This is a study to assess the efficacy and safety of the addition of cetuximab to the combined regimen of capecitabine, oxaliplatin and bevacizumab in patients with previously untreated advanced colorectal carcinoma. It is an open, comparative study, comparing the effects of capecitabine, oxaliplatin and bevacizumab to those of the same regimen plus cetuximab.

Seven hundred fifty patients will be included. Treatment will continue until disease progression or serious toxicity and follow up will continue until death. It is anticipated that the addition of cetuximab will lead to an increase in progression free survival.

Primary objective: To assess the efficacy, defined as progression-free survival (PFS), of adding cetuximab to capecitabine/oxaliplatin/bevacizumab for advanced CRC.

Secondary objectives: To assess tumour response (CR, PR or SD), response duration, overall survival, toxicity profile, quality of life, translational research.

Methodology: Open, randomised multicenter phase III study. The number of patients is 750.

Test products: All cycles will be administered q 3 weeks. Oxaliplatin will be discontinued after 6 cycles in both study arms. The dose of capecitabine will be increased to 1250 mg/m2 b.i.d. as of cycle 7.

Arm A: capecitabine 1000 mg/m2 orally b.i.d. on day 1-14 (1250 mg/m2 after 6 cycles), oxaliplatin 130 mg/m2 i.v. infusion on day 1 during 6 cycles, bevacizumab 7.5 mg/kg i.v. infusion on day 1.

Arm B: capecitabine 1000 mg/m2 orally b.i.d. on day 1-14 (1250 mg/m2 after 6 cycles), oxaliplatin 130 mg/m2 i.v. infusion on day 1 during 6 cycles, bevacizumab 7.5 mg/kg i.v. infusion on day 1. Cetuximab 400 mg/m2 i.v. day 1 of cycle 1, thereafter weekly 250 mg/m2 i.v.

Duration of treatment and follow-up: Treatment is continued until disease progression, or unacceptable toxicity. Patients will be evaluated every 9 weeks for response while on treatment, or at any other time point when progression is suspected. After cessation of therapy for reasons other than disease progression, patients will be followed every 3 months until progression or death. Death and/or progression should be reported whenever it occurs.

In case chemotherapy (i.e. capecitabine and/or oxaliplatin) is discontinued for reasons of toxicity, treatment with bevacizumab (arm A) or bevacizumab + cetuximab (Arm B) should be continued until progression or unacceptable toxicity. Also, if chemotherapy plus bevacizumab is discontinued in Arm B for reasons of toxicity, treatment with cetuximab should be continued until progression or unacceptable toxicity.

Criteria for evaluation:

Efficacy: All eligible patients will be included in the analysis (intent-to-treat). All patients receiving > 9 weeks of treatment (i.e. 3 cycles) will be considered evaluable for response, unless documented progression occurred earlier.

Safety profile: Safety will be analysed in each treatment group. Patients having received ≥ 1 treatment doses are evaluable for toxicity. Evaluation will be performed on the safety population (having received treatment, assignment to treatment groups as treated). Clinical and laboratory toxicity/symptomatology will be graded according to NCI common toxicity criteria, version 3.0. The adverse events which are not reported in NCI common toxicity criteria will be graded as: mild, moderate, severe, life threatening.

Statistical methodology: The main endpoint of the study is the progression free survival interval (PFS). PFS curves will be constructed by means of the Kaplan Meier method. Comparisons of PFS curves will performed by mean of the log rank test. Similar methods will be used to analyse the duration of survival. All analyses will be done according to the intention-to-treat principle.

The expected median PFS in Arm A (standard arm) is 11 months. The minimum increase in PFS in Arm B (experimental arm) will be 3 months (21% hazard ratio reduction). 540 events are required for 80% power. 740 patients are needed to show this difference (>=0.05, 2-tailed test). To allow for ineligibility in some patients, a total of 750 patients will be included.

Stratification parameters:

Patients will be stratified for the following parameters:

• Prior adjuvant therapy (yes versus no);
• Number of organs affected (1 versus > 1, in case the primary tumour is in situ this will count as one organ);
• Serum LDH (normal versus above normal);
• Per participating institution.

Side studies: Side studies on prognostic factors in tumour samples from included patients will be performed, as well as on circulating tumour cells and endothelial cells and serum proteomics.

Inclusion Criteria:

Histology and Staging Disease

• Histologically proven advanced colorectal cancer (CRC); not amenable to curative surgery
• Of Note: In case of a single metastasis, histological or cytological proof of colorectal carcinoma should be obtained prior to randomisation.
• Unidimensionally measurable disease (>= 1 cm on spiral CT scan or >= 2 cm on chest X-ray; liver ultrasound not allowed). Index lesions should not be in a previously irradiated area. Serum carcinoembryonic antigen (CEA) may not be used as a parameter for disease evaluation.
• In case of previous radiotherapy, at least one measurable lesion should be located outside the irradiated field.

General Conditions

• Signed written informed consent
• Age 18 years and above
• World Health Organization (WHO) performance status 0-1
• Adequate bone marrow function (white blood cell count [WBC] > 3.0 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin [Hb] > 6 mmol/L)
• Adequate hepatic function: total bilirubin < 2 x upper normal limit, aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) < 3 x upper normal limits (in case of liver metastases < 5 x upper normal limits)
• Adequate renal function: serum creatinine < 1.5 x upper normal limit
• Urinary protein excretion < 0.5 gram/24h
• Expected adequacy of follow-up

Exclusion Criteria:

• Prior chemotherapy for advanced disease; prior adjuvant chemotherapy is allowed provided that the last administration was given > 6 months prior to randomisation, and that patients have recovered from all toxic events related to adjuvant chemotherapy, and that safety evaluations during adjuvant chemotherapy do not present any risk for serious adverse events during the administration of protocol treatment.
• Previous radiotherapy for rectal cancer or for symptomatic treatment of distant metastases is allowed, provided that at least one measurable lesion is located outside the irradiated field, irradiation has been completed for at least 4 weeks, and patients have recovered from all side effects.
• Previous epidermal growth factor receptor (EGFR) targeting therapy
• Sensory neuropathy > grade 1
• Bleeding diathesis or coagulation disorders or the need for full-dose anticoagulation
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to the start of drug administration
• Anticipated major surgical procedure during the course of the study
• Serious non-healing wound or ulcer
• Any condition preventing the intake or absorption of oral drugs
• Significant cardiovascular disease (unstable angina pectoris, recent myocardial infarction < 12 months, uncontrolled hypertension, previous cerebrovascular disease)
• Pregnancy or lactation
• Patients (males/females) with reproductive potential not implementing adequate contraceptive measures
• Central nervous system metastases (in asymptomatic patients no screening is required)
• Serious active infections
• Other serious concomitant diseases preventing the safe administration of study drugs or likely to interfere with the study assessments
• Other malignancies in the past 5 years with the exception of adequately treated carcinoma in situ of the cervix or squamous or basal cell carcinoma of the skin
• Concomitant treatments: concomitant (or within 4 weeks before randomisation) administration of any other experimental drug under investigation; concurrent treatment with any other anti-cancer therapy; full-dose anticoagulation
• Continuous use of immunosuppressive agents