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Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With Pharmacokinetics

From the Hôpital Paul Brousse, Villejuif; Hôpital Saint-Louis, Paris; Centre René Huguenin, Saint-Cloud; Bellon/Laboratoires Rhône-Poulenc Rorer, Montrouge; Sanofi-Winthrop, Gentilly; and Cvitkovic & Associés Consultants, Kremlin-Bicêtre, France.

Address reprint requests to E. Cvitkovic, MD, FSMSIT, Hôpital Paul Brousse, 12-14 Ave Paul Vaillant Couturier, 94804 Villejuif, Cedex, France; email e.cvitkovic{at}cvitkovic-ac.fr

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 2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m² for oxaliplatin and 150 to 250 mg/m² for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined.

RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. 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-tolerated dose was oxaliplatin 110 mg/m² plus irinotecan 200 mg/m² in one study and oxaliplatin 110 mg/m² plus irinotecan 250 mg/m² in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m² and irinotecan 200 mg/m². At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome 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 CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Presented in part at the Thirty-Third Annual Meeting of the American Society of Clinical Oncology in Denver, CO, May 17-20, 1997, and the Eighth Conference on DNA Topoisomerases in Therapy in Amsterdam, the Netherlands, October 1997.

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