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

Primary Purpose

Ras-mutated Metastatic Colorectal Cancer

Status

Recruiting

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

Bevacizumab

mFOLFOX6 regimen

mOXXEL regimen

Valproic acid

Capecitabine

5-fluorouracil

About this trial

This is an interventional treatment trial for Ras-mutated Metastatic Colorectal Cancer focused on measuring Metastatic colorectal cancer, Ras mutations, Valproic acid

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Istituto Tumori di Napoli - Fondazione G. PascaleRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard

Experimental

Arm Description

Chemotherapy (mFOLFOX-6/mOXELL) + Bevacizumab for 12 cycles (24 weeks) Maintenance treatment (Standard): Fluoropyrimidines (5-Fluorouracil/Capecitabine) + Bevacizumab until disease progression or unacceptable toxicity

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

overall survival (OS)

OS is defined as the time elapsed from randomization to death due to any cause

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

Response rate

according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Number of participants with treatment-related side effects

graded according to Common Criteria for Adverse Events (CTCAE) version 5.0

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

Full Information

NCT ID

NCT04310176

First Posted

November 25, 2019

Last Updated

March 23, 2023

Sponsor

National Cancer Institute, Naples

1. Study Identification

Unique Protocol Identification Number

NCT04310176

Brief Title

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

Acronym

REVOLUTION

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

May 24, 2019 (Actual)

Primary Completion Date

June 2023 (Anticipated)

Study Completion Date

November 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Cancer Institute, Naples

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ras-mutated Metastatic Colorectal Cancer

Keywords

Metastatic colorectal cancer, Ras mutations, Valproic acid

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

200 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Standard

Arm Type

Active Comparator

Arm Description

Arm Title

Experimental

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Bevacizumab

Intervention Description

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)

Intervention Type

Drug

Intervention Name(s)

mFOLFOX6 regimen

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

mOXXEL regimen

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Valproic acid

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Capecitabine

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

5-fluorouracil

Intervention Description

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

Primary Outcome Measure Information:

Title

progression-free survival (PFS)

Description

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

Time Frame

until progression of disease (up to 5 years)

Secondary Outcome Measure Information:

Title

centrally reviewed PFS (CR-PFS)

Description

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

Time Frame

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

Title

overall survival (OS)

Description

OS is defined as the time elapsed from randomization to death due to any cause

Time Frame

5 years

Title

Determination of changes in quality of life

Description

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

Time Frame

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

Title

Response rate

Description

according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Time Frame

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

Title

Number of participants with treatment-related side effects

Description

graded according to Common Criteria for Adverse Events (CTCAE) version 5.0

Time Frame

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

Title

metastases resection rate (R0/R1/R2)

Description

determined at surgery (resection status) by pathologist follow: R0 no cancer cells at the resection margin; R1 microscopic positive margin, R2 macroscopic positive margin

Time Frame

up to 24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Antonio Avallone, MD

Phone

+39 081 590 3629

a.avallone@istitutotumori.na.it

First Name & Middle Initial & Last Name or Official Title & Degree

Maria Carmela Piccirillo, MD

Phone

+39 081 590 3615

m.piccirillo@stitutotumori.na.it

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Antonio Avallone, MD

Organizational Affiliation

National Cancer Institute, Napoli

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Maria Carmela Piccirillo, MD

Organizational Affiliation

National Cancer Institute, Napoli

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Alfredo Budillon, MD

Organizational Affiliation

National Cancer Institute, Napoli

Official's Role

Study Chair

Facility Information:

Facility Name

Istituto Tumori di Napoli - Fondazione G. Pascale

City

Napoli

State/Province

Campania

ZIP/Postal Code

80131

Country

Italy

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Antonio Avallone, MD

Phone

+390815903629

a.avallone@istitutotumori.na.it

First Name & Middle Initial & Last Name & Degree

Antonio Avallone, MD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

32849914

Citation

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.

Results Reference

derived

Links:

URL

https://usc.istitutotumori.na.it/

Description

sponsor web-site for study conduction

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

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