Metastatic Colorectal Cancer

Safety Lead-in In patients with BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC): Primary:  Assess the safety/tolerability of the combination of encorafenib + binimetinib + cetuximab Secondary:  Assess the activity of encorafenib + binimetinib + cetuximab as measured by Investigator-determined objective response rate (ORR), duration of response (DOR) and time to response  Characterize the pharmacokinetics (PK) of encorafenib, cetuximab, binimetinib and the active metabolite of binimetinib (AR00426032) Randomized Phase 3 In patients with BRAFV600E mCRC: Primary:  Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or 5-fluorouracil (5- FU)/folinic acid (FA)/irinotecan (FOLFIRI)/cetuximab (Control Arm) as measured by overall survival (OS)

LGX818 ( Encorafenib) , MEK162( Binimetinib)

Binimetinib
Encorafenib

capsule
Film-coated tablets

75
15

Safety Lead-in
Primary:
 Incidence of dose-limiting toxicities (DLTs)
 Incidence and severity of adverse events (AEs) graded
according to the National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE), version
4.03 (v.4.03), and changes in clinical laboratory parameters,
vital signs, electrocardiograms (ECGs), echocardiogram
(ECHO)/multi-gated acquisition (MUGA) scans and
ophthalmic examinations
 Incidence of dose interruptions, dose modifications and
discontinuations due to AEs
Secondary:
 ORR per the Response Evaluation Criteria in Solid Tumors
(RECIST), version 1.1 (v1.1), defined as the number of
patients achieving an overall best response of complete
response (CR) or partial response (PR) divided by the total
number of patients
 DOR, defined as the time from first radiographic evidence of
response to the earliest documented disease progression or
death due to underlying disease
 Time to response, defined as the time from first dose to first
radiographic evidence of response
 Plasma PK parameters of encorafenib, cetuximab, binimetinib
and the active metabolite of binimetinib (AR00426032)
Randomized Phase 3
Primary:
 OS, defined as the time from randomization to death due to
any cause, of Triplet Arm vs. Control Arm
Key Secondary:
 OS of Doublet Arm vs. Control Arm

Inclusion Criteria
All the following inclusion criteria must be met for a patient to be
included in the study:
1. Provide a signed and dated Screening informed consent
document
2. Age ≥ 18 years at time of informed consent
3. Histologically- or cytologically-confirmed CRC that is
metastatic
4. Presence of BRAFV600E in tumor tissue previously
determined by a local assay at any time prior to Screening
or by the central laboratory
Notes:
a. Only PCR and NGS-based local assays results will be
acceptable.
b. Central testing cannot be repeated to resolve
discordances with a local result once the central
laboratory delivers a definitive result (positive or
negative).
c. If the result from the central laboratory is
indeterminate or the sample is deemed is inadequate
for testing, a second sample may be submitted.
d. If at any time there is discordance in the results
between the local assay and the central laboratory
(potential false-positive local result), or lack of
BRAFV600E confirmation in 18 patients, all subsequent
patients will be required to have BRAFV600E
determined by the central laboratory prior to
enrollment
e. Results from local laboratories with more than 1
discordant result leading to patient enrollment will
not be accepted for further patient enrollment.
5. Able to provide a sufficient amount of representative tumor
specimen (primary or metastatic, archival or newly
obtained) for confirmatory central laboratory testing of
BRAF and KRAS mutation status (minimum of 15 slides)
Note: Tumor samples must be submitted to the central
laboratory for BRAF testing as soon as possible following
the signing of the Molecular Prescreening informed
consent. The BRAF status must be confirmed no later than
30 days following first dose of study drug.
6. Eligible to receive cetuximab per locally approved label
with regard to tumor RAS status
7. Progression of disease after 1 or 2 prior regimens in the
metastatic setting
Notes:
a. Disease relapse during treatment or within 6 months
following adjuvant therapy will be considered
metastatic disease.
b. Maintenance therapy given in the metastatic setting
will not be considered a separate regimen.
c. In the Phase 3 portion of study, the number of patients
having received 2 prior regimens will be limited to 215
(35% of the total randomized). Patients with 2 prior
regimens who have entered Screening at the time that
the limit has been reached will be permitted to continue
into the study if they are otherwise determined to be
eligible.
8. Evidence of measurable or evaluable non-measurable
disease per RECIST, v1.1
9. ECOG PS of 0 or 1
10. Adequate bone marrow function characterized by the
following at screening:
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109
/L;
b. Platelets ≥ 100 × 109
/L;
c. Hemoglobin ≥ 9.0 g/dL
Note: Transfusions will be allowed to achieve this.
Transfusions will be permitted provided the patient has
not received more than 2 units red blood cells in the
prior 4 weeks to achieve this criteria.
11. Adequate renal function characterized by serum creatinine
≤ 1.5 × upper limit of normal (ULN), or calculated by
Cockroft-Gault formula or directly measured creatinine
clearance ≥ 50 mL/min at screening
12. Adequate hepatic function characterized by the following
at screening:
a. Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL
Note: Patients who have a total bilirubin level
> 1.5 × ULN will be allowed if their indirect bilirubin
level is ≤ 1.5 × ULN
b. Alanine aminotransferase (ALT) and/or aspartate
aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN
in presence of liver metastases
13. Adequate cardiac function characterized by the following
at screening:
a. Left ventricular ejection fraction (LVEF) ≥ 50% as
determined by a MUGA scan or ECHO;
b. Mean triplicate QT interval corrected for heart rate
using Fridericia's formula (QTcF) value ≤480 msec
14. Able to take oral medications
15. Willing and able to comply with scheduled visits,
treatment plan, laboratory tests and other study procedures
16. 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
Note: Permitted methods that are at least 99% effective in
preventing pregnancy should be communicated to the
patients and their understanding confirmed. For all
females, the pregnancy test result must be negative at
screening.
17. Males must agree to take appropriate precautions to avoid
fathering a child from screening through follow-up.
Note: permitted methods that are at least 99% effective in
preventing pregnancy should be communicated to the
subjects and their understanding confirmed.

Exclusion Criteria
Patients meeting any of the following criteria will not be included
in the study:
1. Prior treatment with any RAF inhibitor, MEK inhibitor,
cetuximab, panitumumab or other EGFR inhibitors
2. Prior irinotecan hypersensitivity or toxicity that would
suggest an inability to tolerate irinotecan 180 mg/m2
every
2 weeks
3. Symptomatic brain metastasis
Notes: Patients previously treated or untreated for this
condition who are asymptomatic in the absence of
corticosteroid and anti-epileptic therapy are allowed. Brain
metastases must be stable for ≥ 4 weeks, with imaging
(e.g., magnetic resonance imaging [MRI] or computed
tomography [CT]) demonstrating no current evidence of
progressive brain metastases at screening.
4. Leptomeningeal disease
5. History or current evidence of RVO or current risk factors
for RVO (e.g., uncontrolled glaucoma or ocular
hypertension, history of hyperviscosity or
hypercoagulability syndromes)
6. Use of any herbal medications/supplements or any
medications or foods that are strong inhibitors or inducers
of cytochrome P450 (CYP) 3A4/5 ≤ 1 week prior to the
start of study treatment
7. Known history of acute or chronic pancreatitis
8. History of chronic inflammatory bowel disease or Crohn’s
disease requiring medical intervention (immunomodulatory
or immunosuppressive medications or surgery)
≤ 12 months prior to randomization
9. Impaired cardiovascular function or clinically significant
cardiovascular diseases, including any of the following:
a. History of acute myocardial infarction, acute
coronary syndromes (including unstable angina,
coronary artery bypass graft [CABG], coronary
angioplasty or stenting) ≤ 6 months prior to start of
study treatment;
b. Symptomatic congestive heart failure (i.e., Grade 2
or higher), history or current evidence of clinically
significant cardiac 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 systolic
blood pressure ≥ 150 mmHg or diastolic blood pressure
≥ 100 mmHg despite current therapy
11. Impaired hepatic function, defined as Child-Pugh class B
or C
12. Impaired gastrointestinal (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)
13. 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 without Sponsor
approval
14. 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
15. Concurrent neuromuscular disorder that is associated with
the potential of elevated CK (e.g., inflammatory
myopathies, muscular dystrophy, amyotrophic lateral
sclerosis, spinal muscular atrophy)
16. Treatment with any of the following:
a. Cyclical chemotherapy within a period of time that was
shorter than the cycle length used for that treatment
(e.g., 6 weeks for nitrosourea, mitomycin-C) prior to
starting study treatment
b. Biologic therapy (e.g., antibodies) except bevacizumab
or aflibercept, continuous or intermittent small
molecule therapeutics, or any other investigational
agents within a period of time that is ≤ 5 half-lives (t1/2)
or ≤ 4 weeks (whichever is shorter) prior to starting
study treatment
c. Bevacizumab or aflibercept therapy ≤ 3 weeks prior to
starting study treatment
d. Radiation therapy that included > 30% of the bone
marrow
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 HIV infection
19. Active hepatitis B or hepatitis C infection
20. Known history of Gilbert's syndrome or is known to have
any of the following genotypes: UGT1A1*6/*6,
UGT1A1*28/*28, or UGT1A1*6/*28
21. Known contraindication to receive 5-FU or FA
22. Known contraindication to receive cetuximab or irinotecan
at the planned doses
23. Current treatment with a non-topical medication known to
be a strong inhibitor of CYP3A4. However, patients who
either discontinue this treatment or switch to another
medication at least 7 days prior to starting study treatment
are eligible.
24. Concomitant use of St. John’s Wort (hypericum
perforatum)
25. Other severe, acute or chronic medical or psychiatric
condition or laboratory abnormality that may increase the
risk associated with study participation or study drug
administration or that may interfere with the interpretation
of study results and, in the judgment of the Investigator,
would make the patient an inappropriate candidate for the
study
26. Pregnant, confirmed by a positive human chorionic
gonadotropin (hCG) laboratory test result, or nursing
(lactating)
27. Prior enrollment into this clinical study.