Initial phase I evaluation of the novel thymidylate synthase inhibitor, XXXX , using the modified continual reassessment method for dose escalation.

@entity1 @entity137 @entity390 @entity5 @entity1295 @entity448 @entity1398 @entity14 @entity8642
PURPOSE: To determine the @entity137 , maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of @entity8642 , a novel thymidylate synthase (TS) inhibitor. @entity1 AND METHODS: @entity1 with advanced solid @entity5 were administered @entity8642 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one @entity1 treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all @entity1 . RESULTS: Twenty-five @entity1 were administered 58 courses of @entity8642 at doses that ranged from 10 to 40 mg/m2/wk. Reversible @entity1398 was the dose-limiting @entity137 . Inability to maintain the weekly treatment schedule due to @entity1398 limited dose escalation on this schedule. Nonhematologic @entity137 observed included mild @entity1295 , @entity448 , and @entity390 . At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two @entity1 with advanced @entity14 . CONCLUSION: The dose-limiting @entity137 , MTD, and recommended phase II dose of @entity8642 when administered weekly for 4 weeks every 42 days are @entity1398 , 40 mg/m2, and 30 mg/m2, respectively.
