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Open Access Highly Accessed Research article

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

Gunnar Folprecht1*, Susanne Hamann12, Katharina Schütte13, Tanja Trarbach45, Jan Stoehlmacher-Williams16 and Gerhard Ehninger1

Author Affiliations

1 Medical Department I, University Hospital Carl Gustav Carus, University Cancer Center, Fetscherstr 74, 01307 Dresden, Germany

2 Medical Department IV, Klinikum Chemnitz, Chemnitz, Germany

3 Onkologische Gemeinschaftspraxis, Arnoldstr. 18, Dresden, Germany

4 Medical Department/ Tumour research, West Germany Cancer Center, Essen, Germany

5 ioMedico, Freiburg, Germany

6 Onkologische Praxis, Bonn, Germany

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BMC Cancer 2014, 14:521  doi:10.1186/1471-2407-14-521

Published: 19 July 2014



The FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). Adding cetuximab to FOLFOX or FOLFIRI increased efficacy in patients with k-ras wild type mCRC. We explored the dose limiting toxicity and feasibility of the combination cetuximab, irinotecan, oxaliplatin, 5-FU and FA in mCRC patients.


In a dose-escalation study patients with previously untreated mCRC and a WHO performance status 0–1 received cetuximab (500 mg/m2, 2 h), followed by irinotecan (95, 125, and 165 mg/m2 in the dose levels [DL] 1, 2, and 3 respectively), followed by oxaliplatin (85 mg/m2, 2 h) which was given parallel to FA (400 mg/m2, 2 h) and followed by 5-FU (3200 mg/m2, 46 h) in an outpatient setting every two weeks. The primary endpoints were the maximum tolerable dose and the safety. The trial was approved by the local ethics committee.


From 2007 to 2008, twenty patients were treated in this trial. In the first dose level (irinotecan 95 mg/m2) one patient developed neutropenia grade 4. One patient experienced diarrhoea grade 3 as DLT in dose level 2 (irinotecan 125 mg/m2). In dose level 3 (irinotecan 165 mg/m2), three patients experienced a DLT (diarrhoea grade 3 and two patients with neutropenia grade 4). Thus, the recommended dose for a phase II trial is 125 mg/m2 irinotecan in combination with oxaliplatin, 5-FU/FA and cetuximab. Most common grade ≥3 toxicities were neutropenia (40%), diarrhoea (25%) and acne-like rash (15%). No therapy associated death occurred.

The confirmed overall response rate in all cohorts was 75% (95%-CI 51-91%). The best response was reached after a median of 3.0 (95%-CI 2.2 to 3.7) months. Median progression free survival (PFS) is 16 (95%-CI 12.6-19.4) months, overall survival (OS) 33 (95%-CI 26.2-39.8) months.


The combination of cetuximab and FOLFOXIRIis feasible and has an acceptable toxicity profile in patients with a good performance status. The observed clinical activity with a confirmed response rate of 75% is promising and further evaluated in the ongoing CELIM2.

Trial registration webcite: NCT00422773.

Cetuximab; Phase I; Metastatic colorectal cancer; Irinotecan; Oxaliplatin; 5-FU; Chemotherapy