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

• Status: Recruiting
• Trial end date: 2022-11-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Cancer Institute, Naples
• Treatments: Bevacizumab; Capecitabine; Fluorouracil; Oxaliplatin; Valproic Acid

Criteria

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.