Phase I clinical and pharmacologic study of weekly cisplatin combined withweekly irinotecan in patients with advanced solid tumors

Purpose: In vitro synergy between cisplatin and iri-notecan (CPT-11) has be en reported. We designed a combination schedule of these agents to maximize the potential for synergistic interaction. Patients and Methods: To maximize the opportunity for synergy, we divided t he cisplatin into four consecutive weekly treatments, followed by a 2-week rest. Each dose of cisplatin was immediately followed by a dose of irinotec an. The dose of cisplatin was fixed at 30 mg/m(2)/wk. The initial irinoteca n dose was 50 mg/m(2)/wk and this was escalated by 30% increments in succes sive cohorts of three to six patients to establish the maximum-tolerated do se (MTD). Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN- 38 glucuronide (SN-38G), were analyzed. Results: Of 35 patients with solid tumors enrolled onto this trial, 30 were assessable for toxicity and response. The MTD for this regimen was 30 mg/m (2)/wk of cisplatin plus 50 mg/m(2)/wk of irinotecan in previously treated patients and 30 mg/m(2)/wk of cisplatin plus 65 mg/m(2)/wk of irinotecan in chemotherapy-naive patients. Neutropenia was the dose-limiting toxicity (D LT) encountered in this trial. Diarrhea was infrequent and rarely dose-limi ting. Seven of 30 assessable patients achieved a partial response. No alter ation in irinotecan, SN-38, or SN-38G pharmacokinetics resulted from the ad ministration of cisplatin with irinotecan. Conclusion: The administration of: cisplatin and irinotecan on this weekly schedule provides a practical and well-tolerated regimen that has the poten tial to maximize any clinical synergy between the two agents. Evidence of s ubstantial clinical activity was seen in this phase I study. (C) 1998 by American Society of Clinical Oncology.