Primary Objective:

The primary objective is to validate previously identified predictive/prognostic genomic DNA and expression biomarkers of response to combination bvz treatments in K-ras mutant advanced CRC (a CRC) or metastatic CRC (mCRC).

Secondary Objective:

1. To test the efficacy of bvz in combination with FOLFOX in patients with newly diagnosed advanced or metastatic K-ras mutant CRC and
2. To determine the progression free and overall survival of patients under first line FOLFOX + bvz in aCRC or mCRC.

Study Design:

Type of Study: Exploratory, translational, multicenter and multinational Phase II study.

Patient Population:All patients from the intent-to-treat population with aCRC or mCRC, (incurable with any conventional multimodality approach) and who fulfil all inclusion and exclusion criteria.

Number of Patients: 224

Sample Type:

Serial tissue and blood samples will be collected before (week 0), during (week 6, month 3 and 6) and at the end of treatment (month 12).

Inclusion Criteria:

1. Patients ≥ 18 years of age.

2. Patients diagnosed with recurrent or de novo, locally advanced (unresectable) or metastatic adenocarcinoma of the colon or rectum.

3. Planned combination bevacizumab (bvz) treatment with either:

   • leucovorin, fluorouracil and oxaliplatin (FOLFOX)
   • capecitabine and oxaliplatin (XELOX)
   • leucovorin, fluorouracil and irinotecan (FOLFIRI)
   • capecitabine and irinotecan (XELIRI)

4. Naive for bvz

5. An evaluable site of disease

6. ECOG Performance status 0, 1, or 2

7. Adequate renal function as shown by serum creatinine ≤ 1.5 x ULN or GFR ≥ 50ml/min

8. Adequate hematopoietic function [white blood cell (WBC) count ≥ 3000/μl, absolute neutrophil count (ANC) ≥1500/μl, platelets ≥100 000/μl, haemoglobin level ≥ 9.0 g/dl]

9. Adequate end organ function, defined as the following: total bilirubin < 1.5 x ULN, SGOT and SGPT < 3.0 x ULN (in case of liver metastases SGOT and SGPT < 5.0 x ULN)

10. Ability to give signed informed consent prior to any screening procedures

11. FFPE Tissue is available

Exclusion Criteria:

1. Patient has received any other investigational product within 28 days of first day of study drug dosing
2. Patients having familial and/or hereditary CRC
3. CRC associated with ulcerative colitis
4. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

All patients from the intent-to-treat population with aCRC or mCRC, (incurable with any conventional multimodality approach) and who fulfil all inclusion and exclusion criteria.