A phase I study of trimetrexate (NSC 352122) administered by 5-day continuous intravenous infusion.
Trimetrexate (TMTX) is a potent inhibitor of dihydrofolate reductase that circumvents the transport resistance seen with methotrexate and has a wide spectrum of preclinical activity. A total of 18 patients with advanced cancer were treated in a clinical and pharmacological phase I trial with TMTX given as a continuous 5-day intravenous infusion. Neutropenia, thrombocytopenia and stomatitis were the dose-limiting toxicities at the maximum tolerated dose of 50 mg/m2 per 120 h (10 mg/m2 per day for 5 days). There was one septic death associated with neutropenia. Other toxicities were mild rash, mild nausea and transiently raised serum transminase levels. Significant relationships between the dose given and the AUC of plasma TMTX and the steady-state plasma level were established. Significant, although weak, relationships between the percentage of change in neutrophils and platelets and both the AUC and steady-state plasma level of TMTX were also observed. No objective tumour responses were seen, although six patients had stable disease. The recommended phase II dose for a continuous infusion of trimetrexate is 40 mg/m2 per 120 h.
Bishop
J F
JF
Peter MacCallum Cancer Institute, Melbourne, Australia.
Raghavan
D
D
Olver
I N
IN
Reece
P
P
Morris
R
R
Friedlander
M L
ML
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007260:Infusion Pumps; D007262:Infusions, Intravenous / Q000379:methods; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils; D010976:Platelet Count / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013280:Stomatitis / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D016597:Trimetrexate
D000970:Antineoplastic Agents; D011799:Quinazolines; D016597:Trimetrexate