Clinical Cancer Research, Vol 2, Issue 11 1819-1824, Copyright © 1996 by American Association for Cancer Research

ARTICLES

High-dose edatrexate with oral leucovorin rescue: a phase I and clinical pharmacological study in adults with advanced cancer

KM Pisters, LB Tyson, W Tong, M Fleisher, VA Miller, SC Grant, DG Pfister, JR Rigas, CL Densmore, G Krol, RT Heelan, FM Sirotnak, JR Bertino and MG Kris
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Laboratory of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Our objective was to determine the maximum tolerated dose and toxicity of i.v. edatrexate with p.o. leucovorin. Thirty-one adults with advanced solid tumors received edatrexate as a 2-h infusion, once a week for 3 weeks, recycled every 28 days. p.o. leucovorin (10 mg/m2, every 6 h for 10 doses) began 24 h later. All had urinary alkalinization and p.o. hydration. Nine dosage levels ranging from 120 to 3750 mg/m2 were explored. Fatigue, epistaxis, nausea/emesis, mucositis, rash, myalgias, leukopenia, thrombocytopenia, and transient elevations of serum aspartate transferase were observed. Leukoencephalopathy with clinical manifestations occurred in two patients (one had prior cranial irradiation). Pharmacokinetic studies carried out at the 120- and 1080-mg/m2 dose levels revealed no significant difference in the elimination half-life at the two dose levels studied and no significant intrapatient variability between day 1 and day 8 edatrexate administration. Serum edatrexate levels measured using a dihydrofolate reductase inhibition assay correlated with those by high-performance liquid chromatography. Three major and two minor antitumor responses occurred. The maximum tolerated dose was 3750 mg/m2, with grade 3 or 4 leukopenia (one patient), stomatitis (one patient), and leukoencephalopathy (one patient). Because of the occurrence of leukoencephalopathy, further study of high-dose edatrexate with leucovorin rescue is not recommended.

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				S. A. Laurie, D. G. Pfister, M. G. Kris, W. P. Tong, G. Chronowski, K. M. W. Pisters, R. T. Heelan, and F. M. Sirotnak Phase I and Pharmacological Study of Two Schedules of the Antifolate Edatrexate in Combination with Cisplatin Clin. Cancer Res., March 1, 2001; 7(3): 501 - 509. [Abstract] [Full Text]