TY - JOUR
T1 - A phase I study of trimetrexate, an analog of methotrexate, administered monthly in the form of nine consecutive daily bolus injections
AU - Jolivet, Jacques
AU - Landry, Linda
AU - Pinard, Marie France
AU - McCormack, John J.
AU - Tong, William P.
AU - Eisenhauer, Elisabeth
PY - 1987/10
Y1 - 1987/10
N2 - 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.
AB - 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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U2 - 10.1007/BF00253973
DO - 10.1007/BF00253973
M3 - Article
C2 - 2959389
AN - SCOPUS:0023230164
SN - 0344-5704
VL - 20
SP - 169
EP - 172
JO - Cancer chemotherapy and pharmacology
JF - Cancer chemotherapy and pharmacology
IS - 2
ER -