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.