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A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified

D A Rinaldi1, J G Kuhn, H A Burris

  • 1Brooke Army Medical Center, Fort Sam Houston, TX, USA.

Cancer Chemotherapy and Pharmacology
|September 29, 1999
PubMed
Abstract

Insights

The maximally tolerated dose (MTD) for novel antifolate MTA is 600 mg/m(2), with neutropenia and thrombocytopenia as dose-limiting toxicities. MTA shows potential antitumor activity in advanced cancers.

Area of Science:

  • Pharmacology and Oncology
  • Drug Development

Background:

  • MTA is a novel antifolate compound targeting thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR).
  • Understanding its toxicity and efficacy is crucial for clinical application.

Purpose of the Study:

  • To determine the toxicities and maximally tolerated dose (MTD) of MTA.
  • To characterize the pharmacokinetic profile of MTA.
  • To evaluate the potential antitumor activity of MTA in patients with advanced solid tumors.

Main Methods:

  • Phase I clinical trial involving intravenous administration of MTA every 21 days.
  • Dose escalation guided by the modified continual reassessment method (MCRM).
  • Pharmacokinetic studies conducted in all participating patients.

Main Results:

  • The MTD of MTA was established at 600 mg/m(2), with neutropenia and thrombocytopenia as dose-limiting toxicities.
  • Pharmacokinetic analysis revealed a mean half-life of 3.08 h, with 78% of the compound excreted unchanged in urine.
  • Partial responses observed in patients with advanced pancreatic and colorectal cancers; minor responses in colorectal cancer patients.

Conclusions:

  • The recommended dose for Phase II trials of MTA is 600 mg/m(2) intravenously every 21 days.
  • MTA demonstrates promise as a new anticancer agent with manageable toxicities.

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