ENCORAFENIB for Colon cancer (BRAF V600E-mutated, localized)|Upper rectum cancer (BRAF V600E-mutated, localized)

Inclusion criteria

• {"criterion_text":"- Informed consent dates and signed by the patient and the investigator\n- Serum total bilirubin ≤ 25 μmol/L, ALT and/or AST ≤ 2.5 x ULN.\n- Cardiac function considered satisfactory: o Mean QT interval corrected for heart rate according to Fridericia formula (QTcF) ≤ 480 msec.\n- Patient able to take medicinal products by mouth.\n- 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\n- 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 (\n- Patient to be covered by a regimen of French Social Security system.\n- Age ≥18 years at time of informed consent\n- 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.\n- Stage rT4 or rT3 tumour with ≥ 5 mm extra-mural extension in CT-scan.\n- 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.\n- WHO performance status 0 or 1\n- Haematological function considered satisfactory: o Polymorphonuclear neutrophils (PMN) ≥ 1,500/mm3 o Platelets ≥ 100,000/mm3 o Hb ≥ 9g/dL\n- Creatinine clearance > 50 mL/min (according to MDRD formula).\n- Serum magnesium within normal limits of the centre."}

Exclusion criteria

• {"criterion_text":"- Existence of distant metastases or adjacent nodules of peritoneal carcinosis (M1).\n- Child-Pugh class B or C cirrhosis.\n- Decreased gastro-intestinal function or GI disease which may significantly deteriorate the absorption of encorafenib\n- Previous or concomitant malignant tumour within 5 years prior to the study.\n- A concomitant neuro-muscular disease associated with high level of creatinine kinase (CK).\n- History of infection with human immunodeficiency virus (HIV).\n- Active hepatitis B or hepatitis C infection.\n- Known Gilbert syndrome or known genotypes such as UGT1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28.\n- 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.\n- 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)\n- 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.\n- Existence of a dual-tumour location.\n- Persons who are deprived of their freedom or who are under guardianship.\n- Known RAS mutation\n- Peritonitis (secondary to perforation of the tumour)\n- Patient in whom an indication for radiotherapy is chosen by the multidisciplinary meeting/board pre-operatively.\n- Previous treatment with a BRAF inhibitor, cetuximab or other anti-EGFR treatment.\n- History of acute or chronic pancreatitis within the 6 months prior to start of the study treatment.\n- A history of chronic inflammatory bowel disease requiring treatment (immuno-modulators or immuno-suppressants) ≤ 12 months before start of study treatment.\n- 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.\n- Colonic obstruction that has not been defunctioned* *Patients with symptomatic bowel obstruction cannot be included unless the obstruction has been relieved by defunctioning"}

Primary endpoints

• {"endpoint_text":"- To assess, in patients with localized BRAFV600E mutated CRC treated with neoadjuvant encorafenib and cetuximab: Safety and Feasibility","definition_or_measurement_approach":"Not specified in the record"}

Secondary endpoints

• {"endpoint_text":"- Non serious Toxicities (related and not related).","definition_or_measurement_approach":"No detailed measurement approach specified for non-serious toxicities in the record"}
• {"endpoint_text":"- Overall survival","definition_or_measurement_approach":"Overall survival (OS) reported; secondary objectives specify OS at 2 and 3 years"}
• {"endpoint_text":"- Disease free survival","definition_or_measurement_approach":"Disease-free survival (DFS) to be assessed (record indicates DFS according to the investigator; DFS/RFS assessed at 2 and 3 years)"}
• {"endpoint_text":"- The response rate in CT-scan according to RECIST 1.1 criteria","definition_or_measurement_approach":"Response rate assessed by CT-scan according to RECIST 1.1 criteria by investigator and by centralised review (per secondary objective)"}
• {"endpoint_text":"- Post-operative morbidity and mortality","definition_or_measurement_approach":"Post-operative complication rate at D30 (30 days) is specifically listed in secondary objectives"}
• {"endpoint_text":"- Quality of life (EQ5D)","definition_or_measurement_approach":"Quality of life measured using EQ-5D questionnaire"}
• {"endpoint_text":"- Tumour regression rate (TRG0 to TRG2)","definition_or_measurement_approach":"Tumour regression assessed as TRG 0 to 2 according to Ryan's modified score of the AJCC 2010 with centralized review (per secondary objective)"}
• {"endpoint_text":"- Recurrence free survival","definition_or_measurement_approach":"Recurrence-free survival (RFS) to be assessed (record indicates DFS and RFS according to the investigator; timepoints include 2 and 3 years)"}
• {"endpoint_text":"- The dose intensity of cetuximab and encorafenib","definition_or_measurement_approach":"Dose intensity and compliance measured for cetuximab and encorafenib (no further detail provided)"}

France

Earliest CTIS Part Ii Submission Date

27-06-2024

Latest Decision Or Authorization Date

29-01-2026

Processing Time Days

578

Number Of Sites

31

Number Of Participants

30

Primary sponsor

Full Name

Fondation Franc.Cancerologie Digestive

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France

Third parties

• {"country":"","full_name":"MERCK","duties_or_roles":"Monetary support","organisation_type":""}
• {"country":"","full_name":"PIERRE FABRE","duties_or_roles":"Monetary support","organisation_type":""}