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Trial Title:
Neoadjuvant Encorafenib, Binimetinib and Cetuximab for Patients With BRAF V600E Mutated/pMMR Localized Colorectal Cancer
NCT ID:
NCT05510895
Condition:
Colorectal Cancer
Colon Cancer
BRAF V600E
BRAF V600 Mutation
Localized Cancer
Conditions: Official terms:
Colorectal Neoplasms
Cetuximab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Binimetinib
Description:
Triplet combination administered neoadjuvant and adjuvant, depending on TRG
Arm group label:
neoadjuvant and adjuvant triplet combination of encorafenib, binimetinib and cetuximab
Other name:
Encorafenib
Other name:
Cetuximab
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.
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Biopsy-confirmed adenocarcinoma of the colon or upper rectum if too high for
radiotherapy.
2. 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.
3. BRAF V600E mutation and pMMR or MSS (as determined by a validated test, preferably
PCR or NGS).
4. ECOG performance status ≤ 1.
5. Age ≥ 18 years.
6. Adequate hematologic function at screening as follows:
ANC ≥ 1.5 x 109/L, platelets ≥ 100 x109/L, hemoglobin ≥ 9.0 g/dL.
7. 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.
8. Adequate renal function at screening: serum creatinine ≤ 1.5 x ULN.
9. 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.
10. 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.
11. Negative serum pregnancy test at screening for women of childbearing potential.
12. 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).
13. Signed and dated written informed consent.
14. Ability to take oral medication.
15. 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.
Exclusion Criteria:
1. Any prior systemic therapy, surgery or radiotherapy of the colorectal cancer
disease.
2. 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).
3. 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).
4. 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).
5. Pregnancy or lactation.
6. Known alcohol or drug abuse.
7. 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.
8. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure
≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
9. Preexisting interstitial lung disease.
10. 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).
11. History of thromboembolic or cerebrovascular events ≤ 6 months prior to enrolment,
including transient ischemic attacks, cerebrovascular accidents, deep vein
thrombosis or pulmonary emboli.
12. Concurrent neuromuscular disorder that is associated with the potential of elevated
CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
sclerosis, spinal muscular atrophy).
13. Known human immunodeficiency virus (HIV) infection or active hepatitis B or C
infection.
14. All other significant diseases, which, in the opinion of the Investigator, might
impair the subject's tolerance of trial treatment.
15. Any psychiatric condition that would prohibit the understanding or rendering of
informed consent.
16. 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.
17. 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.
18. Concomitant use of St. John's Wort (hypericum perforatum).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Hämatologisch-Onkologische Praxis Eppendorf
Address:
City:
Hamburg
Zip:
20249
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Alexander Stein, Prof. Dr.
Start date:
September 1, 2022
Completion date:
January 31, 2025
Lead sponsor:
Agency:
AIO-Studien-gGmbH
Agency class:
Other
Collaborator:
Agency:
Pierre Fabre Pharma GmbH
Agency class:
Industry
Collaborator:
Agency:
Merck Serono GmbH, Germany
Agency class:
Industry
Collaborator:
Agency:
Universitätsklinikum Hamburg-Eppendorf
Agency class:
Other
Source:
AIO-Studien-gGmbH
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05510895
https://www.aio-portal.de/
https://www.aio-studien-ggmbh.de/
