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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Cancer; Colorectal Cancer; RAS Mutation
• Intervention / Treatment: Drug: Bevacizumab; Drug: 5-FU; Drug: Irinotecan; Drug: Calcium levofolinate; Drug: Cetuximab

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.

• Study Type: Interventional
• Enrollment (Anticipated): 280
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Carmine Pinto, MD; Phone Number: +39 052295181; Email: carmine.pinto@ausl.re.it
• Study Contact Backup: Name: Angela Damato, MD; Phone Number: 052296858; Email: angela.damato@ausl.re.it

Study Locations

• Italy
  • Reggio Emilia, Italy, 42123
    • Recruiting
    • AUSL/IRCCS di Reggio Emilia
  • L'Aquila
    • Coppito, L'Aquila, Italy, 67100
      • Recruiting
      • Ospedale San Salvatore
      • Contact: Corrado Ficorella, MD; Phone Number: +39 0862368761; Email: corrado.ficorella@univaq.it
  • Reggio Emilia
    • Guastalla, Reggio Emilia, Italy, 42016
      • Recruiting
      • Ospedale Civile di Guastalla
      • Contact: Giuseppe Prati, MD; Phone Number: 0522837219; Email: giuseppe.prati@ausl.re.it
  • VE
    • Mirano, VE, Italy, 30035
      • Recruiting
      • Azienda Ulss 3 Serenissima
      • Contact: Giuseppe Azzarello, MD; Phone Number: +39 041 2608482; Email: giuseppe.azzarello@aulss3.veneto.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: 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: 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 Names: 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 Names: 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 Names: Levofolinic acid; 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 Names: Erbitux

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	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.	up to 36 months
Objective response rate (ORR)	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.	up to 36 months
Prevalence of RAS mutation	Percentage of RAS mut patients on the total of patients who undergone to liquid biopsy at the first and second evaluations.	up to 36 months
Patients Safety	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.	up to 36 months
Compliance	The compliance to treatment will be described presenting number of administered cycles; frequency and reasons for drug discontinuation and treatment modifications.	up to 36 months

Collaborators and Investigators

• Sponsor: Azienda Unità Sanitaria Locale Reggio Emilia
• Collaborators: Istituto Di Ricerche Farmacologiche Mario Negri; Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale
• Investigators: Study Chair: Erika Gervasi, AUSL IRCCS Reggio Emilia

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 30, 2021
• Primary Completion (ANTICIPATED): April 29, 2023
• Study Completion (ANTICIPATED): April 29, 2024

Study Registration Dates

• First Submitted: February 23, 2021
• First Submitted That Met QC Criteria: February 25, 2021
• First Posted (ACTUAL): March 2, 2021

Study Record Updates

• Last Update Posted (ACTUAL): September 16, 2021
• Last Update Submitted That Met QC Criteria: September 10, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: liquid biopsy; mCRC; RAS
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Bevacizumab; Leucovorin; Irinotecan; Calcium; Levoleucovorin; Cetuximab
• Other Study ID Numbers: 2020-005078-82

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No