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

Lombardi Cancer Center, Georgetown Medical Center, 3800 Reservoir Road NW, Washington, DC 20007-2113, USA.
Clinical Cancer Research (Impact Factor: 8.72). 08/2010; 16(15):4038-45. DOI: 10.1158/1078-0432.CCR-10-0822
Source: PubMed


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.
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.
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/m(2) due to these infusional CNS events. The 3-hour infusion schedule studied in GX005 had improved tolerability, and the obatoclax MTD was 20 mg/m(2). 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.
The 1-hour infusion schedule of obatoclax was associated with neuropsychiatric dose-limiting toxicities at relatively low doses (MTD, 1.25 mg/m(2)). 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.

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    • "This class of small molecules acts by binding to the hydrophobic BH3-cleft of antiapoptotic Bcl-2 proteins thereby mimicking proapoptotic Bcl-2 proteins and promoting cell death [17]. Safety and dose finding trials with Obatoclax have been carried out in solid malignancies and lymphoma [18], [19]. Despite the fact that BH3-mimetics have already entered early clinical trials, only few is known about the effects of Bcl-2 protein inhibition apart from cell death regulation [18], [19]. "
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    • "It should be noted that obatoclax, another BH3-mimetic that targets BCL-2, BCL-XL, and BCL-W but also MCL-1 and BCL2A1, has been shown to enhance the activity of BRAF inhibitors in preclinical studies, however human studies with obatoclax have been limited by the CNS toxicity profile of this agent and there are currently no open clinical trials studying obatoclax according to [41]–[44]. "
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