A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation
Da. Rinaldi et al., A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation, CANC CHEMOT, 44(5), 1999, pp. 372-380
Purpose: To determine toxicities, maximally tolerated dose (MTD), pharmacok
inetic profile, and potential antitumor activity of MTA, a novel antifolate
compound which inhibits the enzymes thymidylate synthase (TS), glycinamide
ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHF
R). Methods: Patients with advanced solid tumors were given MTA intravenous
ly over 10 min every 21 days. Dose escalation was based on the modified con
tinual reassessment method (MCRM), with one patient treated at each minimal
ly toxic dose level. Pharmacokinetic studies were performed in all patients
. Results: A total of 37 patients (27 males, 10 females, median age 59 year
s, median performance status 90%) were treated with 132 courses at nine dos
e levels, ranging from 50 to 700 mg/m(2). The MTD of MTA was 600 mg/m(2), w
ith neutropenia and thrombocytopenia, and cumulative fatigue as the dose-li
miting toxicities. Hematologic toxicity correlated with renal function and
mild reversible renal dysfunction was observed in multiple patients. Other
nonhematologic toxicities observed included mild to moderate fatigue, anore
xia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase
elevations. Three patients expired due to drug-related complications. Phar
macokinetic analysis during the first course of treatment at the 600 mg/m(2
) dose level demonstrated a mean harmonic half-life, maximum plasma concent
ration (Cpmax), clearance (CL), area under the curve (AUC), and apparent vo
lume of distribution at steady state (Vdss) of 3.08 h, 137 mu g/ml, 40.0 ml
/min per m(2), 266 mu g.h/ml, and 7.0 l/m(2), respectively. An average of 7
8% of the compound was excreted unchanged in the urine. Partial responses w
ere achieved in two patients with advanced pancreatic cancer and in two pat
ients with advanced colorectal cancer. Minor responses were obtained in six
patients with advanced colorectal cancer. Conclusions: The MTD and dose fo
r phase II clinical trials of MTA when administered intravenously over 10 m
in every 21 days was 600 mg/m(2). MTA is a promising new anticancer agent.