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

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) bega...

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Bibliographic Details
Published in:Clinical cancer research 1996-11, Vol.2 (11), p.1819-1824
Main Authors: PISTERS, K. M. W, TYSON, L. B, HEELAN, R. T, SIROTNAK, F. M, BERTINO, J. R, KRIS, M. G, TONG, W, FLEISHER, M, MILLER, V. A, GRANT, S. C, PFISTER, D. G, RIGAS, J. R, DENSMORE, C. L, KROL, G
Format: Article
Language:English
Subjects:
Administration, Oral
Adult
Aged
Aminopterin - administration & dosage
Aminopterin - analogs & derivatives
Aminopterin - metabolism
Aminopterin - pharmacokinetics
Aminopterin - therapeutic use
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Chemotherapy
Drug Interactions
Drug Monitoring
Female
Humans
Leucovorin - pharmacology
Leucovorin - therapeutic use
Male
Medical sciences
Middle Aged
Neoplasms - drug therapy
Neoplasms - metabolism
Pharmacology. Drug treatments
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Summary: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.
ISSN:1078-0432
1557-3265