Status:
UNKNOWN
Valproic Acid in Combination With Bevacizumab and Oxaliplatin/Fluoropyrimidine Regimens in Patients With Ras-mutated Metastatic Colorectal Cancer
Lead Sponsor:
National Cancer Institute, Naples
Conditions:
Ras-mutated Metastatic Colorectal Cancer
Eligibility:
All Genders
18+ years
Phase:
PHASE2
Brief 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 (PF...
Detailed Description
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. Th...
Eligibility Criteria
Inclusion
- 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.
Exclusion
Key Trial Info
Start Date :
May 24 2019
Trial Type :
INTERVENTIONAL
Allocation :
ESTIMATED
End Date :
November 1 2024
Estimated Enrollment :
200 Patients enrolled
Trial Details
Trial ID
NCT04310176
Start Date
May 24 2019
End Date
November 1 2024
Last Update
November 13 2023
Active Locations (1)
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1
Istituto Tumori di Napoli - Fondazione G. Pascale
Napoli, Campania, Italy, 80131