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

• Published in: Clinical cancer research Vol. 4; no. 3; pp. 605 - 610
• Main Authors: MCDONALD, A. C, VASEY, P. A, CALVERT, A. H, TWELVES, C. J, CASSIDY, J, KAYE, S. B, ADAMS, L, WALLING, J, WOODWORTH, J. R, ABRAHAMS, T, MCCARTHY, S, BAILEY, N. P, SIDDIQUI, N, LIND, M. J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.03.1998
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Chemotherapy; 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; Medical sciences; Metabolic Clearance Rate; Middle Aged; Neoplasms - blood; Neoplasms - drug therapy; Neutropenia - chemically induced; Pemetrexed; Pharmacology. Drug treatments; Platelet Count - drug effects; Regression Analysis; Antineoplastic agent; Human; Intravenous administration; Enzyme; Toxicity; Transferases; Enzyme inhibitor; Tolerance; Malignant tumor; Thymidylate synthase; Antifolate; Chemotherapy; Treatment; Methyltransferases; Secondary effect; Phase I trial; Advanced stage; Pharmacokinetics
• ISSN: 1078-0432; 1557-3265

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.