Phase II, open-label, single arm, multicenter study of encorafenib, binimetinib plus cetuximab in subjects with previously untreated BRAF V600E -mutant Metastatic Colorectal Cancer

1. Provide a signed and dated informed consent document.
2. Male or female * 18 years of age at time of informed consent.
3. Histologically or cytologically confirmed CRC that is metastatic and
unresectable at time of study entry (i.e. not suitable for complete surgical
resection at screening).
4. Presence of BRAFV600E mutation in tumor tissue previously determined by a
local assay at any time prior to screening.
Notes:
a. Only PCR and NGS-based local assays results will be acceptable.
b.If at any time there is lack of confirmation of the BRAFV600E mutation in a
total of 6 subjects (* 6% of the total targeted 90 treated subjects) or
discordance between the local assay and the central laboratory in 3 subjects (*
3% of the total targeted 90 treated subjects), all subsequent subjects will be
required to have BRAFV600E determined by the central lab prior to study
treatment assignment.
c. Central testing cannot be repeated to resolve discordances with a local
result once the central laboratory delivers a definitive result (positive or
negative).
d. If the result from the central laboratory is indeterminate or the sample is
deemed inadequate for testing, additional samples may be submitted (archival
material only).
e. If more than 1 discordant result from any local laboratory lead to subject
enrollment, subsequent results from this local laboratory will not be accepted
for further subject enrollment.
5. Eligible to receive cetuximab per locally approved label with regards to
tumor RAS status
e.g.: In agreement with EU label, evidence of wild type RAS (KRAS and NRAS)
status in EU countries
6. Able to provide a sufficient amount of representative tumor specimen
(primary or metastatic, archival or newly obtained) for testing of BRAF and RAS
mutation status(FFPE tumor tissue block or a minimum of 10 slides, optimally up
to 15 slides)
7. Evidence of measurable disease, as per RECIST 1.1.
Note: Lesions in areas of prior radiotherapy or other loco-regional therapies
are considered measurable only if progression has been documented in the region
following therapy.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
9. Adequate bone marrow function at screening and baseline:
i. Absolute neutrophil count (ANC) * 1.5 x 1 000 000 000 /L.
ii. Platelets * 100 x 1 000 000 000/L
iii. Hemoglobin * 9.0 g/dL.
Blood transfusions are allowed provided that the subject has not received more
than 2 units of red blood cells in the 4 weeks prior to achieve the minimum
required hemoglobin level.
10. Adequate renal function at screening and baseline:
i. Serum creatinine * 1.5x upper limit of normal (ULN).
ii. Calculated creatinine clearance (CrCl)* 50 mL/min by Cockroft-Gault formula.
11. Adequate electrolytes at screening and baseline, defined as serum potassium
and magnesium levels within institutional normal limits.
Replacement treatment to achieve adequate electrolytes will be allowed
12. Adequate hepatic function at screening and baseline:
i. Serum total bilirubin * 1.5 x ULN and < 2 mg/dL. Total bilirubin > 1.5
x ULN is allowed if direct (conjugated) bilirubin is * 1.5 x ULN.
ii. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) *
2.5 x ULN, or * 5 x ULN in the presence of liver metastases.
13. Adequate cardiac function at screening:
i. Left ventricular ejection fraction (LVEF) * 50% as determined by MUGA scan
or ECHO.
ii. Mean triplicate QT interval corrected for heart rate according to
Fridericia*s formula (QTcF) value * 480 msec.
14. Subject able to take oral medications.
15. Willing and able to comply with scheduled visits, treatment plan,
laboratory tests and other study procedures.
16. Female subjects are either postmenopausal for at least 1 year, are
surgically sterile for at least 6 weeks, or must agree to take appropriate
precautions to avoid pregnancy.
(a) Precautions to avoid pregnancy must be conducted from screening through 6
months after the last dose of cetuximab or through 30 days after the last dose
of encorafenib or binimetinib, whichever is later if of childbearing potential.
(b) Permitted methods of contraception as provided (in Section 5.3.1) should be
communicated to the subjects and their understanding confirmed. For all
females, the pregnancy test must be negative at screening and baseline.
17. Male subject must agree to take appropriate precautions to avoid fathering
a child
(a) from screening through 6 months after the last dose of cetuximab or through
90 days after the last dose of encorafenib or binimetinib, whichever is later.
(b) permitted methods of contraception as provided (in Section 5.3.1) should be
communicated to the subjects and their understanding confirmed.
18. Patients under guardianship or partial guardianship will be eligible unless
prohibited by local laws or by local/central ethic committees.
Note: where allowed, all procedures prescribed by law must be followed.
19. Affiliated to a social security system, or is a beneficiary (if applicable
in the national regulation).

1. Prior systemic therapy for metastatic disease.
Note: previous adjuvant/neoadjuvant therapy is allowed provided that 1) the
interval from the end of chemotherapy to relapse is >6 months 2) in the case
of neoadjuvant therapy, complete surgical resection was achieved and the
interval from the end of chemotherapy to relapse is >12 months. Prior
locoregional radiotherapy is allowed.
2. Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab or other
anti- EGFR treatment.
3. Symptomatic brain metastasis.
Note: subjects previously treated or untreated for these conditions who are
asymptomatic in the absence of corticosteroid and anti-epileptic therapy are
allowed. Brain metastases must be stable for * 4 weeks with imaging
4. Leptomeningeal disease.
5. 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 syndrome or hypercoagulability syndrome.
6. Use of any herbal medications/supplements or any medications or foods that
are moderate or strong inhibitors or inducers of CYP3A4/5 * 1 week prior to the
start of treatment.
Note: However, subjects who either discontinue moderate or strong inhibitors or
inducers of CYP3A4/5 or switch to another medication at least 7 days prior to
starting study treatment are eligible.
7. Known history of acute or chronic pancreatitis within 6 months prior to the
start of the treatment.
8. History of chronic inflammatory bowel disease or Crohn*s disease requiring
medical intervention (immunomodulatory or immunosuppressive medications or
surgery) * 12 months prior to first dose.
9. Impaired cardiovascular function or clinically significant cardiovascular
diseases, including any of the following:
i. History of acute myocardial infarction, acute coronary syndromes (including
unstable angina, coronary artery bypass graft, coronary angioplasty or
stenting) * 6 months prior to start of study treatment.
ii. Symptomatic congestive heart failure (Grade 2 or higher), history or
current evidence of clinically significant arrhythmia and/or conduction
abnormality * 6 months prior to start of study treatment, except atrial
fibrillation and paroxysmal supraventricular tachycardia.
10. Uncontrolled hypertension defined as persistent elevation of systolic blood
pressure * 150 mmHg or diastolic blood pressure * 100 mmHg despite optimal
therapy.
11. Impaired hepatic function, defined as Child-Pugh class B or C.
12. No more applicable from protocol v6.
13. Impaired gastrointestinal function or disease which may significantly alter
the absorption of encorafenib or binimetinib or recent changes in bowel
function suggesting current or impending bowel obstruction.
14. Previous or concurrent malignancy within 5 years of study entry or other
noninvasive or indolent malignancy without Sponsor approval except cured basal
or squamous cell skin cancer, superficial bladder cancer, prostate
intraepithelial neoplasm, carcinoma in-situ of the cervix.
15. History of thromboembolic or cerebrovascular events * 6 months prior to
starting study treatment including transient ischemic attacks, cerebrovascular
accidents, deep vein thrombosis or pulmonary emboli.
16. Concurrent neuromuscular disorder that is associated with the potential of
elevated Creatine Kinase e.g. inflammatory myopathies, muscular dystrophy,
amyotrophic lateral sclerosis, spinal muscular atrophy.
17. Residual CTCAE * Grade 2 toxicity from any prior anticancer therapy, with
the exception of Grade 2 alopecia or Grade 2 neuropathy.
18. Known history of human immunodeficiency virus infection.
19. Active hepatitis B or hepatitis C infection.
20. Known contraindication to receive cetuximab at the planned doses.
21. Subjects who have any medical condition that would, in the Investigator*s
judgment, prevent the subject*s participation in the clinical study due to
safety concerns or compliance with study procedures.
22. Any medical or psychiatric condition or laboratory abnormality that may
increase the risk with study participation or study drug administration or that
may interfere with the interpretation of study.
23. Pregnancy, confirmed by a positive human chorionic gonadotropin laboratory
test result, or breastfeeding.
24. Is a family member of the Investigator or any associate, colleague, or
employee assisting in the conduct of the study
25. Is in a position likely to represent a conflict of interest.
26. Participation in a clinical study with administration of an investigational
product within 4 weeks before the first dose of study treatment.
27. Is mentally unable to understand the nature, objectives and possible
consequences of the trial; or he/she refuses to its constraints.