Phase I/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 hydroxylating enzymes involved in steroid biosynthesis and retinoic acid catabolism. 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 five 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 entered into the MTD-1 dose stratum. The long-term safety of liarozole was assessed based on treatment-emergent signs and symptoms and clinically significant laboratory results.

Results: Thirty-eight patients were enrolled. The MTD was determined to be 300 mg twice daily. Side effects that defined the MTD included lethargy, somnolence, body rash, and paresthesias. Two deaths occurred during the trial (pneumonia and myocardial infarction). Four patients had a > 50% decrease in prostate-specific antigen (PSA) levels (two at 150 mg, two at 300 mg). Of nine patients with measurable disease, two had partial responses.

Conclusions: Liarozole was generally well tolerated with no evidence of adrenal insufficiency. Preliminary evidence of activity in this indication was observed based on dose-dependent decreases in PSA levels and improvement in soft-tissue metastasis.