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 combination with irinotecan to determine the dose-limiting toxicity (DLT), the 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 safety 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 included in the study. Docetaxel was administered as a 1-hour IV infusion after 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 levels (docetaxel/irinotecan): 40/140 mg/m², 50/175 mg/m², 60/210 mg/m², 60/250 mg/m², 60/275 mg/m², 60/300 mg/m², and 70/250 mg/m². Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m² and 60/300 mg/m²; the DLTs were febrile neutropenia and diarrhea. Neutropenia was 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 irinotecan were not modified with the administration schedule of this study. Conclusion: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m², respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types. (C) 2000 by American Society of Clinical Oncology.