A PHASE-II TRIAL OF ALL-TRANS-RETINOIC ACID IN HORMONE-REFRACTORY PROSTATE-CANCER - A CLINICAL-TRIAL WITH DETAILED PHARMACOKINETIC ANALYSIS

Retinoids have been shown to have substantial anticancer activity in a number of preclinical and clinical situations. There are considerable epidemiologic, in vitro and in vivo data which indicate that retinoid s may have a role in the prevention and therapy of human prostate canc er. Based on anecdotal evidence of response in one patient with hormon e-refractory prostate cancer (HRPC), we conducted a phase II trial in HRPC during which we also examined changes in pharmacokinetics of all- trans-retinoic acid (ATRA) which occurred during therapy. Enrolled in the study were 17 patients with HRPC who received 50 mg/m(2) ATRA thre e times daily orally on days 1-14, repeated every 22 days. The pharmac okinetics of ATRA were assessed with the first dose on day 1, again on day 14 and after a 7-day interruption in ATRA therapy on day 22. Pati ents were evaluable for response if they completed two 14-day courses of ATRA; among 13 such patients no responses were seen. Four patients were considered unevaluable for response owing to rapid disease progre ssion in three and intercurrent illness in one. Apparent clearance of ATRA changed substantially during therapy: day 1 3779 +/- 4215 ml/min, day 14 7179 +/- 3197 ml/min, day 22 3213 +/- 2357 ml/min. Area under the curve was proportionately diminished on day 14 compared with day 1 and had returned to baseline by day 22. We conclude that ATRA is not active in HRPC. Failure of this agent in HRPC may be related to failur e of drug delivery associated with enhanced mechanisms of ATRA clearan ce which occur within a few days of beginning ATRA treatment.