748 Trimetrexate (TMTX) modulation of 5-fluorouracil/leucovorin (5-FU/LV) for advanced colorectal cancer

TMTX is a dihydrofolate reductase inhibitor which has been shown to potentiate FU cytotoxicity by increasing PRPP levels. Unlike methotrexate, TMTX does not compete with LV for cellular uptake and metabolism. In in vitro studies, TMTX enhances the cytotoxicity of FU/LV. Conti, et al . ( J Clin Oncol 12:695; 1994) have reported a 20% PR rate in patients previously treated with 5-FU chemotherapy when TMTX was combined with FU/LV. In the current phase II trial, this regimen was evaluated in previously untreated patients with advanced colorectal cancer. TMTX, 110 mg/m 2 IV was administered 24 hours prior to leucovorin, 200 mg/m 2 IV and 5-FU, 500 mg/m 2 IV, fullowed by oral leucovorin, 15 mg q6hx7. Treatment was repeated weekly × 6 followed by 2 weeks rest. Accrual to this study has now been completed with 39 patients treated Eleven are currently evaluable for response; objective responses have been achieved in 8 patients (78%) with 1 CR. The regimen has been generally well tolerated Side effects include diarrhea and nausea/vomiting. This study will serve as the basis fur a phase III trial of this regimen.