Bi-weekly Cetuximab Combined With 5-fluorouracil/Leucovorin/Oxaliplatin (FOLFOX-6) in Metastatic Colorectal Cancer

Bi-weekly Cetuximab Combined With FOLFOX-6 as First-line Treatment in Metastatic Colorectal Cancer Patients With Wild-type K-ras Status

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.

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