Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer

Key Inclusion Criteria:

- Age ≥ 18 years at time of informed consent

- Histologically- or cytologically-confirmed CRC that is metastatic

- Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any
time prior to Screening or by the central laboratory

- Progression of disease after 1 or 2 prior regimens in the metastatic setting

- Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1

- Adequate bone marrow, cardiac, kidney and liver function

- Able to take oral medications

- Female patients 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
from screening through follow-up if of childbearing potential

- Males must agree to take appropriate precautions to avoid fathering a child from
screening through follow-up

Key Exclusion Criteria:

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

- Prior irinotecan hypersensitivity or toxicity that would suggest an inability to
tolerate irinotecan 180 mg/m2 every 2 weeks

- Symptomatic brain metastasis or leptomeningeal disease

- History or current evidence of retinal vein occlusion or current risk factors for
retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of
hyperviscosity or hypercoagulability syndromes)

- Known history of acute or chronic pancreatitis

- History of chronic inflammatory bowel disease or Crohn's disease requiring medical
intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months
prior to randomization

- Uncontrolled blood pressure despite medical treatment

- 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)

- Concurrent or previous other malignancy within 5 years of study entry, except cured
basal or squamous cell skin cancer, superficial bladder cancer, prostate
intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or
indolent malignancy

- 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

- Concurrent neuromuscular disorder that is associated with the potential of elevated CK
(e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis,
spinal muscular atrophy)

- Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the
exception of Grade 2 alopecia or Grade 2 neuropathy

- Known history of HIV infection

- Active hepatitis B or hepatitis C infection

- Known history of Gilbert's syndrome

- Known contraindication to receive cetuximab or irinotecan at the planned doses