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

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Multitargeted antifolate (MTA, LY231514) is a novel antifolate antimetabolite.
• MTA exhibits antitumor activity through the inhibition of thymidylate synthase, glycinamide formyl transferase, and dihydrofolate reductase.

Purpose of the Study:

• To investigate three different dosing schedules for MTA in a phase I setting.
• To determine the maximum tolerated doses (MTD) and dose-limiting toxicities for each schedule.
• To select an optimal schedule for phase II evaluation based on safety, tolerability, and efficacy.

Main Methods:

• Phase I clinical trial evaluating three MTA dosing schedules: daily x5 every 21 days, weekly x4 every 42 days, and once every 21 days.
• Assessment of dose-limiting toxicities, primarily neutropenia and liver biochemistry disturbances.
• Determination of maximum tolerated doses (MTD) for each schedule.

Main Results:

• The MTDs were determined as 4.0 mg/m², 30 mg/m², and 600 mg/m² for the daily x5, weekly x4, and once every 21 days schedules, respectively.
• Neutropenia was the major dose-limiting toxicity across all schedules.
• The daily x5 schedule showed a greater incidence of reversible liver biochemistry disturbances.

Conclusions:

• MTA exhibits manageable and reversible toxicities across different dosing schedules.
• The every-21-day dosing schedule was selected for phase II evaluation due to its convenience and favorable toxicity profile.
• Antitumor activity and optimal dosing warrant further investigation in phase II trials.