Randomized Phase II Study to Explore the Influence of BRAF and PIK3K Status on the Efficacy of FOLFIRI Plus Bevacizumab or Cetuximab, as First Line Therapy of Patients With KRAS Wild-type Metastatic Colorectal Carcinoma and < 3 Circulating Tumor Cells
1. Patient's Informed consent in written.
2. Age between 18-70 years old.
3. ECOG 0-1.
4. Life expectancy of at least 3 months.
5. Histological confirmation of adenocarcinoma of the colon or rectum.
6. Sample of tumour tissue available for evaluation of genes KRAS, BRAF and PI3K. To be
included in the study patients should present < 3 CTC in peripheral blood and KRAS
wild-type present in the sample of tumor tissue.
7. Measurable metastatic stage IV disease with at least 1 measurable metastatic lesion
following RECIST criteria v 1.1 (non suitable for radical surgery at the inclusion
8. Prior radiotherapy is allowed but must be completed at least 4 weeks before
randomization (if applicable).
9. Adequate bone marrow, liver and renal function.
10. Women of childbearing potential must have a negative serum or urine pregnancy test.
Postmenopausal women must have been amenorrheic for at least 12 months.Both men and
women participating in this study must use adequate contraception.
11. Subject must have the ability, in the opinion of the investigator, to comply with all
the study procedures and follow-up examinations.
1. Previous chemotherapy for metastatic disease.
2. Prior treatment with Bevacizumab, or EGFR inhibitors
3. Any anticancer treatment (chemotherapy, hormonal treatment, radiation treatment,
surgery , immunotherapy, biologic therapy or tumour embolization) within 4 weeks
4. Use of any investigational drug within 4 weeks before start the treatment.
5. Clinical or radiographic evidence of brain metastasis.
6. Uncontrolled hypertension (systolic blood pressure >150 mmHg and/or diastolic blood
pressure >100 mmHg on repeated measurement) despite optimal medical management.
7. Previous history of hypertensive encephalopathy or hypertensive crises.
8. Current or history of peripheral neuropathy > or equal to 1 NCICTCAE.
9. Patients classified as fragile according to criteria listed in the protocol.
10. Significant cardiovascular disease (e.g. AVC, myocardial infarction, within 6 months
before randomization). Unstable angina, congestive heart failure New York Heart
Association (NYHA) ≥ class II, arrhythmia that requires treatment within 3 months
11. Significant vascular disease (e.g. aortic aneurism requiring surgical intervention,
pulmonary embolic, peripheral arterial thrombosis) within 6 months before
12. Previous history of significant haemorrhage /severe, within 1 month before
13. Major surgery, open surgical biopsy or significant traumatic injury within 4 weeks
14. Large bore needle biopsy of a major organ within 14 days before randomization.
Placement of central venous access port > or equal to 7 days before randomization is
15. Evidence or history of bleeding diathesis or coagulopathy.
16. INR >1.5 within 14 days prior to starting study treatment. EXEMPTION: patients on
full anticoagulation must have an in-range INR[usually between 2-3]. Any
anticoagulation therapy must be at stable dosing prior to enrolment.
17. History of previous abdominal fistula or gastrointestinal perforation within 6 months
18. Serious non-healing wound, ulcer or bone fracture.
19. Acute or sub-acute of intestinal occlusion or history of intestinal inflammatory
20. History of uncontrolled convulsive crises.
21. History of pulmonary fibrosis, acute lung disease or interstitial pneumonia.
22. Chronic, actual o recent use (10 days prior first drug administration) of
acetylsalicylic acic (aspirin) > 325 mg/day or clopidogrel (75mg/day) or other
treatments that can cause gastrointestinal ulcer (low-dose aspirin is permitted < or
equal to 325 mg/day).
23. Urinary protein excretion > or equal to 2+ (dipstick). If > or equal 2 g proteinuria
is detected with dipstick, a 24-hour period urine test will be performed and the
result should be < or equal to 1 g/24 hours to permit the inclusion of the patient in
the clinical trial
24. Known human immunodeficiency virus infection or chronic hepatitis B or C infection or
other uncontrolled, severe concurrent infection .
25. Current infection > or equal to Grade 2 (NCI-CTCAE).
26. Any previous or concurrent cancer different to colorectal carcinoma within 5 years
before to start the treatment. Subjects with successfully treated, non-invasive
cancers, including cervical cancer in situ, basal cell carcinoma will be allowed to
participate in the clinical trial. Or those cancer treated with curative intention
without disease evidence in the last 5 years at least
27. Known or suspected allergy or hypersensitivity to any component of bevacizumab,
cetuximab, irinotecan, or 5-FU/LV.
28. Any medical, psychological, or social condition that may interfere with the subject's
participation in the study or evaluation of the study results.
29. Any psychological, familial or geographic situation that interferes in the adequate
follow-up and adherence to the study protocol.
30. Women who are pregnant or breast-feeding.