Dose escalating study of 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) and cetuximab in first-line therapy of patients with metastatic colorectal cancer

e15025 Background: Highly active chemotherapy schedules are necessary in several clinical situations, i.e. for conversional chemotherapy in order to resect liver metastases. Adding oxaliplatin or cetuximab to 5-FU / FA / irinotecan was shown to increase the efficacy of chemotherapy in patients with metastatic colorectal cancer (Falcone et al, JCO 2007, Van Cutsem et al, ASCO 2008). Methods: We performed a phase I study in patients (pts) with metastatic colorectal cancer, WHO PS 0–1 who had not been pretreated for metastatic disease. They received cetuximab (500 mg/m 2 , 2h), oxaliplatin (85 mg/m 2 , 2h), folinic acid (400 mg/m 2 , 2h), irinotecan (95, 125, or 165 mg/m 2 , 1h), 5-FU (3200 mg/m 2 , 46 h), each on day 1 in biweekly cycles. Dose was escalated if dose limiting toxicities (DLT) were absent in the first three pts per cohort, or if <2 DLTs in six pts. Non-evaluable pts were replaced. Pts were not selected for EGFR IHC or KRAS status. Results: Twenty-one pts were enrolled into the study between Jan 2007 and June 2008, six evaluable pts per each cohort. Two pts who had adverse events deemed unrelated to study during the first cycle (morphine overdosing, mechanical ileus) were replaced, one patient (port dysfunction during first dose) was excluded from analysis. Patient characteristics were as follows: median age 59 (33–72) years, 16 pts WHO PS 0, 15 pts male, 10 pts rectal cancer primary, 3 pts previous adjuvant chemotherapy. In the first two cohorts, 95 and 125 mg/m 2 irinotecan, one DLT occurred per dose level (neutropenia gr. 4 and diarrhea gr. 3). In the 165 mg/m 2 cohort, 2 DLTs were observed (neutropenia grade 4). Most common grade ≥ 3 toxicities were neutropenia (40%), diarrhea (25%), skin toxicities (15%), thrombopenia (10%) and infections (15%). One patient had a confirmed complete response, 14 pts had confirmed partial response (ORR 75%, 95% CI: 51–91%), 5 pts stable disease. Median progression free survival has not yet been reached. Conclusions: With the combination of FOLFOXIRI/cetuximab, the recommended dose of irinotecan is 125 mg/m 2 for further investigation in clinical trials in patients with good performance status. The observed response rate of 75% is very promising. [Table: see text]