Phase I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer

Purpose: To determine the maximum tolerated dose (MTD) and the dose-limitin g toxicities (DLTs) of the raltitrexed plus oxaliplatin combination regimen , to explore its safety and pharmacokinetics, and to assess its antitumor a ctivity in patients with advanced solid tumors, Patients and Methods: Forty-eight patients received the combination of ralt itrexed plus oxaliplatin. Raltitrexed was administered as a 15-minute infus ion followed by oxaliplatin as a 2-hour infusion 1 hour later, repeated eve ry 3 weeks. Seven dose levels were explored, ranging from 2 to 3.75 mg/m(2) and from 85 to 130 mg/m(2) for raltitrexed and oxaliplatin, respectively. The pharmacokinetics of both raltitrexed and oxaliplatin was assessed at th e last three dose levels. Results: Forty-six patients were assessable for toxicity. Severe toxicities usually occurred from dose level V (raltitrexed 3 mg/m(2) and oxaliplatin 130 mg/m(2)). This combination was not myelosuppressive, eliciting only spo radic grades 3 and 4 neutropenia and/or thrombocytopenia without complicati ons. There was no alopecia. DLTs were asthenia and nausea/vomiting, despite systematic antiemetic prophylaxis. Dose level VI (raltitrexed 3.5 mg/m(2) and oxaliplatin 130 mg/m(2)) was deemed to be the MTD, Eight confirmed part ial responses were observed: six patients with malignant mesothelioma (both pretreated and nonpretreated), one with fluorouracil-refractory pancreatic carcinoma, and one with renal carcinoma. Evaluation of the pharmacokinetic s of both drugs did not suggest any drug interaction. Conclusion: The combination of raltitrexed and oxaliplatin given as consecu tive short infusions every 3 weeks seems to be an acceptable regimen that a llows a dose-intensity as high as the sum of the recommended doses of each agent given alone. The dose recommended for further phase II studies is ral titrexed 3 mg/m(2) and oxaliplatin 130 mg/m(2) every 3 weeks. Promising ant itumor activity has been observed in patients with malignant mesothelioma. J Clin Oncol 18:2293-2300. (C) 2000 by American Society of Clinical Oncolog y.