Valproic Acid in Combination With Bevacizumab and Oxaliplatin/Fluoropyrimidine Regimens in Patients With Ras-mutated Metastatic Colorectal Cancer

Inclusion criteria * Age \>=18 years * Histologically confirmed diagnosis of colorectal adenocarcinoma * Stage IV of disease (according to TNM 8th edition) * RAS mutations * Clinical or radiologic evidence of disease (at least one target or non target lesion according to RECIST 1.1) * ECOG performance status 0 to 1 * Life expectancy \> 3 months * Use of an acceptable mean of contraception for men and women of childbearing potential * Adequate recovery from previous surgery. At least 28 days should elapse from a surgical procedure or from performing a biopsy for the enrolment into the study * Written informed consent Exclusion criteria Cancer related * RAS wild type colorectal cancer Prior, current or planned treatment related * Prior chemotherapy or any other medical treatment for advanced colorectal cancer (previous adjuvant chemotherapy is allowed if ended \> 6 months before relapse or \> 24 months if the adjuvant treatment included oxaliplatin) * Radiotherapy to any site for any reason within 28 days prior to randomization (palliative radiotherapy to bone lesions is allowed if \>=14 days before randomization) * Patient who have had prior treatment with an HDAC inhibitor and patients who have received compounds with HDAC inhibitor like activity, such as valproic acid * Full dose anticoagulation with warfarin * Current or recent (within the last 10 days) use of aspirin (\>325 mg/day) or chronic use of other full dose nonsteroidal antiinflammatory drugs (NSAIDs) with antiplatelet activity Laboratory related * Inadequate coagulation parameters: * activated partial thromboplastin time (APTT) \>1.5 x or the upper limit of normal (ULN) or * INR \>1.5 * Inadequate liver function, defined as: * AST/SGOT or ALT/SGPT \>2.5 x ULN e/o serum (total) bilirubin \>1.5 xULN for the institution * AST/SGOT or ALT/SGPT \>5 x ULN e/o serum (total) bilirubin \> 3 xULN for the institution in case of liver metastases. * Inadequate renal function, defined as: * Creatinine clearance \< 50 mL/min or serum creatinine \>1.5 x ULN for the institution * urine dipstick for proteinuria \>2pos. Patients with 1pos proteinuria at baseline dipstick analysis should undergo a 24hour urine collection and must demonstrate \<=1g of protein in their 24hour urine collection * Inadequate bone marrow function, defined as: * Neutrophils \< 2000/mm3 * Platelets \< 100.000/ mm3 * Hemoglobin (Hgb) \< 9 g/dL Prior or concomitant conditions or procedures related * Known dihydropyrimidine dehydrogenase (DPD) deficiency * Pregnancy or breastfeeding * Inadequately controlled hypertension (defined as systolic blood pressure \>150 and/or diastolic blood pressure \>100 mmHg on antihypertensive medications) * History of any of the following within 6 months prior to randomisation: serious systemic disease, unstable angina, New York Heart Association (NYHA) Grade 2 or greater Congestive Heart Failure (CHF), clinically significant peripheral vascular disease, abdominal fistula, gastrointestinal perforation, or intra abdominal abscess * History of arrhythmia, bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. * Patients with long QT syndrome or QTc interval duration \> 480 msec or concomitant medication with drugs prolonging QTc (see list in the appendix) * Serious, non healing wound, ulcer, or bone fracture * History of inflammatory bowel disease or active disease * Evidence of bleeding diathesis or coagulopathy or other serious or acute internal bleeding within 6 months prior to randomization * Central Nervous System (CNS) bleeding; history or clinical evidence of CNS stroke (hemorrhagic or thrombotic) within the last 6 months * Inpatient surgical procedure, or significant traumatic injury within 28 days prior to randomization * Minor surgical procedure, fine needle aspirations or core biopsy within 7 days prior to randomization * Inability to take oral medication or requirement for intravenous (IV) alimentation or total parenteral nutrition with lipids, or prior surgical procedures affecting absorption * Evidence of confusion or disorientation, or history of major psychiatric illness that may impair the patient's understanding of the Informed Consent Form or their ability to comply with study requirements * Any other invasive malignancies within 5 years (except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer or surgically resected prostate cancer with normal PSA) * Brain metastasis * HIV positive patients * Any other concomitant pathologies or laboratory alterations that prevent or contraindicate the use of study drugs.