Summary
Trimetrexate glucuronate (TMTX) is a methotrexate (MTX) analog that is active against transport-deficient MTX-resistant tumor cells. We performed a phase I study of TMTX administered by daily bolus for 9 consecutive days since this schedule is one of the most active in experimental murine tumor models. The drug was administered in this fashion every 4 weeks for at least two cycles. Fifteen patients with refractory metastatic cancers were studied and all had received prior chemotherapy. The dose-limiting toxicity was a rapidly reversible thrombocytopenia first seen at a daily dose of 4.0 mg/m2 which occurred 7 days after the end of TMTX administration. There was great inter-and intrapatient variability in the platelet nadirs observed in the six patients treated at 4.0 mg/m2. One patient died of massive hemoptysis during a platelet nadir at that dose level. Granulocyte counts never dropped below 1500/mm3. Only one patient had significant non-hematological toxicity: a radiation recall skin toxicity along with a self-limited maculopapular rash. One patient with melanoma and lung metastases treated at 4.0 mg/m2 had a partial response. TMTX plasma levels were measured by HPLC every 3 days prior to daily dosing in patients receiving 4 mg/m2 to determine whether drug accumulation occurred during this prolonged administration schedule. Nadir drug levels varied from less than 0.02 to 0.35 μM and did not seem to increase during the 9-day schedule in individual patients. By comparison with other phase I trials, the hematologic toxicity of TMTX seems to be schedule-dependent, with less drug being tolerated and more severe thrombocytopenia observed with more protracted treatment protocols. A firm phase II starting dose for daily bolus x 9 schedules is difficult to recommend in view of the variable toxicity observed in the patients treated at 4.0 mg/m2 daily, who, in addition, had all been extensively pretreated. A reasonable starting dose might be 3.0 mg/m2 daily with built-in dosage increases or decreases.
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Supported by the National Cancer Institute of Canada Clinical Trials Group.
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Jolivet, J., Landry, L., Pinard, MF. et al. A phase I study of trimetrexate, an analog of methotrexate, administered monthly in the form of nine consecutive daily bolus injections. Cancer Chemother. Pharmacol. 20, 169–172 (1987). https://doi.org/10.1007/BF00253973
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DOI: https://doi.org/10.1007/BF00253973