A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate

Clin Cancer Res. 1998 Mar;4(3):605-10.


LY231514 is a novel antifolate that principally inhibits thymidylate synthase, but with additional folate-dependent enzyme targets. A Phase I study of single-agent LY231514 administered as a daily i.v. infusion over 10 minutes for 5 days, repeated every 3 weeks, was conducted to evaluate the maximum tolerated dose, pharmacokinetic profile, and antitumor activity of the drug using this schedule. Thirty-eight patients with advanced malignancies that were refractory or not amenable to standard therapy were treated with a total of 116 courses of LY231514, escalating treatment doses through 10 dose levels, from 0.2-5.2 mg/m2/day. No objective clinical responses were observed, although minor antitumor activity not fulfilling the response criteria was seen in three patients. A maximum tolerated dose of 4.0 mg/m2/day was determined, with neutropenia as the predominant dose-limiting toxicity. Reversible disturbances of liver biochemistry, fulfilling the protocol definitions of dose-limiting toxicity, were also observed. Other toxicities included diarrhea, mucositis, skin rash, and fatigue. Pharmacokinetic studies were performed at all treatment levels. Analysis showed a linear relation between administered dose and both maximum plasma concentration (Cmax) and area under the plasma concentration/time curve. The drug was cleared with a day 1 total body clearance of 108.9 +/- 38.8 ml/min/m2, with plasma concentrations declining with a mean harmonic terminal half-life of 1.4 +/- 0.98 h. When given by this schedule, LY231514 is tolerable, and Phase II studies are in progress.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Creatinine / blood
  • Dose-Response Relationship, Drug
  • Female
  • Glutamates / adverse effects*
  • Glutamates / blood
  • Glutamates / pharmacokinetics*
  • Guanine / adverse effects
  • Guanine / analogs & derivatives*
  • Guanine / blood
  • Guanine / pharmacokinetics
  • Humans
  • Leukocyte Count / drug effects
  • Liver Function Tests
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Neutropenia / chemically induced
  • Pemetrexed
  • Platelet Count / drug effects
  • Regression Analysis


  • Antineoplastic Agents
  • Glutamates
  • Pemetrexed
  • Guanine
  • Creatinine