Sequential Treatment Strategy for Metastatic Colorectal Cancer

Inclusion Criteria:

1. Histologically or cytologically confirmed untreated metastatic or locally advanced,non resectable CRC; previous adjuvant chemotherapy for CRC or neoadjuvant/adjuvantchemoradiotherapy for rectal cancer is permitted but must have been completed atleast 6 months prior to enrolment;

2. Resected CRC patients who have developed metastases do not require separatehistological or cytological confirmation unless > 5 yrs have elapsed between primarysurgery or primary tumor stage I;

3. Evaluation of Kras status from the primary tumor or metastases

4. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECISTcriteria)

5. Age ≥ 18 years and < 70 years with Performance Status (ECOG) ≤ 2 or age > 70 yearswith ECOG ≤ 1;

6. Estimated life expectancy of at least 12 weeks;

7. Adequate hematological, hepatic and renal function, as follows: hemoglobin ≥ 9g/dl,absolute neutrophil count ≥1,500/μL, platelets ≥100,000/μL, total bilirubin ≤1.5 x upper limit of normal (ULN),alkaline phosphatase, aspartate aminotransferase (AST(SGOT)) and alanine aminotransferase (ALT(SGPT)) ≤ 2.5 x ULN (≤ 5 x ULN if livermetastases present), serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance >50 mL/min (calculated on the basis of Standard Cockcroft and Gault Formula, urinaryexcretion (if protein > 30 mg/dL or +1, patients must have ≤ 1 g of protein/24hours)

8. Either international normalized ratio (INR) or activated partial thromboplastin time (APTT) < 1.5 x ULN and D-dimer within normal range (if abnormal, thromboembolicevents must be excluded);

9. Negative pregnancy test no more than 7 days before randomization; test pregnancy canbe omitted only in women without any reproductive potential (e.g.: postmenopausalwomen, i.e. amenorrhoea ≥2 years or with previous hysterectomy or bilateralovariectomy). Women of child-bearing potential and men must agree to use adequatecontraception at the time of randomization and for the duration of studyparticipation. Should a woman become pregnant or suspect she is pregnant whileparticipating in this study, she must inform her treating physician and coordinatingcentre (CC) immediately; women in lactation period must be excluded;

10. Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

1. Prior treatment with cetuximab, bevacizumab or other anti Epidermal Growth FactorReceptor (antiEGFR) or anti-angiogenesis agents;

2. Prior chemotherapy or immunotherapy for metastatic or advanced disease;

3. Participation in another clinical trial with any investigational agents ≤ 30 daysprior to study randomization;

4. Contraindications or hypersensitivity to study drugs;

5. Treatment with other concomitant antineoplastic drugs;

6. Other known malignant neoplastic diseases in the patient's medical history with adisease-free interval of less than 5 years (except for previously treated basal cellcarcinoma and in situ carcinoma of the uterine cervix);

7. Symptomatic brain or central nervous system metastases or clinically relevantcentral nervous diseases (for example: primary brain tumor, uncontrolled convulsionswith medical therapy, carcinomatous meningitis);

8. Grade > 1 peripheral neuropathy (as defined by the National Cancer Institute -Common Toxicity Criteria for Adverse Effects (NCI CTCAE) v3.0);

9. Clinically significant (i.e. active) cardiovascular disease e.g. cerebrovascularaccidents ≤ 6 months prior to randomization), myocardial infarction (≤ 1 year priorto randomization), uncontrolled hypertension whilst receiving chronic medication,unstable angina, New York Heart Association (NYHA) grade II or more congestive heartfailure,or serious cardiac arrhythmia requiring medication;

10. Malabsorption syndrome or lack of physical integrity of the gastrointestinal tract.Diverticulitis. Patients with colostomy or ileostomy may enter at the investigator'sdiscretion. History of trachea-oesophageal fistula or any other type of fistula (e.g. abdominal), gastrointestinal perforation, intra-abdominal abscess;

11. Interstitial pneumonia or extensive symptomatic fibrosis of the lungs;

12. Serious, non-healing wound, ulcer, or bone fracture; significant traumatic injury inthe 4 weeks prior to enrolment (complete recover must have occurred);

13. Major surgery (e.g. laparotomy) in the 4 weeks prior to study randomization;

14. Minor surgery in the 2 weeks prior to study randomization. Insertion of a centralvascular access device for chemotherapy infusion must be done at least 2 days priorto the start of treatment. Patients will be randomized only if they have recoveredfrom all surgery related toxicities;

15. Bleeding diathesis or coagulopathy;

16. Pulmonary embolism or any arterial thromboembolism;

17. Deep vein thrombosis or other significant thromboembolic event;

18. Clinically significant peripheral vascular disease;

19. Previous organ transplantation that requires immunosuppressive therapy;

20. Need for chronic oral steroid use ( ≥10 mg/day of methylprednisolone or equivalent)for the treatment of a nonmalignant condition other than intermittent prophylacticuse as an antiemetic and inhaled steroid use;

21. Chronic use of aspirin (> 325 mg/day) or other non steroidal anti-inflammatoryagents (those known to inhibit platelet function at doses used to treat chronicinflammatory diseases);

22. In treatment with antiplatelets agents (i.e clopidogrel > 75 mg/day,ticlopidine,dipyridamole);

23. Undergoing treatment with sorivudine or its chemically-related analogues (such asbrivudine);

24. Full-dose oral or parenteral anticoagulants or thrombolytic treatment fortherapeutic purposes ≤10 days prior to study randomization;

25. Geographic inaccessibility;

26. Any radiation therapy completed ≤ 4 weeks prior to study randomization. If theradiated lesion/s is/are the only site of disease, and if it/they show progressionafter the radiotherapeutic procedure, the patient will become eligible for thestudy;

27. Previous embolization or thermoablation of metastases ≤ 30 days prior to studyrandomization. If these lesions are the only site of disease, and if they showprogression after the embolization or thermoablation procedure, the patient willbecome eligible for the study;

28. Laboratory abnormality or medical or psychiatric disorders that would interfere withinformed consent or compliance, or which could indicate a contraindication topatient enrolment into the study (also known dihydropyrimidine dehydrogenasedeficit);

29. HIV-positivity, whether or not symptomatic.