Neoadjuvant Encorafenib, Binimetinib and Cetuximab for Patients With BRAF V600E Mutated/pMMR Localized Colorectal Cancer

NCT05510895 | Completed Phase 2 DMC

• 1 other identifier: AIO-KRK-0420
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

AIO-KRK-0420 NeoBRAF is a single arm, multicenter, phase II trial with neoadjuvant encorafenib, binimetinib and cetuximab for patients with BRAF V600E mutated/pMMR localized colorectal cancer.

Conditions

Colorectal Cancer; Colon Cancer; BRAF V600E; BRAF V600 Mutation; Localized Cancer

Outcome Measures

Primary Outcomes (1)

• Tumor regression grade (TRG)

  Tumor regression will be centrally graded according to the grading system developed by Dworak et al (Dworak, Keilholz et al. 1997).

  immediately after the surgery

Secondary Outcomes (9)

• Safety and tolerability (acc. to NCI CTC AE v5.0) incl. vital signs, clinical parameters and overall feasibility of the regimen

  max 54 months

• Perioperative morbidity and mortality

  max 24 months

• R0-resection rate

  max 24 months

• Overall Response Rate (ORR) according to RECIST v1.1

  max 54 months

• Disease free survival

  max 54 months

Study Arms (1)

neoadjuvant and adjuvant triplet combination of encorafenib, binimetinib and cetuximab

EXPERIMENTAL

Neoadjuvant treatment with encorafenib, binimetinib and cetuximab for up to 8 weeks (4 biweekly cycles). In Week 10-12 surgery of the tumor followed by central determination of tumor regression grade (TRG). TRG0-1: insufficient response to neoadjuvant triplet. Standard chemotherapy with fluoropyrimidines and oxaliplatin should be applied. TRG2-4: 4-8 weeks after surgery adjuvant treatment with encorafenib, binimetinib and cetuximab continues for up to 16 Weeks (8 biweekly cycles).

Drug: Binimetinib

Interventions

Binimetinib DRUG

Triplet combination administered neoadjuvant and adjuvant, depending on TRG

Also known as: Encorafenib, Cetuximab

neoadjuvant and adjuvant triplet combination of encorafenib, binimetinib and cetuximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Biopsy-confirmed adenocarcinoma of the colon or upper rectum if too high for radiotherapy.
• Radiologically (CT/MRI) staged disease as: T3-4 (as invasion of surrounding tissue structures or organs) and/or nodal positive (N+ defined as regional lymph node(s) without fat hilus and short axis diameter of ≥1 cm), M0.
• BRAF V600E mutation and pMMR or MSS (as determined by a validated test, preferably PCR or NGS).
• ECOG performance status ≤ 1.
• Age ≥ 18 years.
• Adequate hematologic function at screening as follows:
• ANC ≥ 1.5 x 109/L, platelets ≥ 100 x109/L, hemoglobin ≥ 9.0 g/dL.
• Adequate liver function at screening as measured by serum transaminases (AST \& ALT) ≤ 2.5 x ULN and total bilirubin ≤ 1.5 x ULN. Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled.
• Adequate renal function at screening: serum creatinine ≤ 1.5 x ULN.
• Adequate serum electrolytes at screening defined as serum potassium and magnesium levels within institutional normal limits (Note: replacement treatment to achieve adequate electrolytes will be allowed.
• Adequate cardiac function at screening characterized by left ventricular ejection fraction (LVEF) ≥ 50% as determined by ECHO and QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤ 480 msec.
• Negative serum pregnancy test at screening for women of childbearing potential.
• Highly effective contraception for both male and female subjects if the risk of conception exists. (Note: The effects of the trial drugs on the developing human fetus are unknown; thus, women of childbearing potential and men able to father a child must agree to use highly effective contraception, defined as methods with a failure rate of less than 1 % per year, containing at least 1 form of non-hormonal contraception. Highly effective contraception is required at least 28 days prior, throughout and for at least 6 months after interventional study treatment (encorafenib, binimetinib and cetuximab).
• Signed and dated written informed consent.
• Ability to take oral medication.

You may not qualify if:

• Any prior systemic therapy, surgery or radiotherapy of the colorectal cancer disease.
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
• Known severe hypersensitivity reactions to monoclonal antibodies or BRAF-/MEK-inhibitors (grade ≥ 3 NCI-CTCAE v 5), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
• Pregnancy or lactation.
• Known alcohol or drug abuse.
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (≤ 6 months prior to enrolment); myocardial infarction (≤ 6 months prior to enrolment), acute coronary syndromes \[including unstable angina, coronary artery bypass graft (CABG), coronary angioplasty or stenting) ≤ 6 months prior to enrolment\]; congestive heart failure (≥New York Heart Association Classification Class II); or history or current evidence of clinically significant arrhythmia and/or conduction abnormality (≤ 6 months prior to enrolment), except rate controlled atrial fibrillation and paroxysmal supraventricular tachycardia.
• Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
• Preexisting interstitial lung disease.
• Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption).
• History of thromboembolic or cerebrovascular events ≤ 6 months prior to enrolment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli.
• Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
• Known human immunodeficiency virus (HIV) infection or active hepatitis B or C infection.
• All other significant diseases, which, in the opinion of the Investigator, might impair the subject's tolerance of trial treatment.
• Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
• Any approved anticancer therapy, including chemotherapy, hormonal therapy or radiotherapy, within 5 half-lives or 4 weeks (the longer period applies) prior to initiation of study treatment.

Sponsors & Collaborators

• AIO-Studien-gGmbH: lead
• Pierre Fabre Pharma GmbH: collaborator
• Merck Serono GmbH, Germany: collaborator
• Universitätsklinikum Hamburg-Eppendorf: collaborator

Study Sites (1)

Hämatologisch-Onkologische Praxis Eppendorf

Hamburg, 20249, Germany

Location

Related Links

• Working Group for Medical Oncology from the German Cancer Society
• AIO-Studien-gGmbH

MeSH Terms

Conditions

Colorectal Neoplasms; Colonic Neoplasms

Interventions

binimetinib; encorafenib; Cetuximab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Alexander Stein, Prof. Dr.

  Hämatologisch-Onkologische Praxis Eppendorf, 20249 Hamburg, Germany

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 17, 2022
• First Posted: August 22, 2022
• Study Start: September 1, 2022
• Primary Completion: July 31, 2024
• Study Completion: January 31, 2025
• Last Updated: October 1, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)