A phase I study of trimetrexate, an analog of methotrexate, administered monthly in the form of nine consecutive daily bolus injections.
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 microM 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.
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D016597:Trimetrexate
D000970:Antineoplastic Agents; D011799:Quinazolines; D016597:Trimetrexate