Data from 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

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> Thirty-five patients were enrolled in studies GX001 (<i>n</i> = 8) and GX005 (<i>n</i> = 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<sup>2</sup> 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<sup>2</sup>. 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.</p><p><b>Conclusions:</b> The 1-hour infusion schedule of obatoclax was associated with neuropsychiatric dose-limiting toxicities at relatively low doses (MTD, 1.25 mg/m<sup>2</sup>). The 3-hour i.v. infusion of obatoclax administered once weekly to patients with solid tumors was better tolerated (MTD, 20 mg/m<sup>2</sup>), and evidence of clinical activity was observed. Clin Cancer Res; 16(15); 4038–45. ©2010 AACR.</p></div>