Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer

Purpose: To evaluate the safety and pharmacokinetics of BCL-2 antisense oligonucleotide (G3139) administered by prolonged i.v. infusion in patients with advanced cancer. Experimental Design: A total of 35 patients was treated in cohorts of 3-6 with 0.6-6.9 mg/kg/day of BCL-2 antisense oligonucleotide as a continuous infusion for 14 or 21 days. Plasma levels of intact antisense oligonucleotide were measured in all patients. Results: G3139 was generally well tolerated. At the highest dose level examined in this study (6.9 mg/kg/day), fatigue and transient reversible elevations of serum transaminases (grades 2-3) became apparent after ≥7 days of treatment. Both reactions were believed to be drug related. Pharmacokinetic analyses showed that steady-state plasma concentrations of G3139 were reached ∼10 h after starting the infusion and increased linearly across the range of doses administered ≤6.9 mg/kg/day. The terminal plasma half-life was ∼2 h. Exploratory studies using Western blots, performed on peripheral blood mononuclear cells on selected patients, demonstrated a decline in bcl-2 protein levels during treatment. No major antitumor responses were observed. Conclusions: BCL-2 antisense therapy is well tolerated. Relative to other dose-finding studies of G3139, fatigue was somewhat more prominent in this study, possibly because of the protracted i.v. infusion schedule of the antisense oligonucleotide. Current randomized trials are using the highest daily dose established in this study given by shorter infusion periods (i.e., 7 mg/kg/day for 5-7 days) to enhance the antitumor activity of standard cytotoxic drugs.