We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04776655
Recruitment Status : Recruiting
First Posted : March 2, 2021
Last Update Posted : September 16, 2021
Sponsor:
Collaborators:
Istituto Di Ricerche Farmacologiche Mario Negri
Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale
Information provided by (Responsible Party):
Carmine Pinto, Azienda Unità Sanitaria Locale Reggio Emilia

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.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Metastatic Colorectal Cancer RAS Mutation Drug: Bevacizumab Drug: Cetuximab Drug: 5-FU Drug: Irinotecan Drug: Calcium levofolinate Phase 3

Detailed Description:

In this prospective, randomized phase III study, first of all we aim 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.

Patients RAS mut at first liquid biopsy will be randomized with a 1:1 ratio, to receive FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab.

Patients with RAS wt at first biopsy will be treated with FOLFIRI plus cetuximab up to 8 cycles outside the protocol. Patients not progressed after 4 months (8 cycles of treatment) will undergo to a second liquid biopsy. In case of mutation of RAS, the patients will be randomized with a 1:1 ratio to continue cetuximab or to switch to bevacizumab.

The treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, other conditions compromise subject safety or patient refusal.

Plasma samples will be analyzed for mutations of KRAS, NRAS and in BRAF V600 using the Idylla system (Biocartis). Samples will be retrospectively analysed by next generation sequencing using the Oncomine Pan-Cancer Cell-free Assay, which assesses genetic alterations in 52 driver genes, in order to evaluate the possible correlation of tumor heterogeneity with patients' outcome.

With this study we could identify the best monoclonal antibody treatment in mCRC RAS/BRAF wild type on tumor tissue and RAS mutated on liquid biopsy and if liquid biopsy can be used in clinical practice as an integrated analysis to mutational tissue evaluation, to identify RAS mutations not detected on tissue.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Phase III, randomized, open-label, comparative, multi-centre study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase III Study in mCRC Patients With RAS/BRAF Wild Type Tissue and RAS Mutated in LIquid BIopsy to Compare in First-line Therapy FOLFIRI Plus CetuxiMAb or BevacizumaB (LIBImAb Study)
Actual Study Start Date : April 30, 2021
Estimated Primary Completion Date : April 29, 2023
Estimated Study Completion Date : April 29, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Biopsy

Arm Intervention/treatment
Experimental: Bevacizumab in combination with FOLFIRI chemotherapy

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

This is the treatment assigned to experimental arm:

All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.

Other Name: Avastin

Drug: 5-FU

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.

Other Name: 5 Fluorouracil

Drug: Irinotecan

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.

Other Name: Irinotecano

Drug: Calcium levofolinate

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.

Other Name: Levofolinic acid

Active Comparator: Cetuximab in combination with FOLFIRI chemotherapy
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

This is the treatment assigned to control arm:

All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.

Other Name: Erbitux

Drug: 5-FU

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.

Other Name: 5 Fluorouracil

Drug: Irinotecan

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.

Other Name: Irinotecano

Drug: Calcium levofolinate

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.

Other Name: Levofolinic acid




Primary Outcome Measures :
  1. Progression free survival (PFS) in patients with RASmut at liquid biopsy and RASwt on tissue. [ Time Frame: From the date of randomization to the date of first progression or death for any cause, whichever occurs first, assessed up to 36 months ]
    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.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: up to 36 months ]
    Overall survival (OS) defined as the time from start of treatment to the date of death for any cause or, for living patients, the date of last contact.

  2. Objective response rate (ORR) [ Time Frame: up to 36 months ]
    Objective Response Rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR) as best response during treatment as determined by RECIST 1.1.

  3. Prevalence of RAS mutation [ Time Frame: up to 36 months ]
    Percentage of RAS mut patients on the total of patients who undergone to liquid biopsy at the first and second evaluations.

  4. Patients Safety [ Time Frame: up to 36 months ]
    The maximum toxicity grade experienced by each patient, for each toxicity, according to NCI-CTCAE v. 5.0; the number of patients experiencing grade 3-4 toxicity for each toxicity; type, frequency and nature of SAEs; patients with at least a SAE; patients with at least a SADR; patients with at least a SUSAR.

  5. Compliance [ Time Frame: up to 36 months ]
    The compliance to treatment will be described presenting number of administered cycles; frequency and reasons for drug discontinuation and treatment modifications.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of written informed consent;
  2. Male or female > 18 years of age;
  3. Histologically confirmed diagnosis of colorectal adenocarcinoma RAS/BRAF wild type (analysed either on primary and/or related metastasis);
  4. Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease;
  5. Patient with left colorectal cancer;
  6. Patients suitable for first line chemotherapy;
  7. Life expectancy > 3 months;
  8. At least one site of measurable disease per RECIST criteria ver. 1.1;
  9. ECOG Performance status = 2;
  10. Adequate bone marrow, liver and renal function assessed before starting study treatment;
  11. If DPD status is known it must be wild type. No restrictions are applied if DPD status in unknown;
  12. 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.
  13. 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).

Exclusion Criteria:

  1. Previous chemotherapy treatment, with the exception of patient treated in adjuvant setting completed at least 6 months before the randomization;
  2. Any contraindication to the use of Cetuximab, Bevacizumab, Irinotecan, 5FU or folinic acid;
  3. Radiotherapy to any site within 4 weeks before the randomization;
  4. Serious, non-healing wound, ulcer, or bone fracture;
  5. Evidence of bleeding diathesis or coagulopathy;
  6. Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy;
  7. 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;
  8. Active and untreated brain (CNS) metastases and/or carcinomatous meningitis;
  9. Active infection requiring systemic therapy or active disseminated intravascular coagulation;
  10. History of Human Immunodeficiency Virus (HIV) (HIV 1/2 antobodies);
  11. Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection;
  12. Chronic, daily treatment with high-dose aspirin (>325 mg/day);
  13. Any previous venous thromboembolism > NCI CTCAE Grade 3;
  14. 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;
  15. Current, recent (within 10 days prior to study treatment start) or ongoing treatment with anticoagulants for therapeutic purposes;
  16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study;
  17. History of any severe hypersensitivity reactions to any monoclonal antibody;
  18. A significant concomitant disease which, in the investigating physician's opinion, rules out the patient's participation in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04776655


Contacts
Layout table for location contacts
Contact: Carmine Pinto, MD 052295181 ext +39 carmine.pinto@ausl.re.it
Contact: Angela Damato, MD 052296858 angela.damato@ausl.re.it

Locations
Layout table for location information
Italy
Ospedale San Salvatore Recruiting
Coppito, L'Aquila, Italy, 67100
Contact: Corrado Ficorella, MD    +39 0862368761    corrado.ficorella@univaq.it   
Ospedale Civile di Guastalla Recruiting
Guastalla, Reggio Emilia, Italy, 42016
Contact: Giuseppe Prati, MD    0522837219    giuseppe.prati@ausl.re.it   
Azienda ULSS 3 Serenissima Recruiting
Mirano, VE, Italy, 30035
Contact: Giuseppe Azzarello, MD    +39 041 2608482    giuseppe.azzarello@aulss3.veneto.it   
AUSL/IRCCS di Reggio Emilia Recruiting
Reggio Emilia, Italy, 42123
Contact: Carmine Pinto, MD    0522296614    carmine.pinto@ausl.re.it   
Sponsors and Collaborators
Azienda Unità Sanitaria Locale Reggio Emilia
Istituto Di Ricerche Farmacologiche Mario Negri
Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale
Investigators
Layout table for investigator information
Study Chair: Erika Gervasi AUSL IRCCS Reggio Emilia
Study Chair: Irene De Simone Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Layout table for additonal information
Responsible Party: Carmine Pinto, Director, Azienda Unità Sanitaria Locale Reggio Emilia
ClinicalTrials.gov Identifier: NCT04776655    
Other Study ID Numbers: 2020-005078-82
First Posted: March 2, 2021    Key Record Dates
Last Update Posted: September 16, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Carmine Pinto, Azienda Unità Sanitaria Locale Reggio Emilia:
mCRC
liquid biopsy
RAS
Additional relevant MeSH terms:
Layout table for MeSH terms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Bevacizumab
Cetuximab
Fluorouracil
Irinotecan
Calcium
Levoleucovorin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Calcium-Regulating Hormones and Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents