INITIAL PHASE-I EVALUATION OF THE NOVEL THYMIDYLATE SYNTHASE INHIBITOR, LY231514, USING THE MODIFIED CONTINUAL REASSESSMENT METHOD FOR DOSE

Purpose: To determine the toxicities, maximal-tolerated dose (MTD), ph armacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. Patients and Methods: Pati ents with advanced solid tumors were administered LY231514 intravenous ly over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokineti c studies were performed in all patients. Results: Twenty-five patient s were administered 58 courses of LY231514 at doses that ranged from 1 0 to 40 mg/m(2)/wk. Reversible neutropenia wets the dose-limiting toxi city. Inability to maintain the weekly treatment schedule due to neutr openia limited dose escalation on this schedule. Nonhematologic toxici ties observed included mild fatigue, anorexia, and nausea. At the 40-m g/m(2)/wk dose level, the mean harmonic half-life, maximum plasma conc entration, clearance, and apparent volume of distribution at steady-st ate were 2.02 hours, 11.20 mu g/mL, 52.3 mL/min/m(2), and 6.64 L/m(2), respectively. No major antitumor responses were ob served; however, m inor responses were achieved in two patients with advanced colorectal cancer. Conclusion: The dose-limiting toxicity, MTD, and recommended p hase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m(2), and 30 mg/m(2), respectively. (C) 1 995 by American Society of Clinical Oncology.