Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: Results of two independent phase I studies with pharmacokinetics

Purpose: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. Patients and Methods: Patients with a performance status (PS) of less than or equal to 2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinote can administered over a 30-minute period, every 3 weeks. Dose levels that w ere explored ranged from 85 to 110 mg/m(2) for oxaliplatin and 150 to 250 m g/m(2) for irinotecan. Plasma pharmacokinetics of total and ultrafiltmble p latinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. Results: Thirty-nine patients with gastrointestinal carcinomas (24 with col orectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cyc les. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-toler ated dose was oxaliplatin 110 mg/m(2) plus irinotecan 200 mg/m(2) in one st udy and oxaliplatin 110 mg/m(2) plus irinotecan 250 mg/m(2) in the at her s tudy. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxi cities; other toxicities included emesis and dose-cumulative neuropathy. Re commended dose for phase II studies is oxaliplatin 85 mg/m(2) and irinoteca n 200 mg/m2. At this dose (72 patients, 65 cycles), grade 3 and 4 toxicitie s per patient included the following: emesis in 42% of patients, neutropeni a in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed d iarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syn drome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. Conclusion: This combination is feasible, with activity in 5-FU-resistant C RC patients. Phase I studies that explore the every-2-weeks schedule, in ad dition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing. (C) 1999 by A merican Society of Clinical Oncology.