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Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given prolonged administration in patients with solid tumors

Lookup NU author(s): Professor Alan Boddy, Gordon Taylor, Professor Herbie Newell, Professor Alan Calvert


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Purpose: A phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects. Methods: In vitro and in viva preclinical studies demonstrated increased activity with prolonged nolatrexed exposure. In 32 patients, nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days. Pharmacokinetics were determined from high- performance liquid chromatography (HPLC) analyses of plasma and urine. In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition. Results: The MTD was 904 mg/m2/d for 5 days and the recommended phase II dose is 800 mg/m2/d for 5 days. The dose-limiting toxicity was neutropenia with clinically significant thrombocytopenia and mucositis. These antiproliferative toxicities of nolatrexed were predictable and reversible. A partial response that lasted 3 months occurred in a patient with metastatic colarectal cancer. Pharmacokinetics were nonlinear, with the median plasma clearance (CI) decreasing from 151 mL/min/m2 (range, 124 to 211) at 96 mg/m2/d for 5 days to 49 mL/min/m2 (range, 30 to 84) at 768 mg/m2/d for 5 days. The half-life (t 1/4 ) was 173 minutes (range, 43 to 784) and 18% (range, 9% to 35%) of the dose was excreted unchanged in the urine. Plasma UdR increased, but returned to pretreatment levels after the end of infusion. Hematologic toxicity was significantly related to nolatrexed plasma concentrations and dose. Conclusion: Nolatrexed can be safely administered to patients at o dose of 800 mg/m2/d over 5 days continuous intravenous infusion and this schedule is associated with antitumor effects. The phase II evaluation of nolatrexed is ongoing.

Publication metadata

Author(s): Rafi, I., Boddy, A. V., Calvete, J., Taylor, G. A., Newell, D. R., Bailey, N. P., Lind, M., Green, M., Hines, J., Johnstone, A., Clendeninn, N., Calvert, A. H.

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Oncology

Year: 1998

Volume: 16

Issue: 3

Pages: 1131-1141

Print publication date: 01/03/1998

ISSN (print): 0732-183X

ISSN (electronic):


PubMed id: 9508200