A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate.
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.
McDonald
A C
AC
CRC Department of Medical Oncology, Beatson Oncology Centre, Glasgow, United Kingdom. alecm@ccotrust.co.uk
Vasey
P A
PA
Adams
L
L
Walling
J
J
Woodworth
J R
JR
Abrahams
T
T
McCarthy
S
S
Bailey
N P
NP
Siddiqui
N
N
Lind
M J
MJ
Calvert
A H
AH
Twelves
C J
CJ
Cassidy
J
J
Kaye
S B
SB
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
D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D003404:Creatinine