Phase I and pharmacokinetic study of docetaxel and irinotecan in patients with advanced solid tumors

Purpose: We conducted a phase I and pharmacokinetic study of docetaxel in c ombination with irinotecan to determine the dose-limiting toxicity (DLT), t he maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safe ty and pharmacokinetic profiles in patients with advanced solid tumors. Patients and Methods: patients with only one prior chemotherapy treatment ( without taxanes or topoisomerase I inhibitors) for advanced disease were in cluded in the study. Docetaxel war administered as a I-hour IV infusion aft er premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. Results: Forty patients were entered through the following seven dose level s (docetaxel/irinotecan): 40/140 mg/m(2), 50/175 mg/m(2), 60/210 mg/m2, 60/ 250 mg/m(2), 60/275 mg/m2, 50/300 mg/m(2), and 70/250 mg/ m(2). Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m(2) and 60/ 300 mg/m(2); the DLTs were kebrile neutropenia and diarrhea. Neutropenia we ts the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinoteca n were not modified with the administration schedule of this study. Conclusion: The recommended dose of docetaxel in combination with irinoteca n is 60/275 mg/m(2), respectively. At this dose level, the safety profile i s manageable. The activity of this combination should be evaluated in phase II studies in different tumor types. (C) 2000 by American Society of Clini cal Oncology.