Phase I study of weekly oxaliplatin plus irinotecan in previously treated patients with metastatic colorectal cancer

Abstract

Background: In vitro synergy between Oxal (oxaliplatin) and CPT-11 (irinotecan) has been reported. Oxaliplatin exerts its antineoplastic activity through the formation of platinum-DNA adducts. Resistance to oxaliplatin is through repair of these adducts, which is inhibited by irinotecan. Patients and methods: Oxaliplatin and irinotecan were administered weekly for 4 weeks followed by a 2-week rest period. The dose of oxaliplatin was escalated first, starting at 30 mg/m2. Once a dose of 60 mg/m2 was attained, the weekly dose of irinotecan was escalated, from 40 mg/m2 to 85 mg/m2. A total of 49 previously treated patients with metastatic colorectal cancer were entered in order to establish the maximum tolerated dose. Pharmacokinetics of oxaliplatin and irinotecan were analyzed. Results: Forty-nine patients were evaluable for toxicity. The recommended phase II doses for this combination are oxaliplatin 60 mg/m2 and irinotecan 50 mg/m2, weekly × 4 q 6 weeks. Diarrhea was the most common dose-limiting toxicity. No pharmacological interactions were noted between oxaliplatin and irinotecan. Twelve of the 47 evaluable patients (26%) achieved a partial response. Conclusion: Weekly combination of oxaliplatin and irinotecan appears to be a well tolerated and active regimen in patients previously treated for metastatic colorectal cancer. Further investigations of this regimen are warranted.