title: A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate.
abstract: 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.
authors.affiliation: CRC Department of Medical Oncology, Beatson Oncology Centre, Glasgow, United Kingdom. alecm@ccotrust.co.uk
authors.forename: A C
authors.initials: AC
authors.lastname: McDonald
authors.forename: P A
authors.initials: PA
authors.lastname: Vasey
authors.forename: L
authors.initials: L
authors.lastname: Adams
authors.forename: J
authors.initials: J
authors.lastname: Walling
authors.forename: J R
authors.initials: JR
authors.lastname: Woodworth
authors.forename: T
authors.initials: T
authors.lastname: Abrahams
authors.forename: S
authors.initials: S
authors.lastname: McCarthy
authors.forename: N P
authors.initials: NP
authors.lastname: Bailey
authors.forename: N
authors.initials: N
authors.lastname: Siddiqui
authors.forename: M J
authors.initials: MJ
authors.lastname: Lind
authors.forename: A H
authors.initials: AH
authors.lastname: Calvert
authors.forename: C J
authors.initials: CJ
authors.lastname: Twelves
authors.forename: J
authors.initials: J
authors.lastname: Cassidy
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005971:Glutamates / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects; D008111:Liver Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D000068437:Pemetrexed; D010976:Platelet Count / Q000187:drug effects; D012044:Regression Analysis
chemical_list: D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D003404:Creatinine