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.
• 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