Clinical trial to compare the efficacy of two treatment sequencing schemes with chemotherapy (the regime called FOLFOX and FOLFIRI) in combination with biologic drugs (panitumumab and bevacizumab).

Prior treatment

• History of prior or concurrent central nervous system metastases.
• Treatment for systemic infection < 14 days before the start of study treatment.
• Evidence of previous acute hypersensitivity reaction, of any grade, to any component of the treatment.
• Recent (< 6 months before the start of study treatment) gastroduodenal ulcer active or uncontrolled.
• Recent (< 6 months before the start of study treatment) pulmonary embolism, deep vein thrombosis, or another significant venous event.
• Pre-existing bleeding diathesis and/or coagulopathy with exception of well-controlled anticoagulation therapy (< 6 months before the start of study treatment).
• Recent (< 28 days prior to inclusion in the study) major surgical procedure (excluding diagnostic biopsy, placement of a central venous catheter, colonic stents, or any minor surgery), open biopsy, or significant traumatic injury not yet recovered from prior major surgery.
• History of another primary cancer, except: curatively treated in situ cervical cancer, or curatively resected non-melanoma skin cancer, or other primary solid tumour curatively treated with no known active disease present and no treatment administered for ≥ 5 years before randomization.
• Any investigational agent <30 days prior to inclusion.
• Full dose radiotherapy <28 days prior to inclusion in the study. Short course radiotherapy for local control of primary tumor or other palliative indication is allowed.
• Prior adjuvant chemotherapy for colorectal cancer (stage I, II or III) terminated less than 6 months before metastatic disease was diagnosed.
• Unresolved toxicities of a previous systemic treatment that, in the opinion of the Investigator, make the patient unfit for inclusion.
• Prior approved or experimental antitumoral treatment ≤ 30 days before inclusion.Hormonal sustitutive treatment is allowed.
• Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiating study treatment or history of ventricular arrhythmia.

Other illness

• History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest computed tomography (CT).
• Active acute or subacute intestinal occlusion and/or active inflammatory bowel disease or another bowel disease that causes chronic diarrhoea (defined as grade ≥ 2 diarrhoea according to NCI-CTCAE version 4.03).
• Known mutation in the UGT1A1 gene or known dihydropyrimidine deficiency syndrome.
• History of any disease that may increase the risks associated with study participation or may interfere with the interpretation of study results.
• Known positive test for human immunodeficiency virus infection, hepatitis C virus, and chronic active hepatitis B infection.
• Any disorder that compromises the patient’s ability to provide written informed consent and/or comply with study procedures.
• Psychological, geographical, familiar or sociological conditions that potentially prevent compliance with the study protocol and follow-up schedule.
• Uncontrolled hypertension.

Lab values

• Prior chemotherapy or other systemic anticancer therapy for treatment of metastatic colorectal carcinoma (including adjuvant QT for resected stage IV disease)
• Prior use (as monotherapy or adjuvant treatment) of anti-EGFR antibody therapy (e.g.cetuximab), anti-VEGF or small molecule tyrosine kinase inhibitors (e.g. regorafenib).

Age

• Male or female of childbearing age who do not agree with taking adequate contraceptive precautions, (i.e. use double barrier contraception (such as diaphragm plus condoms) or abstinence during the course of the study and for 6 months after the last administration of study drug for women and men.

Other

• Clinically significant peripheral sensory neuropathy.
• Pregnant or breastfeeding women.
• The patient is unwilling or unable to meet the requirements of the study.

• Man or woman of at least 18 years old.
• Capable to understand, sign and date an informed consent approved by an IEC.
• Histologically confirmed adenocarcinoma of the left colon or rectum (originated in the splenic flexure, descending colon, sigmoid colon, or rectum) in patients with unresectable or non-potentially resectable (not amenable to radical surgery of metastases at the study inclusion) metastatic (M1) disease.
• Patients who had wild-type RAS status confirmed as per standard of care according to international guidelines prior to first-line initiation. *RAS analysis should include at least KRAS exons 2, 3 and 4 (codons 12, 13, 59, 61, 117 and 146) and NRAS exons 2, 3 and 4 (codons 12, 13, 59, 61 and 117)
• At least one measurable lesion per RECIST criteria (version 1.1).
• ECOG performance status < 2.
• Adequate bone marrow function: neutrophils ≥1.5 x109/ L; platelets ≥100 x109/L; haemoglobin ≥9 g/dL.
• Hepatic, renal and metabolic function as follows: - Total bilirubin count ≤1.5 x upper limit of normal (ULN), serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) and serum glutamic oxaloacetic transaminase/aspartate aminotransferase (SGOT/AST) ≤ 2.5 x ULN (5 x ULN for subjects with liver involvement of their cancer) - Renal function, calculated as creatinine clearance or 24-hour creatinine clearance ≥ 50 mL/min.