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

NCT04310176 | Unknown Phase 2 DMC

• 2 other identifiers: REVOLUTION2018-001414-15
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

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 (PFS) as compared with bevacizumab and oxaliplatin/fluoropyrimidine regimens alone as first-line treatment in patients with metastatic colorectal cancer with mutation of RAS.

Conditions

Ras-mutated Metastatic Colorectal Cancer

Keywords

Metastatic colorectal cancer; Ras mutations; Valproic acid

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• centrally reviewed PFS (CR-PFS)

  at week 12th and 24th and thereafter every 12 weeks until progression of disease (up to 5 years(

• overall survival (OS)

  5 years

• Determination of changes in quality of life

  at baseline, at week 12th and 24th and every 12 weeks thereafter until progression disease (up to 5 years)

• Response rate

  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

  baseline, day 1 of each cycle and on maintenance treatment until progression disease (up to 5 years)

Study Arms (2)

Standard

ACTIVE COMPARATOR

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; Drug: mFOLFOX6 regimen; Drug: mOXXEL regimen; Drug: Capecitabine; Drug: 5-fluorouracil

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; Drug: mFOLFOX6 regimen; Drug: mOXXEL regimen; Drug: Valproic acid; Drug: Capecitabine; Drug: 5-fluorouracil

Interventions

Bevacizumab DRUG

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)

Experimental; Standard

mFOLFOX6 regimen DRUG

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

Experimental; Standard

mOXXEL regimen DRUG

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

Experimental; Standard

Valproic acid DRUG

given orally from 500mg-1500mg daily and an intra-patient titration for a target serum level of 50-100µg/ml

Experimental

Capecitabine DRUG

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

Experimental; Standard

5-fluorouracil DRUG

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; Standard

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute, Naples: lead

Study Sites (1)

Istituto Tumori di Napoli - Fondazione G. Pascale

Napoli, Campania, 80131, Italy

RECRUITING

Related Publications (1)

• 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.

  PMID: 32849914 DERIVED

Related Links

• sponsor web-site for study conduction

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Bevacizumab; Valproic Acid; Capecitabine; Fluorouracil

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Antonio Avallone, MD

  National Cancer Institute, Napoli

  PRINCIPAL INVESTIGATOR

• Maria Carmela Piccirillo, MD

  National Cancer Institute, Napoli

  STUDY CHAIR

• Alfredo Budillon, MD

  National Cancer Institute, Napoli

  STUDY CHAIR

Central Study Contacts

Antonio Avallone, MD

CONTACT

+39 081 590 3629; a.avallone@istitutotumori.na.it

Maria Carmela Piccirillo, MD

CONTACT

+39 081 590 3615; m.piccirillo@stitutotumori.na.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2019
• First Posted: March 17, 2020
• Study Start: May 24, 2019
• Primary Completion: December 1, 2023
• Study Completion: November 1, 2024
• Last Updated: November 13, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)