safety of cetuximab and oxaliplatin/5-fu/fa/irinotecan in first-line treatment of metastatic colorectal cancer

Conditions: Metastatic Colorectal Cancer

Summary: 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.

Eligibility criteria:
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

Keywords: phase i/ii cetuximab oxaliplatin irinotecan 5-fu chemotherapy dose escalation safety