Phase III Trial Comparing FOLFIRI Plus Cetuximab Versus Bevacizumab in First-Line Treatment of mCRC with RAS/BRAF Wild-Type Tissue and Mutated Liquid Biopsy
- Trial ID
- 2024-517863-22-00
- Protocol
- LIBImAb
Trial statistics
Objectives
The primary objective of this Phase III study is to evaluate whether the combination of **bevacizumab** plus chemotherapy is superior to **cetuximab** plus chemotherapy in terms of progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) who exhibit **RAS/BRAF** mutations in liquid biopsy and are **RAS/BRAF** wild type on tissue. This is clinically relevant as it may inform first-line treatment strategies for mCRC, potentially improving patient outcomes by identifying the most effective therapeutic combination.
Secondary objectives include:
- Assessing whether the combination of bevacizumab plus chemotherapy is superior to cetuximab plus chemotherapy in terms of overall survival (OS).
- Evaluating the superiority of bevacizumab plus chemotherapy over cetuximab plus chemotherapy in terms of objective response rate (ORR).
- Describing the prevalence of **RAS/BRAF** mutations evaluated through liquid biopsy in a population of mCRC with **RAS/BRAF** wild type on tumor tissue.
- Describing the safety profiles of the two treatment arms.
- Describing the compliance rates of the two treatment arms.
Participants
The clinical trial involves a **study population** of patients diagnosed with metastatic colorectal cancer (**mCRC**) who have not previously received systemic treatment for advanced or metastatic disease. Participants are candidates for first-line therapy with FOLFIRI plus cetuximab or bevacizumab. The trial includes both male and female subjects over the age of 18, with no upper age limit specified. Participants must have a histologically confirmed diagnosis of colorectal adenocarcinoma with RAS/BRAF wild type status, and they should be suitable for first-line chemotherapy. The trial does not include a vulnerable population. Participants are required to have a life expectancy greater than three months and an ECOG Performance status of 2 or less. Adequate bone marrow, liver, and renal function are prerequisites for participation. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the trial data. Key inclusion criteria include the provision of written informed consent and, for women of childbearing potential, a negative blood pregnancy test within 24 hours prior to the start of study treatment. The trial does not apply restrictions based on DPD status if it is unknown.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **bevacizumab** plus chemotherapy compared to **cetuximab** plus chemotherapy in patients with metastatic colorectal cancer (mCRC) who have RAS/BRAF wild type tissue and RAS/BRAF mutations detected in liquid biopsy. This is a Phase III, randomized, double-blind, controlled trial. The primary endpoint is progression-free survival (PFS), with secondary endpoints including overall survival, objective response rate, prevalence of RAS/BRAF mutation, safety, and compliance. The trial is expected to run from August 2021 to May 2025, with an estimated participant involvement of up to 8 months, depending on individual response and treatment tolerance.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis of colorectal adenocarcinoma, life expectancy greater than 3 months, and adequate organ function. Following successful screening, participants will be randomized to receive either the bevacizumab or cetuximab regimen. Treatment will be administered via **intravenous** infusion, with dosing schedules tailored to the specific regimen. Regular follow-up visits will be conducted to monitor treatment response, manage any adverse events, and ensure compliance with the study protocol. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. Additionally, any significant protocol deviations or non-compliance may also result in early termination. The trial aims to provide robust data on the comparative effectiveness of these treatment regimens, contributing to optimized therapeutic strategies for mCRC patients.
Treatment
The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments**. **Fluorouracil**, a chemical substance, is administered in the form of an infusion. The pharmaceutical form is designated as PHF00231MIG. The maximum daily dose is 400 mg/m², with a total dose not exceeding 400 mg/m² over a treatment period of up to 8 weeks. The administration route is via infusion, and participant compliance is monitored throughout the study.
**Calcium Folinate**, also known as Leucovorin Calcium, is another chemical substance used in the trial. It is administered through intravenous infusion, with a pharmaceutical form of PHF00231MIG. The maximum daily and total dose is 200 mg/m², administered over a maximum treatment period of 8 weeks. This substance serves as an antidote in the study protocol.
**Cetuximab**, a protein-based substance, is administered via infusion. The pharmaceutical form is PHF00230MIG, with a maximum daily and total dose of 500 mg/m². The treatment period is limited to 8 weeks. Cetuximab is used as a comparator in the study, and its administration is closely monitored for participant compliance.
**Bevacizumab**, another protein-based substance, is administered intravenously. The pharmaceutical form is PHF00230MIG, with a maximum daily and total dose of 5 mg/kg. The treatment period is up to 8 weeks. Bevacizumab is the test drug in the study, and its administration is monitored to ensure adherence to the dosing schedule.
**Irinotecan Hydrochloride**, a chemical substance, is administered intravenously. The pharmaceutical form is PHF00230MIG, with a maximum daily and total dose of 180 mg/m². The treatment period is up to 8 weeks. This substance is used as an auxiliary treatment in the study, and compliance is monitored throughout the trial.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**. This primary endpoint will determine the superiority of the combination of bevacizumab plus chemotherapy compared to cetuximab plus chemotherapy in patients with RAS/BRAF mutations identified through liquid biopsy and RAS/BRAF wild type on tissue. Secondary endpoints include overall survival, objective response rate, prevalence of RAS/BRAF mutation, safety, and compliance. These parameters will be measured and collected at specified intervals throughout the trial duration, with the final analysis conducted at the end of the treatment period. The trial is designed to provide a comprehensive assessment of the therapeutic efficacy and safety of the treatment regimens in the specified patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- Patients suitable for first line chemotherapy
- Life expectancy > 3 months
- At least one site of measurable disease per RECIST 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)
Exclusion Criteria
- 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 antibodies)
- 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. Patients with an active therapy with low molecular weight heparin or NAO may be enrolled
- 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
- History of any severe hypersensitivity reactions to any monoclonal antibody
- A significant concomitant disease which, in the investigating physician's opinion, rules out the patient’s participation in the study
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 20 Aug 2021 | 996 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
FLUOROURACIL | Other | PHF00231MIG | INFUSION | 400 | 8 | SCP1165178 |
BEVACIZUMAB | Test | PHF00230MIG | INTRAVENOUS | 5 | 8 | SCP29096188 |
IRINOTECAN | Other | PHF00230MIG | INTRAVENOUS | 180 | 8 | SCP139021 |
CETUXIMAB | Comparator | PHF00230MIG | INFUSION | 500 | 8 | SCP185672 |
CALCIUM LEVOFOLINATE | Other | PHF00231MIG | INTRAVENIOUS INFUSION | 200 | 8 | SCP139914 |