A PHASE-I AND PHARMACOKINETIC STUDY OF LY231514, THE MULTITARGETED ANTIFOLATE

LY231514 is a novel antifolate that principally inhibits thymidylate s ynthase, 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 anti tumor activity of the drug using this schedule, Thirty-eight patients with advanced malignancies that were refractory or not amenable to sta ndard therapy were treated with a total of 116 courses of LY231514, es calating treatment doses through 10 dose levels, from 0.2-5.2 mg/m(2)/ day, No objective clinical responses were observed, although minor ant itumor activity not fulfilling the response criteria was seen in three patients,A maximum tolerated dose of 4.0 mg/m(2)/day was determined, with neutropenia as the predominant dose-limiting toxicity, Reversible disturbances of liver biochemistry, fulfilling the protocol definitio ns of dose-limiting toxicity, were also observed, Other toxicities inc luded diarrhea, mucositis, skin rash, and fatigue, Pharmacokinetic stu dies were performed at all treatment levels, Analysis showed a linear relation between administered dose and both maximum plasma concentrati on (C-max) and area under the plasma concentration/time curve, The dru g was cleared with a day 1 total body clearance of 108.9 +/- 38.8 ml/m in/m(2), with plasma concentrations declining with a mean harmonic ter minal half-life of 1.4 +/- 0.98 h, When given by this schedule, LY2315 14 is tolerable, and Phase II studies are in progress.