A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit alpha of protein kinase A using a continuous infusion schedule in patients with refractory solid tumors.

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 alpha 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/m(2)/day.

RESULTS

The maximum tolerated dose of GEM231 was 180 mg/m(2)/day, based on dose-limiting elevation of serum transaminases (STs). At the recommended Phase II dose, 120 mg/m(2)/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 >/==" BORDER="0">4 weeks of therapy. There was a positive correlation between weekly dose and change in aspartate and alanine aminotransferase from baseline [r(2) = 0.56 (P = 0.031) and r(2) = 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.