PHASE-I PHASE-II DOSE-ESCALATION STUDY OF LIAROZOLE IN PATIENTS WITH STAGE-D, HORMONE-REFRACTORY CARCINOMA OF THE PROSTATE/

Background: Liarozole binds to the cytochrome P-450-dependent hydroxyl ating enzymes involved in steroid biosynthesis and retinoic acid catab olism. This phase I study investigated the clinical/endocrine toxicity profile of liarozole and determined the maximally tolerated dose (MTD ) in hormone-refractory prostate cancer patients. Methods: Groups of f ive patients were treated with oral liarozole caplets, starting at 37. 5 mg twice daily. The dose was doubled for each subsequent group until the MTD was reached, after which, an additional 18 patients were ente red into the MTD-1 dose stratum. The long-term safety of liarozole was assessed based on treatment-emergent signs and symptoms and clinicall y significant laboratory results. Results: Thirty-eight patients were enrolled. The MTD was determined to be 300 mg twice daily. Side effect s that defined the MTD included lethargy, somnolence, body rash, and p aresthesias. Two deaths occurred during the trial (pneumonia and myoca rdial infarction). Four patients had a >50% decrease in prostate-speci fic antigen (PSA) levels (two at, 150 mg, two at 300 mg). Of nine pati ents with measurable disease, two had partial responses. Conclusions: Liarozole was generally well tolerated with no evidence of adrenal ins ufficiency. Preliminary evidence of activity in this indication was ob served based on dose-dependent decreases in PSA levels and improvement in soft-tissue metastasis.