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Clinical Cancer Research Vol. 8, 679-683, March 2002
© 2002 American Association for Cancer Research

Clinical Trials

Phase I Trial of BCL-2 Antisense Oligonucleotide (G3139) Administered by Continuous Intravenous Infusion in Patients with Advanced Cancer1

Michael J. Morris, William P. Tong, Carlos Cordon-Cardo, Marija Drobnjak, William K. Kelly, Susan F. Slovin, Kathryn L. Terry, Karen Siedlecki, Paul Swanson, Mohmed Rafi, Robert S. DiPaola, Neal Rosen and Howard I. Scher2

Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [M. J. M., W. P. T., C. C-C., M. D., W. K. K., S. F. S., K. L. T., K. S., P. S., N. R., H. I. S.]; Department of Medicine, Weill Medical College of Cornell University, New York, New York [M. J. M., W. P. T., C. C-C., M. D., W. K. K., S. F. S., P. S., N. R., H. I. S.]; and The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey [M. R., R. S. D.]

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.




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