Overview
Sponsor-declared trial summary
Phase
Therapeutic exploratory (Phase II)
Status
Ongoing, recruitment ended
Participants planned
200
Countries
1
Sites
8
Patients with ras-mutated metastatIc colorectal cancer
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 wit…
Key facts
- Sponsor
- IRCCS Istituto Nazionale Tumori Fondazione Pascale
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Neoplasms [C04]
- Trial duration
- 3 Jan 2019 → ongoing
- Decision date (initial)
- 2024-12-09
- Transition trial
- Yes
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- Yes
External identifiers
- EU CT number
- 2024-516844-25-01
- EudraCT number
- 2018-001414-15
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Pharmacogenomic, Therapy, Efficacy, Safety
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.
Secondary objectives 1
- • To compare the two arms in terms of: - centrally reviewed PFS (CR-PFS) - overall survival (OS) - quality of life (EORTC QLQ C30 + CR 29) - objective response rate (RECIST1.1) - adverse events (CTCAE 4.03 version) - metastases resection rate (R0/R1/R2) • To evaluate mechanistically –based pharmacokinetic/pharmacodynamic biomarkers on blood samples • To explore prognostic factors and predictive biomarkers on blood samples, primary tumors, and on resected metastases
Conditions and MedDRA coding
Patients with ras-mutated metastatIc colorectal cancer
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | LLT | 10007446 | Carcinoma of rectum | 10029104 |
Regulatory references
- Plan to share IPD
- No
| EU CT number | Title | Sponsor |
|---|---|---|
| 2024-516844-25-00 | REVOLUTION - Randomized phasE 2 study of Valproic acid in combination with bevacizumab and Oxaliplatin/fLUoropyrimidine regimens in patients with ras-mutated metastaTIc cOlorectal caNcer | IRCCS Istituto Nazionale Tumori Fondazione Pascale |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 1
- • Age = 18 • 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 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 1
- • Tumors without RAS mutations • Prior chemotherapy or any other medical treatment for advanced mCRC (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) • 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) • 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 • Known dihydropyrimidine dehydrogenase (DPD) deficiency • Pregnancy or nursing • Concomitant pathologies or laboratory alterations or concomitant medications use that prevent or contraindicate the use of study drugs • Brain metastases
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- PFS progression-free survival
Secondary endpoints 1
- centrally reviewed PFS (CR-PFS)
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 1
ACIDO VALPROICO E SODIO VALPROATO ratiopharm 500 mg compresse a rilascio prolungato
PRD1904142 · Product
- Active substance
- Valproic Acid
- Pharmaceutical form
- PROLONGED-RELEASE TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 500 mg milligram(s)
- Max total dose
- 500 mg milligram(s)
- Max treatment duration
- 24 Week(s)
- Authorisation status
- Authorised
- ATC code
- N03AG01 — VALPROIC ACID
- Marketing authorisation
- 037839192
- MA holder
- RATIOPHARM GMBH
- MA country
- Italy
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Comparator 4
Capecitabina Glenmark 150 mg comprimidos recubiertos con película EFG
PRD10095269 · Product
- Active substance
- Capecitabine
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 1650 mg/m2 milligram(s)/sq. meter
- Max total dose
- 1650 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 24 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01BC06 — CAPECITABINE
- Marketing authorisation
- 84871
- MA holder
- GLENMARK ARZNEIMITTEL GMBH
- MA country
- Spain
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Avastin 25 mg/ml concentrate for solution for infusion.
PRD2153902 · Product
- Active substance
- Bevacizumab
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 7.5 mg/Kg milligram(s)/kilogram
- Max total dose
- 7.5 mg/kg milligram(s)/kilogram
- Max treatment duration
- 24 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01FG01 — -
- Marketing authorisation
- EU/1/04/300/002
- MA holder
- ROCHE REGISTRATION GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
FLUOROURACILE PFIZER 50 mg/mL, solution à diluer pour perfusion
PRD423054 · Product
- Active substance
- Fluorouracil
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 2800 mg/m2 milligram(s)/sq. meter
- Max total dose
- 2800 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 24 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01BC02 — FLUOROURACIL
- Marketing authorisation
- 34009 572 531 1 0
- MA holder
- PFIZER HOLDING FRANCE
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Oxaliplatino Accord 5 mg/ml concentrato per soluzione per infusione
PRD3332505 · Product
- Active substance
- Oxaliplatin
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 85 mg/m2 milligram(s)/sq. meter
- Max total dose
- 85 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 24 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XA03 — OXALIPLATIN
- Marketing authorisation
- 041274022
- MA holder
- ACCORD HEALTHCARE S.L.U.
- MA country
- Italy
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
IRCCS Istituto Nazionale Tumori Fondazione Pascale
- Sponsor organisation
- IRCCS Istituto Nazionale Tumori Fondazione Pascale
- Address
- Via Mariano Semmola 52
- City
- Naples
- Postcode
- 80131
- Country
- Italy
Scientific contact point
- Organisation
- IRCCS Istituto Nazionale Tumori Fondazione Pascale
- Contact name
- Maria Carmela Piccirillo
Public contact point
- Organisation
- IRCCS Istituto Nazionale Tumori Fondazione Pascale
- Contact name
- Maria Carmela Piccirillo
Locations
1 EU/EEA country · 8 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Italy | Ongoing, recruitment ended | 200 | 8 |
| Rest of world | — | 0 | — |
Investigational sites
Casa di Cura Macchiarella-Palermo
Oncologia, Viale Regina Margherita, 25, Palermo
IRCCS Istituto Nazionale Tumori Fondazione Pascale
SC Oncologia Clinica Sperimentale Addome, Via Mariano Semmola 52, 80131, Naples
Azienda Unita Locale Socio Sanitaria N 8 Berica
SC Oncologia, Viale Ferdinando Rodolfi 37, 36100, Vicenza
Istituto Tumori Bari Giovanni Paolo II
SC Oncologia Medica, Viale Orazio Flacco 65, 70124, Bari
Presidio Ospedaliero Santa Maria delle Grazie
Oncologia, Via domitiana, 80078, Località la Schiana, Pozzuoli (NA)
Pia Fondazione Di Culto E Religione Card G Panico
SC Oncologia, Via Pio X 4, 73039, Tricase
Azienda Ospedaliera Regionale San Carlo
SC Oncologia Medica, Via Potito Petrone, 85100, Potenza
Azienda Ospedaliero Universitaria Ospedali Riuniti
SSD Oncologia Medica e Terapia Biomolecolare, Viale Luigi Pinto 1, 71122, Foggia
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Italy | 2019-01-03 | 2019-05-24 | 2025-09-09 |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 8 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | Emend 1- Protocol REVOLUTION v1 del 25Jun2019 for pubblication | 1 |
| Recruitment arrangements (for publication) | BLANK DOCUMENT | 1 |
| Subject information and informed consent form (for publication) | Emend 1 - Informativa e consenso studio-studio biologico Revolution vers 1 del 25-06-2019 | 1 |
| Subject information and informed consent form (for publication) | Emend 1- Consenso tratt dati pers Revolution vers 1 del 25-06-2019 - for pubblication | 1 |
| Subject information and informed consent form (for publication) | Emend 1- Lettera medico curante Revolution vers1 del 25-06-2019 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | RCP fluorouracile | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | RCP oxaliplatino | 1 |
| Synopsis of the protocol (for publication) | Emend 1 Sinossi Revolution ver 1 del 25-06-2019 - for pubblication | 1 |
Application history
3 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-10-29 | Italy | Acceptable 2024-11-14
|
2024-12-09 |
| 2 | NON SUBSTANTIAL MODIFICATION | NSM-2 | 2025-07-17 | Italy | Acceptable 2024-11-14
|
2025-07-17 |
| 3 | NON SUBSTANTIAL MODIFICATION | NSM-3 | 2025-07-22 | Italy | Acceptable 2024-11-14
|
2025-07-22 |