bi-weekly cetuximab combined with 5-fluorouracil/leucovorin/oxaliplatin (folfox-6) in metastatic colorectal cancer

Conditions: Metastatic Colorectal Cancer

Summary: cetuximab is normally given as a weekly schedule in the therapy of patients with metastatic colorectal cancer. in order to improve the convenience for the patients in first line-therapy this study will evaluate the efficacy and safety of a bi-weekly combination of cetuximab with folfox.

for years the effective treatment of advanced colorectal carcinoma (crc) was limited to fluorouracil (5-fu). combination of 5-fu or a 5-fu analog with oxaliplatin, which has some antitumor activity as a single agent, shows synergistic activity. combining oxaliplatin with a twice monthly folinic acid/5-fu schedule leads to a further improvement in first-line treatment of advanced crc thus emerging to a standard regimen in first-line therapy of metastatic crc. cetuximab is normally given as a weekly schedule. as recently shown a biweekly schedule with 500 mg/m² instead of the weekly standard regimen (initial dose of 400 mg/m² followed by 250 mg/m² every week) exhibits similar pharmacokinetic results with a comparable efficacy. in order to improve the convenience for the patients, this study will evaluate the efficacy and safety of a bi-weekly combination of cetuximab with folfox. out of the various folfox regimens the most convenient folfox-6 schedule is chosen for the study, which has been tested before in two studies in combination with the standard weekly schedule of cetuximab. recent data suggest a decreased efficacy of cetuximab in patients bearing a k-ras mutation in their crc. therefore only patients with no evidence for a mutated k-ras gene in the colorectal carcinoma cells will be included in this study.

Eligibility criteria:
inclusion criteria: * histologically proven metastatic colorectal cancer * molecular test showing no mutation in the k-ras gene of colorectal carcinoma cells * male and female subjects ≥ 18 years of age * 1st occurrence of metastatic disease (not curatively resectable) * life expectancy ≥ 12 weeks * presence of at least 1 bi-dimensionally measurable index lesion (not in an irradiated area) * eastern cooperative oncology group (ecog) performance status ≤ 2 at study entry * adequate bone marrow reserve: leucocytes ≥ 3.0 x 109/l with neutrophils ≥ 1.5 x 109/l, platelets ≥ 100 x 109/l, haemoglobin ≥ 6.21 mmol/l (10 g/dl) * aspartate-aminotransferase (asat) and alanine-aminotransferase (alat) ≤ 2.5 x upper reference range, in case of liver metastasis ≤ 5 x upper reference range * serum creatinine ≤ 1.5 x upper reference range * bilirubin ≤ 1.5 x upper reference range * negative pregnancy test for female and effective contraception for both male and female subjects if the risk of conception exists * signed written informed consent exclusion criteria: * evidence for a mutation of the k-ras gene in the colorectal carcinoma cells * previous exposure to epidermal growth factor receptor-targeting therapy * prior chemotherapy for metastatic disease * prior oxaliplatin based adjuvant chemotherapy or \< 6 months after end of adjuvant treatment * other previous malignancy with exception of a history of a previous curatively treated basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix * radiotherapy, surgery (excluding prior diagnostic biopsy) or any investigational drug in the 30 days before registration * concurrent chronic systemic immune therapy or hormone therapy not indicated in this study protocol * creatinine clearance \< 30 ml/min * known hypersensitivity reaction to any of the components of study treatment * pregnancy (absence to be confirmed by ß-human chorionic gonadotropin (hcg) test) or lactation period * clinically relevant coronary artery disease, history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia * acute or sub-acute intestinal occlusion or history of inflammatory bowel disease * brain metastasis (known or suspected) * medical or psychological conditions that would not permit the subject to complete the study or sign informed consent * known alcohol or drug abuse * participation in another clinical study within the 30 days before registration * peripheral neuropathy \> grade 1 * significant disease which, in the investigator's opinion, would exclude the patient from the study * legal incapacity or limited legal capacity