Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.
OBJECTIVE
To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor.


METHODS
Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients.


RESULTS
Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer.


CONCLUSIONS
The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.
Rinaldi
D A
DA
Institute for Drug Development, Brooke Army Medical Center, Fort Sam Houston, TX, USA.
Burris
H A
HA
Dorr
F A
FA
Woodworth
J R
JR
Kuhn
J G
JG
Eckardt
J R
JR
Rodriguez
G
G
Corso
S W
SW
Fields
S M
SM
Langley
C
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D000068437:Pemetrexed; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase