Study in mCRC Patients RAS/BRAF wt Tissue and RAS Mutated LIquid BIopsy to Compare FOLFIRI Plus CetuxiMAb or BevacizumaB

NCT04776655 | Recruiting Phase 3 DMC

• 1 other identifier: 2020-005078-82
• Study Type: interventional
• Target: 280
• Locations: 1 country
• Sites: 4

Brief Summary

This study is a prospective, randomized phase III, to evaluate if in patients with mCRC RAS/BRAF wild type on tumor tissue and RAS mutations on liquid biopsy, treating in first line with antibody anti-VEGF (bevacizumab) plus chemotherapy (FOLFIRI) is superior in terms of PFS compared to standard treatment with antibody anti-EGFR (cetuximab) plus FOLFIRI, and then in patients RAS/BRAF wild type on tumor tissue who develop RAS mutations on liquid biopsy after the beginning of the first line treatment with cetuximab plus FOLFIRI, in the absence of a clinical or radiological progression disease, to anticipate a change of treatment with bevacizumab plus FOLFIRI further impacts on the PFS.

Conditions

Colorectal Cancer; Metastatic Colorectal Cancer; RAS Mutation

Keywords

mCRC; liquid biopsy; RAS

Outcome Measures

Primary Outcomes (1)

• Progression free survival (PFS) in patients with RASmut at liquid biopsy and RASwt on tissue.

  The primary objective of the study is to assess whether the combination of bevacizumab plus chemotherapy is superior to cetuximab plus chemotherapy in terms of progression free survival (PFS) in patients with RASmut at liquid biopsy and RASwt on tissue.

  From the date of randomization to the date of first progression or death for any cause, whichever occurs first, assessed up to 36 months

Secondary Outcomes (5)

• Overall survival (OS)

  up to 36 months

• Objective response rate (ORR)

  up to 36 months

• Prevalence of RAS mutation

  up to 36 months

• Patients Safety

  up to 36 months

• Compliance

  up to 36 months

Study Arms (2)

Bevacizumab in combination with FOLFIRI chemotherapy

EXPERIMENTAL

Bevacizumab will be administrered at a dose of 5 mg/kg iv every 2 weeks. The first dose of Bevacizumab will be administered over 90 minutes. Then, if the first infusion is well tolerated without infusion-related reaction, the second dose will be administered over 60 minutes. Then, if the second dose is also well tolerated without an infusion reaction, all subsequent doses will be administered over 30 minutes. Dosage form: Intravenous use All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.

Drug: Bevacizumab; Drug: 5-FU; Drug: Irinotecan; Drug: Calcium levofolinate

Cetuximab in combination with FOLFIRI chemotherapy

ACTIVE COMPARATOR

Cetuximab will be administered at a dose of 500 mg/m² iv every 2 week (14 days/cycle) Dosage form: Intravenous use All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.

Drug: Cetuximab; Drug: 5-FU; Drug: Irinotecan; Drug: Calcium levofolinate

Interventions

Bevacizumab DRUG

This is the treatment assigned to experimental arm: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.

Also known as: Avastin

Bevacizumab in combination with FOLFIRI chemotherapy

Cetuximab DRUG

This is the treatment assigned to control arm: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.

Also known as: Erbitux

Cetuximab in combination with FOLFIRI chemotherapy

5-FU DRUG

FOLFIRI regimen: This is the treatment assigned to control and to experimental arms: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.

Also known as: 5 Fluorouracil

Bevacizumab in combination with FOLFIRI chemotherapy; Cetuximab in combination with FOLFIRI chemotherapy

Irinotecan DRUG

FOLFIRI regimen: This is the treatment assigned to control and to experimental arms: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.

Also known as: Irinotecano

Bevacizumab in combination with FOLFIRI chemotherapy; Cetuximab in combination with FOLFIRI chemotherapy

Calcium levofolinate DRUG

FOLFIRI regimen: This is the treatment assigned to control and to experimental arms: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.

Also known as: Levofolinic acid

Bevacizumab in combination with FOLFIRI chemotherapy; Cetuximab in combination with FOLFIRI chemotherapy

Eligibility Criteria

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

You may qualify if:

• Provision of written informed consent;
• Male or female \> 18 years of age;
• Histologically confirmed diagnosis of colorectal adenocarcinoma RAS/BRAF wild type (analysed either on primary and/or related metastasis);
• Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease;
• Patient with left colorectal cancer;
• Patients suitable for first line chemotherapy;
• Life expectancy \> 3 months;
• At least one site of measurable disease per RECIST criteria ver. 1.1;
• ECOG Performance status = 2;
• Adequate bone marrow, liver and renal function assessed before starting study treatment;
• If DPD status is known it must be wild type. No restrictions are applied if DPD status in unknown;
• Women of childbearing potential must have a negative blood pregnancy test within 24 hr prior to the start of study treatment. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive.
• Subjects and their partners must be willing to avoid pregnancy during the trial and until 5 months for WOCBP (Women of Childbearing Potential) and 7 months for male subjects with female partners of WOCBP after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator (barriers contraceptive measure or oral contraception).

You may not qualify if:

• Previous chemotherapy treatment, with the exception of patient treated in adjuvant setting completed at least 6 months before the randomization;
• Any contraindication to the use of Cetuximab, Bevacizumab, Irinotecan, 5FU or folinic acid;
• Radiotherapy to any site within 4 weeks before the randomization;
• Serious, non-healing wound, ulcer, or bone fracture;
• Evidence of bleeding diathesis or coagulopathy;
• Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy;
• Additional malignancy in the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy;
• Active and untreated brain (CNS) metastases and/or carcinomatous meningitis;
• Active infection requiring systemic therapy or active disseminated intravascular coagulation;
• History of Human Immunodeficiency Virus (HIV) (HIV 1/2 antobodies);
• Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection;
• Chronic, daily treatment with high-dose aspirin (\>325 mg/day);
• Any previous venous thromboembolism \> NCI CTCAE Grade 3;
• History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment. History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea;
• Current, recent (within 10 days prior to study treatment start) or ongoing treatment with anticoagulants for therapeutic purposes;

Sponsors & Collaborators

• Azienda USL Reggio Emilia - IRCCS: lead
• Istituto Di Ricerche Farmacologiche Mario Negri: collaborator
• Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale: collaborator

Study Sites (4)

Ospedale San Salvatore

Coppito, L'Aquila, 67100, Italy

RECRUITING

Ospedale Civile di Guastalla

Guastalla, Reggio Emilia, 42016, Italy

RECRUITING

AUSL/IRCCS di Reggio Emilia

Reggio Emilia, Reggio Emilia, 42123, Italy

RECRUITING

Azienda ULSS 3 Serenissima

Mirano, VE, 30035, Italy

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Bevacizumab; Cetuximab; Fluorouracil; Irinotecan; Leucovorin

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; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Camptothecin; Alkaloids; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes

Study Officials

• Erika Gervasi

  AUSL IRCCS Reggio Emilia

  STUDY CHAIR

• Irene De Simone

  Istituto Di Ricerche Farmacologiche Mario Negri

  STUDY CHAIR

Central Study Contacts

Carmine Pinto, MD

CONTACT

052295181; carmine.pinto@ausl.re.it

Angela Damato, MD

CONTACT

052296858; angela.damato@ausl.re.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: Phase III, randomized, open-label, comparative, multi-centre study

Study Record Dates

• First Submitted: February 23, 2021
• First Posted: March 2, 2021
• Study Start: April 30, 2021
• Primary Completion: May 4, 2025
• Study Completion: May 4, 2026
• Last Updated: October 2, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

IT (4)