3513 Background: Cetuximab is an IgG1 monoclonal antibody targeting the EGFR. In irinotecan-refractory metastatic CRC and in first-line therapy trials cetuximab has shown to be active (ASCO 2002, 2003). This phase II trial evaluates the safety and efficacy of cetuximab combined with a FOLFIRI regimen as first-line treatment for pts with EGFR-expressing metastatic CRC. Methods: Cetuximab was given at an initial dose of 400 mg/m2, then 250 mg/m2 i.v. weekly. FOLFIRI was administered every 2 weeks: Irinotecan 180 mg/m2, FA 400 mg/m2 and 5-FU 300 mg/m2 bolus plus infusion of 2,000 mg/m2/46h (low dose group, LD) or 400 mg/m2 bolus plus infusion of 2,400 mg/m2/46h (high dose group, HD). Dose limiting toxicity (DLT) was defined as neutropenia/leukopenia, thrombopenia, alk. phosphatase, bilirubin, ASAT, ALAT or skin toxicity > grade (Gd) 3; neutropenia with fever/infection, anemia, diarrhea, mucositis, creatinine, or any treatment-related organ toxicity > Gd 2 during the first 3 cycles. Results: The first 23 pts were evaluated for DLT, 10 in LD, 13 in HD group. Median age was 66 years (36–76) and median KPS was 90 (60–100). No DLT occurred in the LD group, but 3 DLT in the HD (diarrhea Gd 3, allergy Gd 3, neutropenia Gd 4). 22 pts were evaluable for efficacy: PR 10 (46%, C.I., 25–66%), SD 9 (41%), PD 3 (14%). 7 pts underwent secondary surgery of metastases. So far, median TTP was 10.9 months. To allow a better estimate of safety and efficacy for a planned phase III trial, further 29 patients were enrolled in the HD group that has demonstrated an acceptable safety profile. Safety analysis in the HD group was based on 42 pts. The most frequent grade 3/4 adverse events were diarrhea 14.3%, neutropenia 11.9%, rash, 11.9%, and nausea/vomiting 9.5%. Frequency of acne-like rash of grade 1/2/3/4 was 28.6/26.2/4.8/0 %. 5 pts were still on treatment at the time of abstract submission. Conclusion: The combination of cetuximab with FOLFIRI is safe and feasible in pts with EGFR-expressing metastatic CRC and is clearly active.