encorAfenib, biNimetinib and Cetuximab in Subjects witH previOusly Untreated BRAF-mutant ColoRectal Cancer

The presence of a BRAFV600E mutation is considered a marker of poor prognosis in subjects
with mCRC. The preclinical results and preliminary clinical data together justify the
evaluation of this triple combination in the first-line setting of this population. The
primary objective of the study is to evaluate the antitumor activity of the combination of
encorafenib, binimetinib and cetuximab by assessing the overall response rate in adult
subjects with previously untreated BRAFV600E-mutant metastatic colorectal cancer. It will
also assess the effect of the triple combination on the duration of response, time to
response, progression-free survival and overall survival and assess the effect on quality of
life. It will also characterize the safety and tolerability of the triple combination as well
as describe the pharmacokinetics (PK) of encorafenib, binimetinib, and cetuximab.

Inclusion Criteria:

- Male or female ≥ 18 years of age

- Histologically or cytologically confirmed CRC that is metastatic

- Presence of BRAF V600E in tumor tissue determined by local assay at any time prior to
screening and confirmed by central laboratory

- Evidence of measurable disease as per RECIST, v1.1

- Subject able to receive cetuximab as per approved label with regards to RAS status

- ECOG Status 0 or 1

- Adequate renal, hepatic, cardiac and bone marrow functions and adequate electrolytes
as per protocol

- Subject able to take oral medications

Exclusion Criteria:

- Prior systemic therapy for metastatic disease

- Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab or other anti-EGFR
inhibitors

- Symptomatic brain metastasis or Leptomeningeal disease

- History or current evidence of Retinal Vein Occlusion (RVO) or current risk factors
for RVO

- 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.

- Impaired cardiovascular function or clinically significant cardiovascular diseases:
history of myocardial infarction or coronary disorders within 6 months prior to start
of study treatment, symptomatic congestive heart failure (grade 2 or higher), past or
current clinically significant arrhythmia and/or conduction disorder within 6 months
prior to study treatment start

- History of thromboembolic or cerebrovascular events within 6 months prior to start of
study treatment

- Concurrent neuromuscular disorder that is associated with potential elevation of
Creatine Kinase

- Known contraindication to cetuximab administration as per SPC/approved label