The primary aim of this study is to test whether the combination of valproic acid with bevacizumab and oxaliplatin/fluoropyrimidine regimens (mFOLFOX6/mOXXEL) can prolong progression free survival (PFS) as compared with bevacizumab and oxaliplatin/fluoropyrimidine regimens alone as first-line treatment in patients with metastatic colorectal cancer with mutation of RAS.

Patients will be randomized 1:1 to receive oxaliplatin based chemotherapy (mFOLFOX6/mOXELL) plus bevacizumab for 12 cycles or the same chemotherapy plus bevacizumab and valproic acid for 12 cycle.

Thereafter, in both arms, patients who are progression free after 12 cycles (24 weeks) of treatment continue maintenance bevacizumab+fluoropyrimidines until disease progression or unacceptable toxicity.

Surgery may be carried out in case of appropriate tumour reduction is evident at response evaluation. Resectability has to be evaluated by a multidisciplinary review team and the decision regarding post-surgery chemotherapy is at the discretion of the investigators, according to the policy commonly adopted by their Institution in clinical practice.

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.