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

Randomized Phase 2 Study of Valproic Acid in Combination With Bevacizumab and Oxaliplatin/Fluoropyrimidine Regimens in Patients With Ras-mutated Metastatic Colorectal Cancer

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.

Study Overview

• Status: Recruiting
• Conditions: Ras-mutated Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Bevacizumab; Drug: mFOLFOX6 regimen; Drug: mOXXEL regimen; Drug: Capecitabine; Drug: 5-fluorouracil; Drug: Valproic acid

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.

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.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Antonio Avallone, MD; Phone Number: +39 081 590 3629; Email: a.avallone@istitutotumori.na.it
• Study Contact Backup: Name: Maria Carmela Piccirillo, MD; Phone Number: +39 081 590 3615; Email: m.piccirillo@stitutotumori.na.it

Study Locations

• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • Recruiting
      • Istituto Tumori di Napoli - Fondazione G. Pascale
      • Principal Investigator: Antonio Avallone, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard; Chemotherapy (mFOLFOX-6/mOXELL) + Bevacizumab for 12 cycles (24 weeks) Maintenance treatment (Standard): Fluoropyrimidines (5-Fluorouracil/Capecitabine) + Bevacizumab until disease progression or unacceptable toxicity	Drug: Bevacizumab; 5 mg/m2 as 20-to-30 minute intravenous (i.v.) infusion every two weeks. Maintenance treatment (both arms): 5 mg/m2 every 2 weeks (in combination with 5-Fluorouracil) or 7.5 mg/m2 every 3 weeks (in combination with capecitabine); Drug: mFOLFOX6 regimen; Oxaliplatin 85 mg/m2 as 2-3 hours i.v. infusion on day 1 followed by levo-folinic acid 200 mg/m2 as 1- 2 hours i.v. infusion followed by i.v bolus. 5-fluorouracil 400 mg/m2, and a 46-hour i.v. infusion of 5-fluorouracil 2400 mg/m2 every two week; Drug: mOXXEL regimen; Oxaliplatin 85 mg/m2 as 2-3 hours i.v. infusion on day 1 plus oral capecitabine 1000 mg/m2 twice daily on days 1 to 10, every 2 weeks; Drug: Capecitabine; Maintenance treatment (both arms): 1250 mg/m2 twice daily on days 1 to 14, every 3 weeks or 1250 mg/m2 twice daily on days 1 to 10, every 2 weeks; Drug: 5-fluorouracil; Maintenance treatment (both arms): Levo-folinic acid 200 mg/m2 as 1- 2 hours i.v. infusion followed by i.v bolus. 5-fluorouracil 400 mg/m2, and a 46-hour i.v. infusion of 5-fluorouracil 2400 mg/m2 every two weeks
Experimental: Experimental; Chemotherapy (mFOLFOX-6/mOXELL) + Bevacizumab + Valproic Acid administered oral daily from day -14 increasing doses and an intra-patient titration for a target serum level of 50-100µg/ml for 12 cycles (24 weeks) Maintenance treatment (Experimental): Fluoropyrimidines (5-Fluorouracil/Capecitabine) + Bevacizumab + Valproic Acid until disease progression or unacceptable toxicity	Drug: Bevacizumab; 5 mg/m2 as 20-to-30 minute intravenous (i.v.) infusion every two weeks. Maintenance treatment (both arms): 5 mg/m2 every 2 weeks (in combination with 5-Fluorouracil) or 7.5 mg/m2 every 3 weeks (in combination with capecitabine); Drug: mFOLFOX6 regimen; Oxaliplatin 85 mg/m2 as 2-3 hours i.v. infusion on day 1 followed by levo-folinic acid 200 mg/m2 as 1- 2 hours i.v. infusion followed by i.v bolus. 5-fluorouracil 400 mg/m2, and a 46-hour i.v. infusion of 5-fluorouracil 2400 mg/m2 every two week; Drug: mOXXEL regimen; Oxaliplatin 85 mg/m2 as 2-3 hours i.v. infusion on day 1 plus oral capecitabine 1000 mg/m2 twice daily on days 1 to 10, every 2 weeks; Drug: Capecitabine; Maintenance treatment (both arms): 1250 mg/m2 twice daily on days 1 to 14, every 3 weeks or 1250 mg/m2 twice daily on days 1 to 10, every 2 weeks; Drug: 5-fluorouracil; Maintenance treatment (both arms): Levo-folinic acid 200 mg/m2 as 1- 2 hours i.v. infusion followed by i.v bolus. 5-fluorouracil 400 mg/m2, and a 46-hour i.v. infusion of 5-fluorouracil 2400 mg/m2 every two weeks; Drug: Valproic acid; given orally from 500mg-1500mg daily and an intra-patient titration for a target serum level of 50-100µg/ml

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression-free survival (PFS)	PFS is defined as the time elapsed from the date of randomization to the date of progression, as defined by investigators, or the date of death, whichever comes first	until progression of disease (up to 5 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
centrally reviewed PFS (CR-PFS)	FSCR is also measured as the time elapsed from the date of randomization to the date of progression, as defined by independent blind central review, or the date of death, whichever comes first	at week 12th and 24th and thereafter every 12 weeks until progression of disease (up to 5 years(
overall survival (OS)	OS is defined as the time elapsed from randomization to death due to any cause	5 years
Determination of changes in quality of life	EORTC QLQ-C30, a quality of life questionnaires, composed by 30 items graded from1 (not at all) to 4 (very much) after 1 year from the diagnosis	at baseline, at week 12th and 24th and every 12 weeks thereafter until progression disease (up to 5 years)
Response rate	according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1	at week 12th and 24th and thereafter every 12 weeks until progression of disease (up to 5 years)
Number of participants with treatment-related side effects	graded according to Common Criteria for Adverse Events (CTCAE) version 5.0	baseline, day 1 of each cycle and on maintenance treatment until progression disease (up to 5 years)
metastases resection rate (R0/R1/R2)	determined at surgery (resection status) by pathologist follow: R0 no cancer cells at the resection margin; R1 microscopic positive margin, R2 macroscopic positive margin	up to 24 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute, Naples
• Investigators: Principal Investigator: Antonio Avallone, MD, National Cancer Institute, Napoli; Study Chair: Maria Carmela Piccirillo, MD, National Cancer Institute, Napoli; Study Chair: Alfredo Budillon, MD, National Cancer Institute, Napoli

Publications and helpful links

General Publications

• Avallone A, Piccirillo MC, Di Gennaro E, Romano C, Calabrese F, Roca MS, Tatangelo F, Granata V, Cassata A, Cavalcanti E, Maurea N, Maiolino P, Silvestro L, De Stefano A, Giuliani F, Rosati G, Tamburini E, Aprea P, Vicario V, Nappi A, Vitagliano C, Casaretti R, Leone A, Petrillo A, Botti G, Delrio P, Izzo F, Perrone F, Budillon A. Randomized phase II study of valproic acid in combination with bevacizumab and oxaliplatin/fluoropyrimidine regimens in patients with RAS-mutated metastatic colorectal cancer: the REVOLUTION study protocol. Ther Adv Med Oncol. 2020 Aug 11;12:1758835920929589. doi: 10.1177/1758835920929589. eCollection 2020.

Helpful Links

• sponsor web-site for study conduction

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2019
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): November 1, 2024

Study Registration Dates

• First Submitted: November 25, 2019
• First Submitted That Met QC Criteria: March 12, 2020
• First Posted (Actual): March 17, 2020

Study Record Updates

• Last Update Posted (Actual): March 27, 2023
• Last Update Submitted That Met QC Criteria: March 23, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Metastatic colorectal cancer; Valproic acid; Ras mutations
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Fluorouracil; Capecitabine; Bevacizumab; Valproic Acid
• Other Study ID Numbers: REVOLUTIOn; 2018-001414-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No