Phase I and pharmacologic study of enzastaurin HCl, gemcitabine and cisplatin

3129 Background: Enzastaurin HCl (LY317615, e-HCl), an acyclic bisindolylmaleimide, is a potent inhibitor of Protein Kinase C-β isozyme. The β isoform lies in the signal cascade of VEGF and inhibition of this pathway may lead to a block in tumor angiogenesis. In preclinical studies gemcitabine (G) and cisplatin (C) exerted synergistic effects in combination with e-HCl. The objective of the study is to investigate the feasibility and toxicities of e-HCl in combination with G and C in patients (pts) with advanced malignancies, to evaluate the pharmacokinetics (PK) of all 3 agents and to recommend the Phase II doses when given in combination.

METHODS: Pts received a lead-in treatment period of single-agent oral e-HCl administered daily for 14 days, followed by repeated 21 day (d) combination cycles. In each combination cycle, e-HCl was taken orally on d1 - d21, G was administered as a 30 min. intravenous (iv) infusion on d1 and d8, followed by C as a 3 hr iv infusion on d1. The starting dose of e-HCl was 350 mg once daily and of G and C 1000 and 60 mg/m(2), respectively.

RESULTS: Currently, 17 pts have been treated at 5 dose levels. No dose limiting toxicities have been reported. Drug related adverse events to date include max. CTC grade 2 gastro-intestinal toxicities, vitiligo, anorexia, tinnitus and deafness, and max. CTC grade 3 fatigue, neutropenia, thrombocytopenia, anemia and leukopenia. PK data indicate that the geometric mean (%CV) exposures of e-HCl in Cycle 1 were 20500 (196) nM*h at 350 mg, 32100 (94.8) nM*h at 500 mg; in Cycle 2, 18500(161) nM*h at 350 mg and 25500(83.2) nM*h at 500 mg. No apparent differences in e-HCl exposures were seen when given in combination with G and C. G exposures were not altered when given in combination with e-HCl as compared to historical data. C data is pending. Due to less than dose proportional increase in e-HCl exposures in a previous study, dosing of e-HCl was changed to a bid-dosing regimen. Bid dosing started at the most recent dose level 5; 250 mg bid e-HCl, 1250 mg/m(2) G and 75 mg/m(2) C. 3 Pts showed a PR (prostate, papilla and head/neck cancer).

CONCLUSIONS: Preliminary safety and PK data enable continued dose-escalation. [Table: see text].