Safety of Cetuximab and Oxaliplatin/5-FU/FA/Irinotecan in First-Line Treatment of Metastatic Colorectal Cancer

Open Labeled, Multicenter Phase I/II Study Evaluating the Dose Escalation/Safety of Cetuximab and Oxaliplatin/5-FU/FA/Irinotecan as First-Line Treatment of Metastatic Colorectal Cancer

The purpose of this study is to assess a maximal tolerable dose and to assess the safety of a chemotherapy-combination of cetuximab, irinotecan, oxaliplatin and 5-fluorouracil (5-FU)/folinic acid (FA) as first-line treatment for metastatic colorectal cancer.

Dose escalation:

The first three patients will receive chemotherapy at the dose level 1 for 6 weeks (first three cycles). The dose will be escalated for the next patients by one dose level if none of the three patients at a dose level experience a dose-limiting toxicity (DLT) during the first six weeks. If one of the three patients has a DLT, an additional three patients will be enrolled at this dose level and the dose will be escalated if no additional patients experience a DLT. Otherwise, the dose escalation will be stopped, and the last dose will be regarded as the maximum tolerated dose (MTD). An intra-individual dose escalation is not planned.

Expanded cohort:

The MTD cohort will be expanded to a total of 16 patients.

Inclusion Criteria:

• Diagnosis of non-resectable, histologically confirmed, epithelial growth factor receptor(EGFR)-positive or negative colorectal cancer
• WHO Performance status 0 or 1
• Signed written informed consent
• ≥ 18 years of age
• Effective contraception for both male and female subjects if the risk of conception exists
• Adequate bone marrow function: neutrophil blood cell count (NBC) ≥ 1.5 x 10^9/L, platelet count ≥ 100 x 10^9/L, hemoglobin ≥ 5.96 mmol/L (10 g/dL)
• Adequate liver and renal function: bilirubin ≤ 1.5 x upper normal level (UNL) and not increasing more than 25% within the last 4 weeks; ASAT and ALAT ≤ 5 x UNL; serum creatinine ≤ 1.5 x UNL.

Exclusion Criteria:

• Previous exposure to epidermal growth factor receptor-targeting therapy
• Previous chemotherapy for colorectal cancer except for adjuvant treatment with progression of disease documented > 6 months after end of adjuvant treatment or 5-FU in combination with radiotherapy for rectal cancer
• Radiotherapy or major abdominal or thoracic surgery within the last 4 weeks before inclusion.
• Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy.
• Investigational agents or participation in clinical trials within 30 days before start of the treatment in study.
• Clinically relevant coronary disease or myocardial infarction within 12 months before study entry.
• Peripheral neuropathy > CTC (Common Toxicity Criteria)grade I
• Inflammatory bowel disease
• Previous malignancy (except for colorectal cancer, history of basal cell carcinoma of skin or pre-invasive carcinoma of the cervix with adequate treatment)
• History of severe psychiatric illness
• Drug or alcohol abuse
• Known hypersensitivity reaction to any of the components of study treatment
• Pregnancy (absence to be confirmed by b-hCG (pregnancy-) test) or lactation period
• Brain metastasis and/or leptomeningeal disease (known or suspected)
• Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease