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

Abstract

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.

• Authors: K M Pisters, L B Tyson, W Tong, M Fleisher, V A Miller, S C Grant, D G Pfister, J R Rigas, C L Densmore, G Krol, R T Heelan, F M Sirotnak, J R Bertino, M G Kris
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 2 Issue 11 Pg. 1819-24 (Nov 1996) ISSN: 1078-0432 [Print] United States
• PMID: 9816135 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• edatrexate
• Aminopterin
• Leucovorin

Topics

• Administration, Oral
• Adult
• Aged
• Aminopterin (administration & dosage, analogs & derivatives, metabolism, pharmacokinetics, therapeutic use)
• Antineoplastic Agents (administration & dosage, metabolism, pharmacokinetics, therapeutic use)
• Drug Interactions
• Drug Monitoring
• Female
• Humans
• Leucovorin (pharmacology, therapeutic use)
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism)