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A Phase I Study of Raltitrexed, an Antifolate Thymidylate Synthase Inhibitor, in Adult Patients with Advanced Solid Tumors

National Cancer Institute-Medicine Branch, National Naval Medical Center, Bethesda, Maryland 20889-5105 [J. L. G., E. C., C. H. T., A. P. C., J. M. H., N. M., P. G. J., C. J. A.]; Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland 20892-7426 [J. M. S., S. G. A.]; Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland 20892-8225 [S. M. S.]; Department of Radiology, National Naval Medical Center, Bethesda, Maryland 20889-5000 [D. L.]; Department of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889 [D. L.]; and Pharmacy Department, W. G. Magnusen Clinical Center, Bethesda, Maryland 20892 [B. G.]

The purpose of this study was to perform a Phase I trial of raltitrexed, a selective inhibitor of thymidylate synthase, and to determine the pharmacokinetic and toxicity profiles as a function of raltitrexed dose. Fifty patients with advanced solid tumors and good performance status were treated with raltitrexed as a 15-min i.v. infusion every 3 weeks, at doses escalating from 0.6 to 4.5 mg/m². Asthenia, neutropenia, and hepatic toxicity were the most common dose-limiting toxicities in this largely pretreated patient population, but they occurred during the initial cycle in only one of nine patients treated with 4.0 mg/m² and in two of nine patients treated with 4.5 mg/m². Only 2 of 13 patients treated with 3.5 mg/m² ultimately experienced unacceptable toxicity after three and seven cycles, compared with 42 and 56% of patients receiving 4.0 and 4.5 mg/m² after medians of three and two cycles, respectively. The maximum raltitrexed plasma concentration and the area under the plasma concentration-time curve increased in proportion to dose. Raltitrexed clearance was independent of dose and was associated with the estimated creatinine clearance. Asthenia, neutropenia, and hepatic transaminitis were dose-related and tended to occur more frequently when patients received three or more cycles of therapy. A 3-week treatment interval was feasible in the majority of patients at all doses. Although 4.0 mg/m² appeared to be a safe starting dose in this pretreated patient population, about half who received two or more courses ultimately experienced dose-limiting toxicity. A dose of 3.5 mg/m² was well tolerated in most patients.

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