Ffcd 2006 – Neoraf : a Multi-Centre, Open-Label, Pilot Trial Evaluating the Combination Encorafenib and Cetuximab in a Neoadjuvant Setting in Patients with Braf V600E-MUTATED Localised Colon or Upper Rectum Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondation Franc.Cancerologie Digestive

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Digestive System Diseases [C06]

Trial duration

18 Jul 2024 → ongoing

Decision date (initial)

2024-07-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

MERCK · PIERRE FABRE

External identifiers

EU CT number

2024-514107-34-00

EudraCT number

2021-000828-35

ClinicalTrials.gov

NCT05706779

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Safety

To assess, in patients with localized BRAFV600E mutated CRC treated with neoadjuvant encorafenib and cetuximab: safety and feasibility

Secondary objectives 7

1. The response rate in CT-scan according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumours) according to the investigator and in a centralised review
2. The post-operative complication rate at D30
3. Safety of the combination encorafenib and cetuximab according to the NCI-CTCAE v4.0 classification
4. Dose intensity of cetuximab and encorafenib and compliance with encorafenib
5. DFS and RFS (according to the investigator) and OS at 2 and 3 years
6. Quality of life (EQ5D)
7. To assess the rate of significant tumour regression (TRG 0 to 2 according to Ryan’s modified score of the AJCC 2010) with centralized review after neoadjuvant treatment with encorafenib and cetuximab,

Conditions and MedDRA coding

BRAF V600E-MUTATED LOCALISED COLON OR UPPER RECTUM CANCER

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Informed consent dates and signed by the patient and the investigator
2. Age ≥18 years at time of informed consent
3. 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.
4. Stage rT4 or rT3 tumour with ≥ 5 mm extra-mural extension in CT-scan.
5. 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.
6. WHO performance status 0 or 1
7. Haematological function considered satisfactory: o Polymorphonuclear neutrophils (PMN) ≥ 1,500/mm3 o Platelets ≥ 100,000/mm3 o Hb ≥ 9g/dL
8. Creatinine clearance > 50 mL/min (according to MDRD formula).
9. Serum magnesium within normal limits of the centre.
10. Serum total bilirubin ≤ 25 μmol/L, ALT and/or AST ≤ 2.5 x ULN.
11. Cardiac function considered satisfactory: o Mean QT interval corrected for heart rate according to Fridericia formula (QTcF) ≤ 480 msec.
12. Patient able to take medicinal products by mouth.
13. 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
14. 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 (
15. Patient to be covered by a regimen of French Social Security system.

Exclusion criteria 21

1. Existence of distant metastases or adjacent nodules of peritoneal carcinosis (M1).
2. Child-Pugh class B or C cirrhosis.
3. Decreased gastro-intestinal function or GI disease which may significantly deteriorate the absorption of encorafenib
4. Previous or concomitant malignant tumour within 5 years prior to the study.
5. A concomitant neuro-muscular disease associated with high level of creatinine kinase (CK).
6. History of infection with human immunodeficiency virus (HIV).
7. Active hepatitis B or hepatitis C infection.
8. Known Gilbert syndrome or known genotypes such as UGT1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28.
9. 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.
10. 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)
11. 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.
12. Existence of a dual-tumour location.
13. Persons who are deprived of their freedom or who are under guardianship.
14. Known RAS mutation
15. Peritonitis (secondary to perforation of the tumour)
16. Patient in whom an indication for radiotherapy is chosen by the multidisciplinary meeting/board pre-operatively.
17. Previous treatment with a BRAF inhibitor, cetuximab or other anti-EGFR treatment.
18. History of acute or chronic pancreatitis within the 6 months prior to start of the study treatment.
19. A history of chronic inflammatory bowel disease requiring treatment (immuno-modulators or immuno-suppressants) ≤ 12 months before start of study treatment.
20. 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.
21. Colonic obstruction that has not been defunctioned* *Patients with symptomatic bowel obstruction cannot be included unless the obstruction has been relieved by defunctioning

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To assess, in patients with localized BRAFV600E mutated CRC treated with neoadjuvant encorafenib and cetuximab: Safety and Feasibility

Secondary endpoints 9

1. Non serious Toxicities (related and not related).
2. Overall survival
3. Disease free survival
4. The response rate in CT-scan according to RECIST 1.1 criteria
5. Post-operative morbidity and mortality
6. Quality of life (EQ5D)
7. Tumour regression rate (TRG0 to TRG2)
8. Recurrence free survival
9. The dose intensity of cetuximab and encorafenib

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondation Franc.Cancerologie Digestive

Sponsor organisation

Fondation Franc.Cancerologie Digestive

Address

7 Boulevard Jeanne D Arc

City

Dijon Cedex

Postcode

21079

Country

France

Scientific contact point

Organisation

Fondation Franc.Cancerologie Digestive

Contact name

Claire GALLOIS

Public contact point

Organisation

Fondation Franc.Cancerologie Digestive

Contact name

Claire GALLOIS

Locations

1 EU/EEA country · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications