Since its introduction, 5-fluorouracil (5-FU) has been the cornerstone of treatment for metastatic colorectal cancer (mCRC). Meanwhile the oral 5FU pro-drug Capecitabine (Xeloda®) proved equivalence to 5-FU and is a well tolerated alternative combination partner for Irinotecan (XELIRI) or Oxaliplatin (XELOX) which are widely used for first line treatment of mCRC. Recent advances in molecular biology have resulted in the development of an inhibitor of the vascular endothelial growth factor (VEGF) by the monoclonal humanized antibody bevacizumab (Avastin®).

XELOX or XELIRI +bevacizumab have been investigated in several trials, but not in an approach with clearly defined cross-wise XELIRI-XELOX change criteria. This trial investigates two different sequential treatment options with XELIRI/ XELOX in first and second line with the addition of bevacizumab and tries to give answer to the question if there is an optimal sequence for the benefit of the patient.

This is a prospective, randomized, open-label, 2-arm pilot trial in patients with mCRC who did not receive systemic treatment for their metastatic disease. The study is designed to evaluate the efficacy of XELIRI followed by XELOX and XELOX followed by XELIRI + bevacizumab in terms of Duration of Disease Control (DDC).

Patients will be treated with an established first line therapy consisting of either XELOX or XELIRI + bevacizumab. The chemotherapy treatment will be given for 6 months except prior disease progression, unacceptable toxicity or patient refusal. Bevacizumab will be given until disease progression, unacceptable toxicity or patient refusal.

Capecitabine can be given in addition at the investigators' discretion until disease progression, unacceptable toxicity or patient refusal.

If serious side effects occur despite adequate dose reduction, Oxaliplatin or Irinotecan should be discontinued. In case of Oxaliplatin or Irinotecan-related discontinuation Capecitabine and Bevacizumab should be continued. If Capecitabine also has to be discontinued in first line treatment bevacizumab should be continued. In case of permanent discontinuation of bevacizumab for toxicities, chemotherapy should be continued.

Upon completion of first line chemotherapy patients with disease control will receive bevacizumab maintenance treatment. On investigators decision patients can receive Capecitabine as additional maintenance treatment.

The primary endpoint is to determine the efficacy of a modified XELIRI + bevacizumab followed by XELOX + bevacizumab scheme at progression in comparison with the reverse sequence based on DDC.

Secondary endpoints are first line progression-free survival (PFS), second line PFS, overall response rate, time to response, duration of response, overall survival, tumor assessments (based on RECIST criteria) using CT scans, MRI scans, X-ray, bone scan, clinical examination.

Inclusion Criteria:

1. Written informed consent
2. Age >=18 years
3. Patient must be able to comply with the protocol
4. Histologically or cytologically confirmed carcinoma of the colon and/or rectum with evidence of metastases. 5 )Diagnosis of metastatic disease according to Response Evaluation Criteria in Solid Tumours (RECIST) not more than 3 months prior to enrolment.

6) Life Expectancy of at least 3 months 7) At least one measurable metastatic lesion (as per RECIST criteria) 8) Prior adjuvant or neo-adjuvant chemotherapy/radiotherapy allowed if completed more than 6 months before inclusion. 9) Eastern Collaborative Oncology Group (ECOG) performance score of 0 or 1 10) Adequate haematological function: absolute neutrophil count (ANC) >= 1.5 x 109/L; platelets >= 100 x 109/L, Hb >= 9 g/dL 11) international normalized ratio (INR) <=1.5 and activated partial thromboplastin time (aPTT) <=1.5 x ULN within 7 days prior to starting study treatment 12) Adequate liver function: Serum bilirubin <=1.5 x ULN; alkaline phosphatase and transaminases <=2.5 x ULN (in case of liver metastases < 5 x ULN) 13) Serum Creatinine <=1.5 x ULN 14) Urine dipstick for proteinuria < 2+. If urine dipstick is >= 2+, 24- hour urine must demonstrate <=1 g of protein in 24 hours 15) Negative serum pregnancy test within 7 days of starting study treatment in pre- menopausal women and women < 2 years after the onset of menopause. This test has to be reconfirmed by a urine test, should the 7 days window be exceeded. Fertile women (<2 years after last menstruation) and men must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile).

Exclusion Criteria:

1. Prior chemotherapeutic treatment for metastatic CRC
2. Symptomatic central nervous system (CNS) metastases
3. Significant vascular disease (e.g. aortic aneurysm potentially requiring surgical intervention, pulmonary embolism or recent peripheral arterial thrombosis) within 6 months prior start of study treatment.
4. History of haemoptysis (= a half teaspoon of bright red blood per episode) within 1 month prior start of study treatment
5. Past or current history (within the last 2 years prior to treatment start) of other malignancies (Patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).
6. Clinically significant cardiovascular disease, for example central venous access (CVA) (<=6 months before treatment start), myocardial infarction (<=6 months before treatment start), unstable angina, New York Heart Association (NYHA) >= grade 2, congestive heart failure (CHF), arrhythmia requiring medication, or uncontrolled hypertension.
7. Prior history of hypertensive crisis or hypertensive encephalopathy
8. Treatment with any other investigational agent or any other biological agent (e.g.cetuximab), or participation in another clinical trial within 30 days prior to entering this study.
9. Known hypersensitivity to any of the study drugs
10. Current or recent (within 10 days of first dose of study treatment) chronic use of aspirin (> 325 mg/day)
11. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic (as opposed to prophylactic) purposes.
12. Evidence of bleeding diathesis or coagulopathy.
13. Serious, non healing wound, ulcer, or bone fracture.
14. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment, or anticipation of the need for major surgery during the course of the study. If central venous access device (CVAD) is required for chemotherapy administration, it should be inserted within 2 days prior to study treatment cycle.
15. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior start of study therapy
16. History of abdominal fistula, trachea-oesophageal fistula or any grade 4 non gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess before 1st line therapy.
17. History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) (unless adequately treated with standard medical therapy) e.g. uncontrolled seizures
18. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications
19. Patients with contraindication for cross over chemotherapy (e.g. patients treated with irinotecan based first line therapy and serious polyneuropathy > grade 1, not feasible for oxaliplatin based cross over second line therapy, or patients treated with oxaliplatin based first line therapy and hereditary fructose intolerance not feasible for Irinotecan based cross over second line therapy)
20. Pregnancy or lactation
21. Fertile women (<2 years after last menstruation) and men not willing to use effective means of contraception.