Phase I study of 3-week schedule of irinotecan combined with cisplatin in patients with advanced solid tumors.

PURPOSE: To assess the feasibility, pharmacokinetic interaction, and possible sequence-dependent effects of the irinotecan/cisplatin combination given every 3 weeks, and to assess the influence of additional granulocyte colony-stimulating factor (G-CSF) on the hematologic toxicity. PATIENTS AND METHODS: Patients who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of a 90-minute irinotecan infusion followed by a 3-hour cisplatin infusion on day 1, with cycles repeated once every 3 weeks. After the maximum-tolerated dose was determined, the sequence of administration was reversed. In a separate cohort of six patients, we assessed the effect of G-CSF on the experienced hematologic toxicity and dose-intensity. Irinotecan doses ranged from 175 to 300 mg/m(2) and cisplatin doses ranged from 60 to 80 mg/m(2). RESULTS: Fifty-two patients entered the study; one was not eligible, and two were not assessable for response. Twenty-five patients were pretreated, and 26 were not. Fifty-one patients received a total of 223 courses. The dose-limiting toxicity was a combination of neutropenic fever, diarrhea, and fatigue at a dose level combining irinotecan 300 mg/m(2) with cisplatin 80 mg/m(2). Neutropenia was common (grades 3 to 4, 68%). Irinotecan pharmacokinetics were linear over the dose range studied. No sequence-dependent side effects were observed. Tumor responses included three complete responses and eight partial responses. CONCLUSION: For phase II studies, we recommend irinotecan 260 mg/m(2) combined with cisplatin 80 mg/m(2) once every 3 weeks for chemotherapy-naive patients in good physical condition, and irinotecan 200 mg/m(2) combined with cisplatin 80 mg/m(2) for other patients.