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A Safety Study of a Mixed-backbone Oligonucleotide (GEM231) Targeting the Type I Regulatory Subunit of Protein Kinase A Using a Continuous Infusion Schedule in Patients with Refractory Solid Tumors¹

Albert Einstein Comprehensive Cancer Center [S. G., K. D., A. B., A. F., G. G., S. M.] and Department of Medicine and Oncology [S. G., K. D., A. B., S. M.], Division of Gynecologic Oncology [A. F., G. G.], Albert Einstein College of Medicine, Bronx, New York 10461; Hybridon, Inc., Cambridge, Massachusetts 02139 [S. A., R. M.]; and EPD Pharma Solutions, Alpharetta, Georgia 30022 [M. G.]

Purpose: The purpose of this study was to define the safety and pharmacodynamics of GEM231, a mixed backbone antisense oligonucleotide targeting the type I regulatory subunit of protein kinase A, administered as a continuous i.v. infusion.

Experimental Design: Fourteen cancer patients received escalating doses of GEM231 as a 3-day (1 patient) or a 5-day continuous i.v. infusion (13 patients) at doses ranging from 80 to 180 mg/m²/day.

Results: The maximum tolerated dose of GEM231 was 180 mg/m²/day, based on dose-limiting elevation of serum transaminases (STs). At the recommended Phase II dose, 120 mg/m²/day (n = 8), the median number of cycles delivered was 2 (range, 1–4 cycles). Toxicities were tolerable, with one patient experiencing grade 3 ST elevation after 8 weeks. Plasma activated partial thromboplastin time changes were transient, reached a peak at the end of each weekly infusion, and were not associated with spontaneous bleeding. There was a significant difference between the mean preinfusion and postinfusion activated partial thromboplastin time measurements (2.05 s; P = 0.029). The most significant nonhematological toxicity was elevation in ST, usually observed after 4 weeks of therapy. There was a positive correlation between weekly dose and change in aspartate and alanine aminotransferase from baseline [r² = 0.56 (P = 0.031) and r² = 0.64 (P = 0.019), respectively]. ST elevations were reversible to near baseline in all patients within 3–4 weeks of interruption of GEM231 dosing. Low-grade fatigue was common (57%), cumulative by weeks 4–6, and reversible after GEM231 discontinuation.

Conclusions: GEM231 administered as a continuous infusion is safe; however, continuous protracted dosing is limited by ST elevations. Alternative dosing schedules should include intermittent administration to minimize cumulative toxicity. Additional studies using intermittent continuous infusion schedules of GEM231 are warranted.