Summary
Trimetrexate (TMTX) is an analog of methotrexate and a potent inhibitor of the enzyme dihydrofolate reductase. In this phase I study, TMTX was given intravenously to 32 patients as a constant infusion over 24 hours every 28 days. The maximum-tolerated dose of TMTX was 200 mg/m2, with myelosuppression as the dose-limiting toxicity. Other toxicities included nausea and vomiting, stomatitis, erythema and phlebitis at the site of infusion, rash and skin hyperpigmentation, and elevated serum hepatic enzymes. Two drug-related deaths occurred secondary to leukopenia and sepsis.
Twenty-six patients were evaluable for antitumor response. Twenty-one patients had progressive disease, while three patients had disease stabilization. There were two partial responses observed — one in a patient with breast cancer and a second in a patient with nasopharyngeal carcinoma.
TMTX pharmacokinetics were studied in 15 patients. The drug had a mean terminal half-life of 13 hours. Steady-state was not achieved during the 24-hour infusions. Only 6% of the parent compound was excreted unchanged in the urine, and CSF levels averaged less than 2% of simultaneously measured plasma levels.
A dose of 150 mg/m2 is recommended for phase II trials of TMTX using this 24-hour infusion schedule.
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Allegra, C.J., Jenkins, J., Weiss, R.B. et al. A phase I and pharmacokinetic study of trimetrexate using a 24-hour continuous-infection schedule. Invest New Drugs 8, 159–166 (1990). https://doi.org/10.1007/BF00177251
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DOI: https://doi.org/10.1007/BF00177251