuropsychiatric doselimiting toxicities at relatively low doses (MTD, 1.25 mg/m2). The 3-hour i.v. infusion of obatoclax administered once weekly to patients with solid tumors was better tolerated (MTD, 20 mg/m 2), and evidence of clinical activity was observed.

Original languageEnglish (US)
Pages (from-to)4038-4045
Number of pages8
JournalClinical Cancer Research
Volume16
Issue number15
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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