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) 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.
Pisters
K M
KM
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.
Tyson
L B
LB
Tong
W
W
Fleisher
M
M
Miller
V A
VA
Grant
S C
SC
Pfister
D G
DG
Rigas
J R
JR
Densmore
C L
CL
Krol
G
G
Heelan
R T
RT
Sirotnak
F M
FM
Bertino
J R
JR
Kris
M G
MG
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000630:Aminopterin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; C040210:edatrexate; D000630:Aminopterin; D002955:Leucovorin