Phase I clinical and pharmacogenetic trial of irinotecan and raltitrexed administered every 21 days to patients with cancer

Purpose: Irinotecan and raltitrexed display schedule-dependent synergy in v itro, which supports the clinical investigation of the combination. Functio nal polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene r esult in intracellular redistribution of folate derivatives, which may affe ct raltitrexed-associated cytotoxicity. Patients and Methods: Patients with a range of solid cancers and good perfo rmance status received irinotecan as a 90-minute infusion on day 1 and ralt itrexed as a 15-minute infusion on day 2, repeated every 21 days. Samples w ere collected for MTHFR C677T genotyping and fasting plasma homocysteine du ring the first cycle. Results: Thirty-nine assessable patients received 127 cycles of therapy. Ir inotecan doses ranged from 100 to 350 mg/m(2), and raltitrexed, 1.0 to 4.0 mg/m(2). Raltitrexed doses of more than 3.0 mg/m(2) were not tolerated and were associated with dose-limiting asthenia, diarrhea, and AST/ALT elevatio n. Irinotecan/raltitrexed doses of 350/3.0 mg/m(2) were well-tolerated; pri ncipal toxicities included neutropenia, diarrhea, and fatigue. Two partial responses were observed in patients with pretreated gastroesophageal cancer s. Homozygotes with the MTHFR 677TT polymorphism incurred significantly les s raltitrexed-associated toxicity than those with either wild-type or heter ozygous genotypes (P = .05). No significant differences were noted in plasm a homocysteine values between the genotypic subtypes, and plasma homocystei ne levels did not predict the risk of toxicity. Conclusion: Irinotecan and raltitrexed doses of 350 and 3.0 mg/m(2) are rec ommended for further study on a day 1, 2 schedule every 21 days. Efficacy r esults suggest that trials in upper and lower gastrointestinal malignancies are warranted. MTHFR C677T genotypes may be predictive of clinical raltitr exed toxicity.