Neoadjuvant Encorafenib and Cetuximab in BRAF V600E-Mutated Localized Colon or Upper Rectum Cancer: A Multicenter Open-Label Pilot Study
- Trial ID
- 2024-514107-34-00
- Protocol
- FFCD 2006 NEORAF
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the significant **tumour regression rate** (TRG 0 to 2 according to Ryan’s modified score from the AJCC 2010) in a centralised review after neoadjuvant treatment with **encorafenib** and **cetuximab** in patients with RAS wild type localised colon cancer carrying the **BRAF V600E mutation**. This objective is clinically relevant as it aims to evaluate the effectiveness of the treatment regimen in reducing tumour size, which is crucial for improving surgical outcomes and potentially increasing survival rates in this patient population.
Secondary objectives include:
- The response rate in CT-scan according to RECIST 1.1 criteria, evaluated by both the investigator and a centralised review.
- The post-operative complication rate at 30 days post-surgery.
- The safety profile of the combination of encorafenib and cetuximab, assessed according to the NCI-CTCAE v4.0 classification.
- The dose intensity of cetuximab and compliance with encorafenib.
- Progression-free survival (PFS) and overall survival (OS) at 2 and 3 years, as evaluated by the investigator.
- Quality of life assessment using the EQ5D instrument.
Participants
The clinical trial involves participants diagnosed with **BRAF V600E-mutated localized colon or upper rectum cancer**. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who are not part of a vulnerable population. Participants are required to have a satisfactory general health status, as indicated by specific laboratory values and cardiac function assessments. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Selection criteria include the ability to provide informed consent, satisfactory haematological and renal function, and a WHO performance status of 0 or 1. Participants must have adenocarcinoma of the colon or upper rectum that is operable and histologically confirmed, with a BRAF V600E mutation. Lifestyle considerations such as diet and physical activity are not explicitly mentioned in the trial data. The trial population was selected based on specific inclusion criteria, ensuring that participants meet the necessary health and medical condition requirements for the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy involving **encorafenib** and **cetuximab** in patients with **BRAF V600E-mutated localized colon or upper rectum cancer**. This is a multi-centre, open-label, pilot trial with a non-comparative randomized phase II study design. The primary objective is to assess the significant tumor regression rate (TRG 0 to 2) according to Ryan’s modified score from the AJCC 2010, following neoadjuvant treatment. The trial is expected to run from May 2023 to May 2029, with a maximum treatment period of six months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, medical history, and laboratory results. The inclusion criteria require patients to have histologically confirmed adenocarcinoma of the colon or upper rectum, with a BRAF V600E mutation, and to be operable and resectable after CT-scan assessment. Following the screening, participants will receive treatment with **Erbitux** (cetuximab) via intravenous infusion and **Braftovi** (encorafenib) orally. The treatment regimen will be monitored through regular follow-up visits to assess safety, tumor response, and overall health status.
The end-of-study visit will occur after the completion of the treatment period, where the primary endpoint of tumor regression will be evaluated through a centralized review. Secondary endpoints include overall safety, survival rates, response rate according to RECIST 1.1 criteria, post-operative morbidity and mortality, and quality of life assessments. Participants are expected to be involved in the study for the duration of the treatment period and follow-up assessments, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study protocols.
Treatment
The clinical trial involves the administration of **Erbitux** (cetuximab), a **solution for infusion** with a concentration of 5 mg/mL. Cetuximab is a protein-based therapeutic agent, specifically classified under the ATC code L01FE01. The medication is administered via **intravenous infusion**. The maximum daily dose is 500 mg/m², with a total treatment period not exceeding six months. The administration schedule is designed to ensure optimal therapeutic levels while monitoring for any adverse reactions. Compliance with the dosing regimen is monitored through regular assessments and infusion records.
Additionally, the trial includes the use of **Braftovi** (encorafenib), which is provided in the form of **hard capsules** containing 75 mg of the active substance. Encorafenib is a chemically synthesized compound, categorized under the ATC code L01EC03. The route of administration is **oral**, with a maximum daily dose of 300 mg and a cumulative dose limit of 12,600 mg over the course of the study. The treatment duration is also capped at six months. Participants' adherence to the oral dosing schedule is tracked through pill counts and patient diaries to ensure compliance and accurate data collection.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial is designed to evaluate the efficacy of the combination of encorafenib and cetuximab in a neoadjuvant setting for patients with BRAF V600E-mutated localized colon or upper rectum cancer. The study protocol includes detailed guidelines for the administration and monitoring of both experimental medications to ensure participant safety and data integrity.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of the **tumour regression rate** (TRG 0 to 2) using Ryan’s modified score from the AJCC 2010. This assessment will be conducted on the primary tumour level after surgery and will undergo a centralised review. The primary endpoint focuses on determining the significant tumour regression rate in patients with RAS wild type localised colon cancer carrying the BRAF V600E mutation, following neoadjuvant treatment with encorafenib and cetuximab.
Secondary endpoints include the overall safety of the treatment, overall survival, progression-free survival, response rate in CT-scan according to RECIST 1.1 criteria, post-operative morbidity and mortality, and quality of life measured by EQ5D. These parameters will be collected and analyzed at various timepoints throughout the trial to provide a comprehensive evaluation of the treatment's efficacy and impact on patient outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Informed consent dates and signed by the patient and the investigator
- Age ≥18 years at time of informed consent
- Adenocarcinoma of the colon or of the upper rectum (supra-peritoneal) considered operable, histologically confirmed, localised mutated BRAF V600E determined in a biopsy specimen and resectable after CT-scan assessment.
- Stage rT4 or rT3 tumour with ≥ 5 mm extra-mural extension in CT-scan.
- Be able to provide a sufficient quantity of representative tumour sample (slides or extracted tumor DNA) for centralised analysis of RAS and BRAF mutation status.
- WHO performance status 0 or 1
- Haematological function considered satisfactory: o Polymorphonuclear neutrophils (PMN) ≥ 1,500/mm3 o Platelets ≥ 100,000/mm3 o Hb ≥ 9g/dL
- Creatinine clearance > 50 mL/min (according to MDRD formula).
- Serum magnesium within normal limits of the centre.
- Serum total bilirubin ≤ 25 μmol/L, ALT and/or AST ≤ 2.5 x ULN.
- Cardiac function considered satisfactory: o Mean QT interval corrected for heart rate according to Fridericia formula (QTcF) ≤ 480 msec.
- Patient able to take medicinal products by mouth.
- Female Patients postmenopausal for at least one year or surgically infertile for at least 6 weeks, or effective contraception (see paragraph 9.3.3 for more details) for male and female patients of childbearing potential for 2 months after the end of the investigational treatments
- A negative pregnancy test for inclusion in the study for all female patients of child-bearing potential. In case of a “urine pregnancy test”, it must be a highly sensitive urine pregnancy test, in accordance with the recommendations of the CTFG regarding pregnancy risk management (
- Patient to be covered by a regimen of French Social Security system.
Exclusion Criteria
- Existence of distant metastases or adjacent nodules of peritoneal carcinosis (M1).
- Child-Pugh class B or C cirrhosis.
- Decreased gastro-intestinal function or GI disease which may significantly deteriorate the absorption of encorafenib
- Previous or concomitant malignant tumour within 5 years prior to the study.
- A concomitant neuro-muscular disease associated with high level of creatinine kinase (CK).
- History of infection with human immunodeficiency virus (HIV).
- Active hepatitis B or hepatitis C infection.
- Known Gilbert syndrome or known genotypes such as UGT1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28.
- Use of medicinal plants/dietary supplements or other medicinal products or foods that are potent inducing agents or inhibitors of cytochrome P450 (CYP) 3A4/5 ≤ 1 week before start of the study treatment.
- Known severe hypersensitivity reactions to monoclonal antibodies or BRAF-inhibitors (grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
- Participation in a clinical study with administration of an investigational product within 4 weeks or five times the half-life of the investigational product, according to the longest period, prior to the first dose of the study treatment.
- Existence of a dual-tumour location.
- Persons who are deprived of their freedom or who are under guardianship.
- Known RAS mutation
- Peritonitis (secondary to perforation of the tumour)
- Patient in whom an indication for radiotherapy is chosen by the multidisciplinary meeting/board pre-operatively.
- Previous treatment with a BRAF inhibitor, cetuximab or other anti-EGFR treatment.
- History of acute or chronic pancreatitis within the 6 months prior to start of the study treatment.
- A history of chronic inflammatory bowel disease requiring treatment (immuno-modulators or immuno-suppressants) ≤ 12 months before start of study treatment.
- Decreased cardiovascular function or clinically significant cardiovascular disease: o History of myocardial infarction, acute coronary syndrome (including unstable angina, coronary artery bypass grafting, coronary angioplasty or stent placement) ≤ 6 months prior to start of the study treatment. o Symptomatic congestive heart failure (grade 2 or higher), history or current evidence of cardiac arrhythmia and/or a clinically significant conduction disorder ≤ 6 months prior to start of the study treatment, except atrial fibrillation with controlled heart rate and paroxysmal supra-ventricular tachycardia.
- Colonic obstruction that has not been defunctioned* *Patients with symptomatic bowel obstruction cannot be included unless the obstruction has been relieved by defunctioning
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 03 May 2023 | 30 |
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 |
|---|---|---|---|---|---|---|
Braftovi 75 mg hard capsules | Test | HARD CAPSULES | ORAL | 300 | 6 | PRD6728382 |
Erbitux 5 mg/mL solution for infusion | Test | SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 500 | 6 | PRD327543 |