Phase I clinical and pharmacokinetic study of Bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma

Purpose: To evaluate the pharmacokinetics and toxicity of an antisense olig onucleotide targeting bcl-2 in patients with non-Hodgkin's lymphoma (NHL) a nd to determine efficacy using clinical and biologic end points. Patients and Methods: Twenty-one patients with Bcl-2-positive relapsed NHL received a 14-day subcutaneous infusion of G3139, an 18-mer phosphorothioat e oligonucleotide complementary to the first six codons of the bcl-2 open r eading frame. Plasma pharmacokinetics were measured by anion exchange highp erformance liquid chromatography. Response was assessed by computed tomogra phy. Changes in Bcl-2 expression were measured by fluorescence-activated ce ll sorting of patients' tumor samples. Results: Eight cohorts of patients received doses between 4.6 and 195.8 mg/ m(2)/d. No significant systemic toxicity was seen at doses up to 110.4 mg/m (2)/d. All patients displayed skin inflammation at the subcutaneous infusio n site. Dose-limiting toxicities were thrombo-cytopenia, hypotension, fever , and asthenia. The maximum-tolerated dose was 147.2 mg/m(2)/d. Plasma leve ls of G3139 equivalent to the efficacious plasma concentration in in vivo m odels were produced with doses above 36.8 mg/m(2)/d. Plasma levels associat ed with dose-limiting toxicity were greater than 4 mu g/mL. By standard cri teria, there was one complete response, 2 minor responses, nine cases of st able disease, and nine cases of progressive disease. Bcl-2 protein was redu ced in seven of 16 assessable patients. This reduction occurred in tumor ce lls derived from lymph nodes in two patients and from peripheral blood or b one marrow mononuclear cell populations in the remaining five patients. Conclusion: Bcl-2 antisense therapy is feasible and shows potential for ant itumor activity in NHL. Downregulation of Bcl-2 protein suggests a specific antisense mechanism. (C) 2000 by American Society of Clinical Oncology.