Overview of phase I trials of multitargeted antifolate (MTA, LY231514).

Multitargeted antifolate (MTA, LY231514) is a novel antifolate antimetabolite, with antitumor activity via inhibition of thymidylate synthase, glycinamide formyl transferase, and dihydrofolate reductase. Three dosing schedules have been investigated in the phase I setting: daily x5 every 21 days, weekly x4 every 42 days, and once every 21 days. The maximum tolerated doses on these schedules were 4.0 mg/m2, 30 mg/m2, and 600 mg/m2, respectively. The major dose-limiting toxicity seen on all schedules was neutropenia, with a greater degree of reversible liver biochemistry disturbances observed on the daily x5 schedule. Given that toxicities were manageable and reversible, the antitumor activity exhibited, and the convenience of an every-21-day dosing schedule, this schedule was selected for phase II evaluation.