Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer (NEORAF)

Combination of Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With Braf v600e-mutates Localised Colon or Upper Rectum Cancer (Neoraf Study)

This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.

If the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.

Furthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; BRAF V600E Mutation Positive
• Intervention / Treatment: Drug: Encorafenib Oral Capsule + Cetuximab

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Project Manager; Phone Number: 0033380393483; Email: ffcd2006.neoraf@ffcd.fr

Study Locations

• France
  • Paris, France
    • Recruiting
    • Chu - Hôpital Européen Georges Pompidou
    • Contact: Claire GALLOIS, Dr; Phone Number: 0156092297; Email: claire.gallois@aphp.fr
    • Principal Investigator: Claire GALLOIS, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Informed consent signed and dated 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 and histologically confirmed, localised, mutated BRAF V600E determined in a biopsy specimen and resectable after CT-scan assessment.

Remark: Centralised analysis of BRAF status will be performed in order to confirm the existence of the mutation concomitantly with the 1st cycle of therapy

• Tumour stage rT4 or rT3 with ≥ 5 mm extra-mural extension in a CT-scan.

  • rT3 with high risk: Tumour spread from the peripheral serosa and extension to the adjacent peritoneal fat of more than 5 mm in its longest diameter (both axial and coronal planes)
  • rT4: Extension to an adjacent organ
• Patient able to provide a sufficient quantity of representative tumour sample (slides or extracted tumor DNA) for centralised analysis of RAS and BRAF mutational status.
• WHO performance status 0 or 1

• Haematological function considered satisfactory:

  • Polymorphonuclear neutrophils (PMN) ≥ 1,500/mm3
  • Platelets ≥ 100,000/mm3
  • Hb ≥ 9g/dL
• Creatinine clearance > 50 mL/min (according to MDRD formula).
• Serum levels of magnesium within normal limits of the centre.
• Total serum bilirubin ≤ 25 μmol/L, ALT and/or AST ≤ 2.5 x ULN.

• Cardiac function considered satisfactory:

  o Corrected mean QT interval for heart rate according to the Fridericia formula (QTcF) ≤ 480 ms.

• Patient able to take medicinal products by mouth (OD).
• Female Patients postmenopausal for at least one year or surgically infertile for at least 6 weeks, or effective contraception for male and female patients of childbearing potential for 2 months after the end of the investigational treatments
• A negative pregnancy test for inclusion for all female patients of child-bearing FFCD 2006 - NEORAF Version 1.0- 21/October2022 Page 7 of 69 potential.
• Patient covered by a plan of the French Social Security system

Exclusion Criteria:

• Existence of distant metastases or adjacent nodules of peritoneal carcinosis (M1).
• Existence of a dual-tumour location.
• known RAS mutation
• Peritonitis (secondary to perforation of the tumour) or symptomatic colonic occlusion or a temporary colostomy to prevent a sub-occlusion.
• Patient in whom an indication for radiotherapy exists based on 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 (with immuno-modulators or immuno-suppressants) ≤ 12 months before start of study treatment.

• Patient with decreased cardiovascular function or clinically significant cardiovascular disease:

  1. 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.
  2. Symptomatic congestive heart failure (CHF) (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.
• Child-Pugh class B or C cirrhosis.
• Deterioration of gastro-intestinal function or a disease which may significantly impair the absorption of encorafenib, e.g.: ulcer disease, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, small bowel resection
• A previous or concomitant malignant tumour within 5 years prior to the study. Except for basal cell or squamous skin cancer, superficial cancer of the bladder, intra-epithelial carcinoma of the prostate, carcinoma in situ of the uterine cervix or any other malignant tumour which has been treated adequately and which has not recurred during the three years prior to entry in the study.
• A concomitant neuro-muscular disease associated with high levels of creatinine kinase (CK).

Remark: inflammatory muscular disease, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy.

• History of infection with human immunodeficiency virus (HIV).
• Active infection with hepatitis B or hepatitis C.
• Known existence of Gilbert syndrome
• 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.
• Persons who are deprived of their freedom or who are under guardianship

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Encorafenib + Cetuximab	Drug: Encorafenib Oral Capsule + Cetuximab; Encorafenib: 4 capsules 75 mg/day (300 mg) , 7 days/7 during 6 weeks Cetuximab: 500mg/m2 intravenous route every 2 weeks (D1, D14, D28), for 3 cycles over 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the rate of significant tumour regression (TRG 0 to 2 according to Ryan's modified score of the AJCC 2010)	with centralised review after neoadjuvant treatment with encorafenib and cetuximab, in patients with RAS wild type localised colon or upper rectum cancer (CC) and carriers of the BRAF V600E mutation.	6 months after completing inclusions

Collaborators and Investigators

• Sponsor: Federation Francophone de Cancerologie Digestive
• Collaborators: Merck Sharp & Dohme LLC; Pierre Fabre Laboratories
• Investigators: Principal Investigator: Claire Gallois, MD, Paris HEGP

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2023
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): May 31, 2029

Study Registration Dates

• First Submitted: January 20, 2023
• First Submitted That Met QC Criteria: January 30, 2023
• First Posted (Actual): January 31, 2023

Study Record Updates

• Last Update Posted (Estimated): September 2, 2025
• Last Update Submitted That Met QC Criteria: August 29, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cetuximab; encorafenib
• Other Study ID Numbers: FFCD 2006 NEORAF

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
• product manufactured in and exported from the U.S.: No