Colorectal CancerPhase 2NeoBRAFNCT05510895
Neoadjuvant Encorafenib, Binimetinib and Cetuximab for Patients With BRAF V600E Mutated/pMMR Localized Colorectal Cancer
A Phase 2 study testing Binimetinib in people with Colorectal Cancer and Colon Cancer, run by AIO-Studien-gGmbH at 1 site in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colorectal Cancer, Colon Cancer, BRAF V600E
- What is being tested?
- Binimetinib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 1 siteGermany
- Study dates
- 1 Sep 2022to 31 Jan 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
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- 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.
- Ability to comply with the protocol for the duration of the study, including hospital/office visits for treatment and scheduled follow-up visits and examinations.
Who cannot join
- 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).
- Malignancies other than disease under study within 5 years prior to inclusion, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS >90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).
- 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.
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- 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.
- Current treatment with a non-topical medication or current intake of herbal preparations / supplements / foods known to be a strong inhibitor of CYP3A4. However, patients who either discontinue such treatment/intake or switch to another medication at least 7 days prior to starting study treatment are eligible.
- Concomitant use of St. John's Wort (hypericum perforatum).
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the detailed description
This is a single arm, multicenter, phase II trial for patients with unresected BRAF V600E mutated/pMMR localized colorectal cancer (CRC). Patients enrolled will be treated with neoadjuvant encorafenib (300mg QD), binimetinib (45mg BID) and cetuximab (500mg/m² biweekly) for 8 weeks. Neoadjuvant treatment will be followed by surgery. First Endpoint is TRG (Tumor-Regression-Grade) which will be analyzed centrally. Patients with TRG>1 will receive adjuvant treatment with encorafenib (300mg QD), binimetinib (45mg BID) and cetuximab (500mg/m² biweekly) for up to 16 weeks. For patients with TRG<2 EOT will be reached 4-6 weeks after last dosage of encorafenib, binimetinib and cetuximab and further treatment is at investigator discretion (CAPOX recommended). All subjects will be followed every 3 months after surgery for up to 4 years after start of recruitment.
- Being tested
- Binimetinib
- Medical subject headings
- Colorectal Neoplasms, Colonic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BinimetinibDrug
Also called Encorafenib, Cetuximab
Triplet combination administered neoadjuvant and adjuvant, depending on TRG
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: Drug: Binimetinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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
Safety assessments will include physical examinations including visual and skin assessment as well as vital signs (blood pressure, heart rate, respiratory rate), performance status (ECOG), clinical laboratory profile, 12-lead ECG and ECHO, ophthalmologic assessment, concomitant medication/therapies/procedures and adverse events. All observed adverse events will be graded according to NCI CTCAE v5. Adverse events will be analysed overall and concerning their potential relationship to study treatment and surgical intervention. Serious adverse events (SAE) will be analysed in the same way.
Measured: max 54 months
Perioperative morbidity and mortality
Perioperative morbidity and mortality are defined as prolongation of hospitalization (discharge >20 days after surgery), re-hospitalization or reoperation under general anaesthesia within 30 days of surgery or death during surgery or within 30 days of surgery; Other severe postoperative complications within 30 days of surgery including surgery-associated bleeding with replacement ≥ 4 units of erythrocyte concentrates, transient liver failure, defined as a bilirubin level >10 mg/dL lasting > 7 days, renal failure requiring dialysis, respiratory failure with renewed necessary mechanical ventilation or >26 h, necessary mechanical ventilation, deep venous thromboembolism, cardiac failure, major impaired wound healing necessitating re-operation or prolonging hospitalization (discharge >20 days after surgery); >8 weeks delay of surgery due to study treatment-related toxicity; and further.
Measured: max 24 months
R0-resection rate
The R0 resection rate will be determined as the rate of R0 resections out of all resected patients. In addition, the R1 and/or R2 resection rates will be determined.
Measured: max 24 months
Overall Response Rate (ORR) according to RECIST v1.1
Response rate to preoperative treatment will be assessed according to RECIST v1.1.
Measured: max 54 months
Disease free survival
Disease free survival will be determined as time from start of study treatment to date of first observed disease recurrence (either local or distant) or death from any cause.
Measured: max 54 months
Overall survival (OS)
Overall survival will be determined as time from start of study treatment to date of death from any cause.
Measured: max 54 months
Translational research 1
Correlation of quantitative BRAF V600E levels (measured by ddPCR) with TRG
Measured: max 54 months
Translational research 2
Evaluation of mechanism of relative resistance in patients with less response (evaluated by tumor and liquid biopsy NGS profiling at baseline and after treatment)
Measured: max 54 months
Translational research 3
Comparison of ctDNA clearance and TRG with a BRAF mutant/pMMR cohort from the planned neoadjuvant PROTECTOR study receiving neoadjuvant chemotherapy
Measured: max 54 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Aug 2022
- Study start1 Sep 2022
- Primary completion31 Jul 2024
- Study completion31 Jan 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Colorectal CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- AIO-Studien-gGmbH
- Sponsor type
- University, hospital or other
- Collaborators
- Pierre Fabre Pharma GmbH, Merck Serono GmbH, Germany, Universitätsklinikum Hamburg-Eppendorf
- Responsible party
- Sponsor
- Investigators
- Alexander Stein, Prof. Dr., Principal investigator, Hämatologisch-Onkologische Praxis Eppendorf, 20249 Hamburg, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05510895
- Sponsor's protocol ID
- AIO-KRK-0420
- Acronym
- NeoBRAF
- Status last verified
- Sep 2025
- First submitted
- 17 Aug 2022
- Last updated
- 1 Oct 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Oct 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neoadjuvant Encorafenib, Binimetinib and Cetuximab for Patients With BRAF V600E Mutated/pMMR Localized Colorectal Cancer
- ClinicalTrials.gov ID
- NCT05510895
- Acronym / sponsor ID
- NeoBRAF / AIO-KRK-0420
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 2 participants (actual)
- Lead sponsor
- AIO-Studien-gGmbHUniversity, hospital or other
- Collaborators
- Pierre Fabre Pharma GmbH, Merck Serono GmbH, Germany, Universitätsklinikum Hamburg-Eppendorf
- Study start
- 1 Sep 2022 (actual)
- Primary completion
- 31 Jul 2024 (actual)
- Study completion
- 31 Jan 2025 (actual)
- First posted
- 22 Aug 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
This is a single arm, multicenter, phase II trial for patients with unresected BRAF V600E mutated/pMMR localized colorectal cancer (CRC). Patients enrolled will be treated with neoadjuvant encorafenib (300mg QD), binimetinib (45mg BID) and cetuximab (500mg/m² biweekly) for 8 weeks. Neoadjuvant treatment will be followed by surgery. First Endpoint is TRG (Tumor-Regression-Grade) which will be analyzed centrally. Patients with TRG>1 will receive adjuvant treatment with encorafenib (300mg QD), binimetinib (45mg BID) and cetuximab (500mg/m² biweekly) for up to 16 weeks. For patients with TRG<2 EOT will be reached 4-6 weeks after last dosage of encorafenib, binimetinib and cetuximab and further treatment is at investigator discretion (CAPOX recommended). All subjects will be followed every 3 months after surgery for up to 4 years after start of recruitment.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| neoadjuvant and adjuvant triplet combination of encorafenib, binimetinib and cetuximab | Experimental | Drug: BinimetinibNeoadjuvant 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- 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.
Key exclusion criteria (18 listed)
- 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).
- Malignancies other than disease under study within 5 years prior to inclusion, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS >90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BinimetinibAlso: Encorafenib, CetuximabTriplet combination administered neoadjuvant and adjuvant, depending on TRG | Drug | neoadjuvant and adjuvant triplet combination of encorafenib, binimetinib and cetuximab |
Primary outcome
Tumor regression grade (TRG)
Time frame: immediately after the surgery
Tumor regression will be centrally graded according to the grading system developed by Dworak et al (Dworak, Keilholz et al. 1997).
9 secondary outcomes
Safety and tolerability (acc. to NCI CTC AE v5.0) incl. vital signs, clinical parameters and overall feasibility of the regimen
Time frame: max 54 months
Perioperative morbidity and mortality
Time frame: max 24 months
R0-resection rate
Time frame: max 24 months
Overall Response Rate (ORR) according to RECIST v1.1
Time frame: max 54 months
Disease free survival
Time frame: max 54 months
Overall survival (OS)
Time frame: max 54 months
Translational research 1
Time frame: max 54 months
Translational research 2
Time frame: max 54 months
Translational research 3
Time frame: max 54 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Oct 2025.
- Working Group for Medical Oncology from the German Cancer SocietyLink provided by the sponsor.
- AIO-Studien-gGmbHLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alexander Stein, Prof. Dr. principal investigator
Hämatologisch-Onkologische Praxis Eppendorf, 20249 Hamburg, Germany
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Binimetinib in people with Colorectal Cancer and Colon Cancer, run by AIO-Studien-gGmbH at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Tumor regression grade (TRG) (time frame: immediately after the surgery). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Oct 2025.