Conditions: BRAF V600E-mutant Metastatic Colorectal Cancer
Keywords: Colorectal cancer BRAF BRAFV600E
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 702
Healthy volunteers: no

Brief summary:
This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the Phase 3 portion of the study.

Detailed description:

Arms:
arm 1: Encorafenib + binimetinib + cetuximab. arm 2: Encorafenib + cetuximab. arm 3: Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.

Interventions: intervention 1: Encorafenib intervention 2: Binimetinib intervention 3: Cetuximab intervention 4: Irinotecan intervention 5: Folinic Acid intervention 6: 5-Fluorouracil
Intervention descriptions: intervention 1: Orally, once daily. intervention 2: Orally, twice daily. intervention 3: Standard of care. intervention 4: Standard of care. intervention 5: Standard of care. intervention 6: Standard of care.

Protocol document:
SAP_002.pdf: 
STATISTICAL ANALYSIS PLAN 
 
The BEACON CRC Study (Binimetinib, Encorafenib, And 
Cetuximab COmbiNed to Treat BRAF-mutant ColoRectal Cancer): 
 
A Multicenter, Randomized, Open-label, 3-Arm Phase 3 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 
 
 
 
  
PROTOCOL NUMBER: 
 ARRAY-818-302 
VERSION: 
 6.0 FINAL 
DATE: 
 23 April 2019 
 
Prepared by: 
 PhD 
Sr. Principal Biostatistician, Biostatistics 
 
Array BioPharma Inc. 
3200 Walnut Street 
Boulder, CO 80301 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and may not be disclosed to 
another party without the permission of the author unless such disclosure is required by law or 
regulations. Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 
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TABLE OF CONTENTS 
 INTRODUCTION ................................................................................................................ 9 
1.0
1.1 
Responsibilities .................................................................................................................9 
 STUDY OBJECTIVES ...................................................................................................... 10 
2.0
2.1 
Primary Objectives ..........................................................................................................10 
2.2 
Key Secondary Objective ................................................................................................10 
2.3 
Secondary Objectives ......................................................................................................10 
 
 
 INVESTIGATIONAL PLAN............................................................................................. 12 
3.0
3.1 
Overall Study Design and Plan .......................................................................................12 
3.2 
Sample Size Considerations ............................................................................................15 
 STUDY ENDPOINTS ........................................................................................................ 18 
4.0
4.1 
Primary Endpoints ...........................................................................................................18 
4.2 
Key Secondary Endpoints ...............................................................................................18 
4.3 
Secondary Endpoints .......................................................................................................18 
 
 
 ANALYSIS SETS ............................................................................................................... 21 
5.0
5.1 
Full Analysis Set ..............................................................................................................21 
5.2 
Safety Set .........................................................................................................................21 
5.3 
Dose-Determining Set .....................................................................................................21 
5.4 
Safety Lead-in Efficacy Set .............................................................................................22 
5.5 
Phase 3 Response Efficacy Set ........................................................................................22 
5.6 
Per-Protocol Set ...............................................................................................................22 
5.7 
Pharmacokinetic Set ........................................................................................................22 
 CHANGES FROM THE STUDY PROTOCOL.............................................................. 23 
6.0
 STATISTICAL METHODS ............................................................................................... 24 
7.0
7.1 
Reporting Conventions and Definitions ..........................................................................24 
7.1.1 
Reporting Conventions ............................................................................................24 
7.1.2 
Death Date ...............................................................................................................25 
7.1.3 
Dates of Antineoplastic Therapies ...........................................................................25 
7.1.4 
Definitions ...............................................................................................................26 
7.2 
Patient Disposition ..........................................................................................................27 
7.3 
Protocol Deviations .........................................................................................................28 
7.4 
Patient Characteristics .....................................................................................................28 
7.4.1 
Demographics and Pretreatment Characteristics .....................................................28 
7.4.2 
Medical History, Baseline Signs and Symptoms .....................................................29 
7.4.3 
Prior Anticancer Therapy .........................................................................................29 
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7.4.4 
Other Prior Medications ..........................................................................................29 
7.5 
Efficacy Analysis .............................................................................................................30 
7.5.1 
Objective Response Rate .........................................................................................32 
7.5.2 
Overall Survival .......................................................................................................35 
7.5.3 
Efficacy Analyses of Secondary Endpoints .............................................................39 
7.5.4 
Duration of Response ..............................................................................................43 
7.5.5 
Time to Response ....................................................................................................44 
7.6 
Assessment of the Binimetinib Contribution to Efficacy ................................................45 
7.7 
Progression After Next Line of Therapy (PFS2) .............................................................45 
7.8 
Safety Analysis ................................................................................................................46 
7.8.1 
Extent of Study Drug Exposure ...............................................................................46 
7.8.2 
Concomitant Medications ........................................................................................48 
7.8.3 
Subsequent Anticancer Therapies ............................................................................50 
7.8.4 
Adverse Events ........................................................................................................50 
7.8.5 
Adverse Events of Special Interest ..........................................................................54 
7.8.6 
Clinical Laboratory Evaluations ..............................................................................55 
7.8.7 
Pregnancy Tests .......................................................................................................58 
7.8.8 
Physical Examinations .............................................................................................58 
7.8.9 
ECOG Performance Status ......................................................................................58 
7.8.10 
Vital Signs ................................................................................................................58 
7.8.11 
Electrocardiograms ..................................................................................................59 
7.8.12 
MUGA/Echocardiogram .........................................................................................60 
7.8.13 
Ophthalmic Examination .........................................................................................60 
7.8.14 
Dermatologic Examination ......................................................................................61 
7.8.15 
Follow-up .................................................................................................................61 
7.8.16 
Comments ................................................................................................................61 
7.9 
Pharmacokinetic Analysis ...............................................................................................61 
7.9.1 
Concentrations of Cetuximab, Encorafenib, Binimetinib, and AR00426032 .........62 
7.9.2 
Pharmacokinetic Parameters for Cetuximab, Encorafenib, Binimetinib, and 
AR00426032 ............................................................................................................62 
 
7.11 Patient-reported Outcomes ..............................................................................................66 
7.12 Interim Safety Reviews ...................................................................................................67 
7.13 Initial Efficacy Analyses .................................................................................................67 
7.14 Subgroup Analyses ..........................................................................................................69 
 DATA AND ANALYSIS QUALITY ASSURANCE ......................................................... 73 
8.0
 REFERENCES ................................................................................................................... 74 
9.0
 CHANGES TO THE STATISTICAL ANALYSIS PLAN ............................................... 76 
10.0
 
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LIST OF TABLES 
Table 3-1: 
Operating Characteristics of Safety Lead-In Criteria for 9 Patients Compared To 
3+3 Rules ................................................................................................................. 15 
Table 7-1: 
Options for PFS Analysis ......................................................................................... 40 
Table 7-2: 
Concomitant Medication Start Date Imputation Example Scenarios ...................... 49 
Table 7-3: 
Concomitant Medication End Date Imputation Example Scenarios ....................... 49 
Table 7-4: 
Hepatic Toxicity Criteria .......................................................................................... 57 
Table 7-5: 
Clinical Notable ECG Criteria ................................................................................. 59 
Table 7-6: 
Expected Number of OS Events and Cumulative Power at Expected OS 
Analysis Timepoints for the Triplet vs. Control Comparison .................................. 69 
Table 7-7: 
Medical History Terms for Cardiac Risk ................................................................. 72 
LIST OF FIGURES 
Figure 7-1: Testing Strategy for ARRAY-818-302 ..................................................................... 32 


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LIST OF ABBREVIATIONS 
Abbreviation or Special Term 
Explanation 
5-FU 
5-Fluorouracil 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
Array 
Array BioPharma Inc. 
AST 
aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the plasma concentration-time curve 
AUC0-x 
area under the plasma concentration-time curve from zero to the specified 
time point 
AUC/D 
dose-normalized AUC 
AUCext 
percentage of AUCinf due to extrapolation from Tlast to infinity 
AUCinf 
area under the plasma concentration-time curve extrapolated to infinity 
AUClast 
area under the plasma concentration-time curve from zero to the last 
measurable time point 
AUCtau 
area under the plasma concentration-time curve over the dosing interval 
BLQ 
below the limit of quantitation 
BP 
blood pressure 
Bpm 
beats per minute 
C1D1 
Day 1 of Cycle 1 
C1DX 
Day X of Cycle 1 
CI 
confidence interval 
Clast 
last measured concentration 
CL/F 
apparent systemic clearance 
Cmax 
observed maximum plasma concentration 
Cmax/D 
dose-normalized Cmax 
CR 
complete response 
 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DILI 
drug-induced liver injury 
DDS 
dose-determining set 
DLT 
dose-limiting toxicity 
EDC 
electronic data capture 
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Abbreviation or Special Term 
Explanation 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC 
European Organization for Research and Treatment of Cancer  
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire 
EQ5D-5L 
EuroQol-5D-5L 
FA 
Folinic Acid 
FACT-C 
Functional Assessment of Cancer Therapy-Colon cancer 
FAS 
full analysis set 
FDA 
United States Food and Drug Administration 
fe= 
fraction of daily dose excreted 
FOLFIRI 
5-FU/FA/irinotecan 
HR 
hazard ratio 
IV 
intravenous(ly) 
IWRS 
Interactive Web Response System 
JSLI 
Japanese Safety Lead-in 
kel 
terminal elimination rate constant 
KM 
Kaplan-Meier 
LFAUC 
linearity factor based on AUC values 
LLT 
lowest level term 
logMAR 
logarithm of the minimum angle of resolution 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRAUC 
metabolite ratio based on AUC values 
MRCmax 
metabolite ratio based on Cmax values 
Msec 
millisecond(s) 
MSI 
microsatellite instability 
n, N 
number 
NC 
not calculated 
NCA 
noncompartmental analysis 
NCI 
National Cancer Institute 
OCT 
optical coherence tomography 
ORR 
objective response rate (overall response rate) 
OS 
overall survival 


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Abbreviation or Special Term 
Explanation 
PAP 
pharmacokinetic analysis plan 
PD 
progressive disease 
PFS 
progression-free survival 
PFS2 
progression after next line of therapy 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic(s) 
PPS 
per protocol set 
PR 
partial response 
PT 
preferred term 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fredericia’s formula 
RAUC 
accumulation ratio based on AUC values 
RCmax 
accumulation ratio based on Cmax values 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI units 
International System of Units 
SOC 
system organ class 
SS 
safety set 
t1/2 
terminal elimination half-life 
SAE 
treatment-emergent serious adverse event 
SLI 
Safety Lead-in 
TBL 
total bilirubin 
Tlast 
observed time of Clast 
TLF 
tables, listings and figures 
Tmax 
observed time of Cmax 
TSST 
time to second subsequent therapy 
TTR 
time to overall response 
ULN 
upper limit of normal 
vs. 
versus 
Vz/F 
apparent volume of distribution 
WHO 
World Health Organization 


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INTRODUCTION 
1.0
This document describes the statistical analyses and data presentations to be performed for the 
clinical protocol ARRAY-818-302 entitled “A Multicenter, Randomized, Open-label, 3-Arm 
Phase 3 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.” This statistical analysis plan (SAP) should be read in conjunction 
with the study protocol and electronic case report forms (eCRFs). This document has been 
developed using the protocol Version 7 dated 25 January 2019 and eCRFs dated 10 August 2018. 
Any further changes to the protocol or eCRFs may necessitate updates to the SAP. 
This SAP provides a comprehensive and detailed description of the strategy, rationale and 
statistical techniques to be used to assess the safety, efficacy, pharmacokinetics (PK) and 
 analyses in patients with BRAF V600EmCRC whose disease has progressed after 1 to 
2 prior regimens in the metastatic setting as outlined in the protocol. The purpose of this SAP is 
to ensure the credibility of the study findings by specifying the statistical approaches for the 
initial and final analysis of study data. This SAP will be finalized and signed prior to the clinical 
database lock for any analyses specified in this SAP. 
Statistical analyses detailed in this SAP will be conducted using 
 
. Noncompartmental PK analyses will be performed with 
 Original sample size 
calculations were conducted using East v6.3.1 (Cytel). For protocol Version 7, 
 
was used in the power calculations. 
1.1 
Responsibilities 
An Array Biostatistician or Statistical Programmer (or delegate) will perform any statistical 
analyses required for patient disposition, protocol deviations, patient characteristics, efficacy and 
safety; an Array Biostatistician (or delegate) is responsible for the production and quality control 
of all tables, figures and listings associated with these analyses. An Array Clinical Pharmacology 
representative (or delegate) will perform any PK parameter analyses, and is responsible for the 
production and quality control of all tables, figures and listings associated with these analyses. 
An Array Translational Medicine representative (or delegate) will perform any 
 
statistical analyses, and is responsible for the production and quality control of all tables, figures 
and listings associated with these analyses. 
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STUDY OBJECTIVES 
2.0
2.1 
Primary Objectives 
o Safety Lead-In: Assess the safety/tolerability of the combination of encorafenib + 
binimetinib + cetuximab 
o Randomized Phase 3: 
• Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. 
irinotecan/cetuximab or 5-FU/FA/irinotecan (FOLFIRI)/cetuximab (Control Arm) as 
measured by overall survival (OS) 
• Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. 
irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) as measured by blinded 
independent central review (BICR) determined objective response rate (ORR) 
2.2 
Key Secondary Objective 
o Randomized Phase 3: Compare the activity of encorafenib + cetuximab (Doublet Arm) 
vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) as measured by OS 
2.3 
Secondary Objectives 
o Safety Lead-In: 
• Assess the activity of encorafenib + binimetinib + cetuximab as measured by blinded 
independent central review (BICR)-determined and Investigator-determined ORR, 
duration of response (DOR), progression-free survival (PFS) and time to response 
• Characterize the pharmacokinetics (PK) of encorafenib, cetuximab, binimetinib and 
the active metabolite of binimetinib (AR00426032) 
o Randomized Phase 3: 
• Compare the Investigator-determined ORR of encorafenib + binimetinib + cetuximab 
(Triplet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) 
• Compare the BICR-determined and Investigator-determined ORR of encorafenib + 
cetuximab (Doublet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control 
Arm) 
• Compare the BICR-determined and Investigator-determined PFS of encorafenib + 
binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or 
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• Compare the BICR-determined and Investigator-determined PFS of encorafenib + 
cetuximab (Doublet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control 
Arm) 
• Compare the activity of Triplet Arm vs. Doublet Arm as measured by OS 
• Compare the BICR-determined and Investigator-determined ORR of Triplet Arm vs. 
Doublet Arm 
• Compare the BICR-determined and Investigator-determined PFS of Triplet Arm vs. 
Doublet Arm 
• Compare BICR-determined and Investigator-determined DOR of Triplet Arm vs. 
Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm 
• Compare BICR-determined and Investigator-determined time to response of Triplet 
Arm vs. Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. 
Doublet Arm 
• Assess the safety/tolerability of Triplet Arm, of Doublet Arm and of Control Arm 
• Compare the effect on QoL of Triplet Arm vs. Control Arm, of Doublet Arm vs. 
Control Arm and of Triplet Arm vs. Doublet Arm  
• Characterize the PK of encorafenib, cetuximab, binimetinib and the active metabolite 
of binimetinib (AR00426032)  
• Assess for drug interactions between encorafenib, cetuximab, binimetinib and the 
active metabolite of binimetinib (AR00426032) based on PK modeling  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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INVESTIGATIONAL PLAN 
3.0
3.1 
Overall Study Design and Plan 
This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + 
cetuximab plus or minus binimetinib versus physician’s choice of either irinotecan/cetuximab or 
FOLFIRI/cetuximab, as controls, in patients with BRAF V600E mCRC whose disease has 
progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety 
Lead-in (SLI) Phase in which the safety and tolerability of encorafenib + binimetinib + 
cetuximab will be assessed prior to the Phase 3 portion of the study in a SLI cohort of US and 
EU patients. In the Japanese Safety Lead-in (JSLI) cohort, patients will be evaluated at a limited 
number of sites in Japan. Six patients will be enrolled on a rolling basis in a single cohort to 
evaluate the Triplet dose. The starting dose in Japanese patients will be the dose assessed to be 
tolerable in the SLI for non-Japanese patients. Similar to the SLI cohort for non-Japanese 
patients, the DMC will evaluate the safety data to confirm tolerability. 
BRAF Testing 
Patients will be eligible for the study based on identification of a BRAF V600E mutation in the 
tumor as determined by the central laboratory as part of the Molecular Prescreening for the trial 
or by a local assay result obtained any time prior to Screening. Only polymerase chain reaction 
(PCR) and next generation sequencing (NGS)-based local assays results will be acceptable. If the 
patient is enrolled based on local assay results, the BRAF mutation status must be confirmed by 
the central laboratory no later than 30 days from first dose of study treatment. 
In cases where there is discordance between the local assay and central laboratory results, or if 
the central laboratory is not able to confirm presence of a BRAF V600E mutation due to 
inadequate or poor sample condition within 30 days of initiating study therapy, patients may only 
continue treatment if there is no clinical indication of deterioration or disease progression and the 
Investigator determines that the patient is deriving benefit. In such instances, patients must be 
informed that the BRAF mutation status is unconfirmed and must sign a separate informed 
consent form that includes this information and describes alternative treatment options. 
If at any time in the Phase 3 portion of the study there is lack of BRAF V600E confirmation by 
the central laboratory (for any reason including discordance and inadequate available tissue) in 
37 total patients (6% of the total planned enrollment of the randomized portion of the trial) or 
discordance (a valid result of “no BRAF V600E mutation” as determined by the central 
laboratory) between the local assay and the central laboratory in 18 patients (3% of the total 
planned enrolment), all subsequent patients will be required to have BRAF V600E determined by 


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the central laboratory prior to enrollment. Central testing cannot be repeated to resolve 
discordances with a local result once the central laboratory delivers a definitive result (positive or 
negative). If the result from the central laboratory is indeterminate or the sample is deemed is 
inadequate for testing, additional samples may be submitted. Results from local laboratories with 
more than 1 discordant result leading to patient enrollment will not be accepted for further 
patient enrollment. Sites with more than 2 randomized patients having indeterminate results will 
be required to enroll all subsequent patients based only on central laboratory assay results. 
Molecular Prescreening 
Prior to eligibility assessment for study enrollment/randomization, patients may undergo 
molecular tumor prescreening with the central laboratory BRAF mutation assay at any time prior 
to Screening as long as they meet all the Molecular Prescreening inclusion/exclusion criteria. 
Note that tumor samples previously determined to be BRAF wild-type by local assessment may 
be submitted to the central laboratory. In particular, tumors with clinicopathological features of 
BRAF mutations may be considered for testing by central laboratory regardless of the results of 
prior local BRAF mutation testing. 
Safety Lead-in 
The Safety Lead-in will be conducted at a limited number of sites. Dose-limiting toxicities will 
be evaluated and the tolerability of the binimetinib, encorafenib, and cetuximab combination will 
be assessed by the Sponsor and the Investigator in (approximately) weekly communications. The 
Data Monitoring Committee (DMC) will evaluate the safety data at pre-specified intervals and at 
additional points during the conduct of the Safety Lead-in, if necessary. The first 9 evaluable 
patients will be enrolled on a rolling basis in a single cohort to evaluate the combination of 
encorafenib 300 mg QD + binimetinib 45 mg BID + cetuximab 400 mg/m2 followed by 
250 mg/m2 IV weekly. Additional patients will be enrolled based on assessments of the safety 
data by the DMC during the Safety Lead-in. Following study treatment discontinuation, patients 
who provide informed consent for survival follow-up will continue to be assessed to determine 
survival status until withdrawal of consent, patient is lost to follow-up, death or defined end of 
study. If informed consent cannot be obtained due to the patient being lost to follow-up or 
previous withdrawal of consent, attempts to determine survival status will be made via access to 
public records where permitted by local laws. The doses for the Triplet Arm in the randomized 
Phase 3 portion of the study will be determined after a total of 25-30 patients have been treated at 
the proposed doses and their data evaluated by the DMC. 


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To confirm that the Triplet dose is tolerable in Japanese patients, a separate JSLI cohort will be 
evaluated in 6 patients at a limited number of sites in Japan. The starting dose in Japanese 
patients will be the dose assessed to be tolerable in the SLI cohort. As done for the SLI cohort, 
the DMC will evaluate safety data in the JSLI to confirm tolerability. After treatment is 
discontinued, SLI and JSLI patients will continue to be followed for OS.   
Phase 3 
Once the tolerability of the proposed doses for the Triplet Arm has been established, the Phase 3 
portion of the study will begin and eligible patients will be randomized in a 1:1:1 ratio to the 
Triplet Arm, Doublet Arm or Control Arm. The number of 3rd line patients (those having 
received 2 prior regimens in the advanced/metastatic setting) will be limited to 215 (35% of the 
total enrollment) after which only patients with 1 prior regimen will be 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. Patients 
randomized to the Control Arm may be treated with either irinotecan + cetuximab or FOLFIRI + 
cetuximab as per Investigator’s choice. The choice of irinotecan or FOLFIRI must be declared 
prior to randomization. Randomization will be stratified by baseline Eastern Cooperative 
Oncology Group performance status (ECOG PS; 0 vs. 1), prior use of irinotecan (yes vs. no) and 
cetuximab source (US-licensed vs. EU-approved). The DMC will review the available safety 
information after the first 30 patients in the randomized Phase 3 portion of the study (i.e., 
approximately 10 patients in each arm) have had the opportunity to complete at least 1 cycle of 
treatment to confirm tolerability. As done for the SLI cohort, the DMC will evaluate safety data 
to confirm tolerability in the JSLI cohort. 
Treatment will be administered in 28-day cycles until disease progression, unacceptable toxicity, 
withdrawal of consent, initiation of subsequent anticancer therapy or death. In special 
circumstances (defined in Section 4.5 of the protocol), continuation of treatment beyond disease 
progression may be allowed. After treatment is discontinued, randomized Phase 3 patients will 
continue to be followed for OS. 
End of Study 
End of study will be defined as the point when all patients have the opportunity to be followed 
for at least 1 year after the randomization date of the last patient enrolled and at least 80% of 
patients have an OS event (or are lost to follow-up). Any patients still receiving study drugs at 
the end of the study will be allowed to continue at the discretion of the Investigator and as long 


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as none of the treatment discontinuation criteria are met. After the end of the study, access to 
study drugs will be provided in accordance with local regulations and requirements. 
For additional information regarding eligibility criteria, schedules of assessments, and other 
study design details and procedures, please refer to the protocol. 
3.2 
Sample Size Considerations 
The planned sample size is approximately 646-651 patients (includes 31-36 patients for the SLI 
and JSLI cohorts and approximately 615 in the randomized Phase 3 portion of the study). 
Additional patients may be included in SLI if lower dose levels are evaluated. 
Safety Lead-In 
During the Safety Lead-In, the first 9 evaluable patients will be enrolled to the starting dose of 
the Triplet Arm. This Triplet dose will be presented to the DMC as tolerable if the observed 
Cycle 1 the dose-limiting toxicity (DLT) rate is < 33% (i.e., < 3 patients with DLTs out of 
9 patients). Table 3-1 provides a comparison of the operating characteristics for this dose-
escalation rule with 9 patients and traditional 3 + 3 rules. The results illustrate the benefit of the 
additional patients as the probability of falsely declaring a dose to be toxic is lowest with a 
9-patient cohort when the true DLT rate is ≤ 20%. Similarly, the probability of correctly 
declaring a dose to be toxic is higher with the 9-patient cohort when the true DLT rate is ≥ 40%. 
In addition, observing no Cycle 1 DLTs in 9 patients would be expected to occur with a 
probability of 0.040 if the true DLT rate is 30%. 
Table 3-1: 
Operating Characteristics of Safety Lead-In Criteria for 9 Patients 
Compared To 3+3 Rules 
True Cycle 1 DLT Rate 
Probability of dose declared toxic 
using 3+3 rules 
Probability of observed Cycle 1 
DLT rate ≥ 33% in 9 patients 
10% 
0.094 
0.053 
20% 
0.291 
0.262 
30% 
0.506 
0.537 
40% 
0.691 
0.768 
50% 
0.828 
0.910 
 
If the DMC determines the doses to be tolerable in the first 9 evaluable patients based on 
observing DLTs in < 33% of patients and evaluation of the overall toxicity profile, the SLI will 


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be expanded by an additional 16-21 patients. A total of 25-30 patients will complete the SLI (the 
initial 9 plus the additional patients in the expansion) at the doses proposed for the randomized 
Phase 3 portion of the study. If dose de-escalation is required during the SLI, additional patients 
may be necessary. 
As in the SLI cohort, a separate safety evaluation of Japanese patients will be conducted once the 
JSLI cohort completes 1 cycle of therapy. For this cohort, 6 patients will be enrolled at a limited 
number of sites in Japan, resulting in a total of 31-36 patients for the entire SLI study portion. 
Randomized Phase 3 
Overall Survival 
Original sample size considerations for the Phase 3 portion are based on East® version 6.3.1 
(Cytel). For protocol Version 7, East® version 6.4 (Cytel) was used for the power calculations. 
During the randomized Phase 3 portion of the study, eligible patients will be randomized 1:1:1 
such that approximately 205 patients will receive binimetinib + encorafenib + cetuximab (Triplet 
Arm), approximately 205 patients will receive encorafenib + cetuximab (Doublet Arm) and 
approximately 205 patients will receive irinotecan/cetuximab or FOLFIRI/cetuximab (Control 
Arm). The number of 3rd-line patients (those having received 2 prior regimens) randomized to 
the Phase 3 portion of the study will be limited to 215 (35% of the total randomized) in order to 
ensure generalizability of the study. 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. Permitting up to 35% of the randomized patients to have 
received 2 prior regimens ensures a sufficient sample size to adequately generalize the results 
across subgroups when incorporating other relevant stratification factors. Randomization will be 
stratified by ECOG PS (0 vs. 1), prior use of irinotecan (yes vs. no), and cetuximab source 
(US-licensed vs. EU-approved).  
The primary endpoints are OS and ORR of the Triplet Arm vs. Control Arm. Historical evidence 
(Peeters et al. 2014) suggests that the median OS of FOLFIRI combined with another EGFR 
inhibitor (panitumumab) will be approximately 5 months in BRAF-mutant mCRC. Existing 
published data suggest only modest differences between irinotecan single-agent and FOLFIRI 
efficacy (Clarke et al. 2011). In addition, available data suggests that treatment-eligible patients 
in the 2nd and 3rd-line settings and with or without prior irinotecan have similar PFS and OS 
with standard therapy approaches (De Roock et al. 2010; Morris et al. 2014; Peeters et al. 2014). 


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Based on these findings, it is assumed that both Control Arm options will have an approximate 
median OS of 5 months. 
The number of patients required for the randomized Phase 3 portion of the study is driven by the 
key secondary endpoint of the OS of the Doublet Arm vs. Control Arm. For this comparison, the 
study is powered to detect an improvement of 2.1 months (7.1 months vs. 5 months; hazard ratio 
[HR] = 0.70). With 338 OS events, the study will have approximately 90% power to detect this 
improvement using a group-sequential design and one-sided α = 0.025. Assuming accrual to the 
randomized Phase 3 portion of the study increases over a period of time before reaching a 
maximum of 25 patients per month (for an accrual duration of approximately 25 months) and 5% 
loss to follow-up, approximately 615 patients will be randomized to reach 338 events. With 338 
events, the null hypothesis that the OS in the Doublet Arm is the same or worse than the Control 
Arm will be rejected if the HR is smaller (i.e., better) than 0.808. 
The final analysis for OS will occur once at least 268 events are observed in the Triplet Arm + 
Control Arm and at least 338 events are observed in the Doublet Arm + Control Arm. This is 
expected to occur approximately 33 months after the first patient is randomized (i.e., 
approximately 8 months after randomization is complete). At the time of the final analysis, it is 
anticipated that approximately 333 OS events will be observed in the Triplet Arm + Control 
Arm, but only the first 268 OS events will be included in the primary analysis. With 268 events, 
there will be approximately 90% power to detect a HR = 0.67 (median OS of 7.5 months vs. 
5 months). The null hypothesis that the OS in the Triplet Arm is the same or worse than the 
Control Arm will be rejected if the HR is smaller (i.e., better) than 0.79. 
Overall Response 
During the initial analysis of the study, the primary analysis of Triplet vs. Control ORR by BICR 
will be conducted based on the first 330 randomized patients. Based on historical data, the ORR 
in the Control Arm is expected to be approximately 10% (Kopetz et al. 2017; Seymour et al. 
2013). A sample size of 110 patients per arm provides 88% power to detect a 20% absolute 
difference in ORR, assuming an ORR of 10% in the Control Arm and an ORR of 30% in the 
Triplet Arm at a one-sided alpha of 0.005. 


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STUDY ENDPOINTS 
4.0
4.1 
Primary Endpoints 
o Safety Lead-In: 
• Incidence of 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 
o Randomized Phase 3: 
• Confirmed ORR (by BICR)) per RECIST, v1.1 of Triplet Arm vs. Control Arm 
• OS, defined as the time from randomization to death due to any cause, of Triplet Arm 
vs. Control Arm 
4.2 
Key Secondary Endpoints 
o Randomized Phase 3 
• OS of Doublet Arm vs. Control Arm 
4.3 
Secondary Endpoints 
o Safety Lead-In: 
• ORR (by BICR and Investigator) 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 
• PFS (by BICR and Investigator), defined as the time from first dose to the earliest 
documented disease progression or death due to any cause 
• DOR (by BICR and Investigator), 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 (by BICR and Investigator), defined as the time from first dose to 
first radiographic evidence of response 


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• PK parameters of encorafenib, cetuximab, binimetinib and the active metabolite of 
binimetinib (AR00426032) 
o Randomized Phase 3: 
• Confirmed ORR (by Investigator) per RECIST, v1.1 of Triplet Arm vs. Control Arm 
• Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 of Doublet Arm vs. 
Control Arm 
• PFS (by BICR and Investigator), defined as the time from randomization to the 
earliest documented disease progression or death due to any cause, of Triplet Arm vs. 
Control Arm 
• PFS (by BICR and Investigator) of Doublet Arm vs. Control Arm 
• OS of Triplet Arm vs. Doublet Arm 
• Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 of Triplet Arm vs. 
Doublet Arm 
• PFS (by BICR and Investigator) of Triplet Arm vs. Doublet Arm 
• DOR (by BICR and Investigator) of Triplet Arm vs. Control Arm, of Doublet Arm vs. 
Control Arm and of Triplet Arm vs. Doublet Arm 
• Time to response (by BICR and Investigator), defined as the time from randomization 
to first radiographic evidence of response, of Triplet Arm vs. Control Arm, of Doublet 
Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm 
• Incidence and severity of AEs, graded according to NCI CTCAE, v 4.03, and changes 
in clinical laboratory parameters, vital signs, ECGs, ECHO/MUGA scans and 
ophthalmic examinations 
• Change from baseline in the European Organization for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire for Cancer Patients (QLQ-C30), 
Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C), EuroQol-5D-5L 
(EQ-5D-5L), and Patient Global Impression of Change (PGIC) of Triplet Arm vs. 
Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm 
• Model-based PK parameters of encorafenib, cetuximab, binimetinib and the active 
metabolite of binimetinib (AR00426032) 
• Model-based PK assessment of drug-drug interactions between encorafenib, 
cetuximab, binimetinib and the active metabolite of binimetinib (AR00426032) 


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ANALYSIS SETS 
5.0
5.1 
Full Analysis Set 
For patients in the SLI and JSLI, the Full Analysis Set (FAS) will consist of all patients who 
receive at least 1 dose of study drug and have at least 1 post-treatment assessment, which may 
include death. 
For patients in the Phase 3 portion, the FAS will consist of all randomized Phase 3 patients. 
Patients will be analyzed according to the treatment arm and stratum they were assigned to at 
randomization. 
5.2 
Safety Set 
The Safety Set (SS) will consist of all patients who receive at least 1 dose of study drug and have 
at least 1 post-treatment assessment, which may include death. Patients will be analyzed 
according to treatment received. 
Patients who received the wrong study treatment for only a part of the treatment period will be 
analyzed according to the randomized treatment. Patients who received a wrong study treatment 
(i.e., a treatment different from the one assigned by randomization) during the whole treatment 
period will be analyzed according to the actual treatment received. 
5.3 
Dose-Determining Set 
The Dose-determining Set (DDS) includes all SLI and JSLI patients from the Safety Set who 
either completed a minimum exposure requirement and have sufficient safety evaluations or 
experienced a DLT. 
A patient is considered to have met the minimum exposure requirement if having received at 
least 75% dose intensity ([Cumulative administered dose in mg in Cycle 1/Cumulative planned 
dose in mg in Cycle 1] × 100) of the planned dose for each of the 3 agents; binimetinib (i.e., 
1890 of the planned 2520 mg dose), encorafenib (i.e., 6300 of the planned 8400 mg dose) and 
cetuximab doses (i.e., 750 of the planned 1000 mg/m2 dose) within the first cycle of dosing. The 
length of a cycle is 28 days. 
Patients who do not experience a DLT during the first cycle will be considered to have sufficient 
safety evaluations if they have been observed for ≥ 28 days following the first dose, and are 
considered by both the Sponsor and Investigators to have enough safety data to conclude that a 
DLT did not occur. 


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5.4 
Safety Lead-in Efficacy Set 
The SLI Efficacy Set will consist of all SLI and JSLI patients in the FAS who were identified at 
screening as having a BRAF V600E mutation (per local or central testing). 
5.5 
Phase 3 Response Efficacy Set 
The Phase 3 Response Efficacy Set will consist of the first 330 randomized patients and any 
additional patients randomized on the same day as the 330th randomized patient, into the Phase 3 
portion of the study. 
5.6 
Per-Protocol Set 
The Per-protocol Set (PPS) consists of all Phase 3 patients from the FAS without any major 
protocol deviations (or other criteria that could largely impact efficacy results) and who received 
at least one dose of study drug. 
The reasons that will lead to exclusion of patients from the PPS are listed below: 
o No histologically or cytologically confirmed CRC that is metastatic; 
o Not positive for BRAF V600E mutation per central assessment; 
o Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or 
other epidermal growth factor receptor (EGFR) inhibitor; 
o Baseline ECOG PS greater or equal to 3 (i.e., at least 2 categories worse than the defined 
inclusion criteria); 
o Study treatment received different from treatment assigned by randomization. 
5.7 
Pharmacokinetic Set 
The PK set will include all patients in the SS who had at least 1 post-dose blood collection for 
PK with associated bioanalytical results. Patients will be analyzed according to the actual 
treatment and dose received. 
 


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CHANGES FROM THE STUDY PROTOCOL 
6.0
This SAP incorporates the following changes from the statistical analyses described in the study 
protocol: 
o Clarified that the formal analysis of the Doublet vs, Control ORR endpoint will be 
conducted on the Phase 3 Response Efficacy Set, assuming that the prior endpoints in the 
testing hierarchy are statistically significant. 


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STATISTICAL METHODS 
7.0
7.1 
Reporting Conventions and Definitions 
7.1.1 
Reporting Conventions 
Durations of events (e.g., duration of treatment) will be calculated in days as (stop date – start 
date + 1). Conversions to weeks, months, years will be days/7, days/30.4375, days/365.25, 
respectively. Handling of missing or partial dates will depend on the specific event and will be 
described in subsequent sections. 
In general, missing values will be handled as follows unless otherwise specified. For continuous 
variables at Baseline, missing values will be excluded from calculation of summary statistics, 
and the number and percent of patients with missing values will be displayed. For categorical 
values at Baseline, the number and percent of patients with a missing value will be displayed. 
For missing post-Baseline values, the method for reporting missing values will depend on the 
summary table. 
All pre-treatment tables and the patient disposition table will be presented by the following 
6 groups: 
Randomized and CSLI 
(Pooled) 
CSLI 
Randomized Portion 
Enco+Bini+Cetux 
Enco+Bini+Cetux 
Enco+Bini+Cetux 
Enco+Cetux 
Control 
Phase 3 Total 
 
The Combined Safety Lead-in [CSLI] includes patients from both the Safety Lead-in and 
Japanese Safety Lead-in. 
All safety tables will be presented by the following 5 treatment groups: 
Randomized and CSLI 
(Pooled) 
CSLI 
Randomized Portion 
Enco+Bini+Cetux 
Enco+Bini+Cetux 
Enco+Bini+Cetux 
Enco+Cetux 
Control 
 
All efficacy tables for the SLI phase of the study will be presented by the following 3 groups: 
SLI 
JSLI 
CSLI 


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All Phase 3 efficacy tables, unless otherwise specified will be presented by the following 
3 treatment arms: 
Randomized Portion 
Enco+Bini+Cetux 
Enco+Cetux 
Control 
 
Data listings will be sorted by treatment group, patient identifier, parameter and the 
corresponding date of assessment. 
7.1.2 
Death Date 
All dates of death must be completed with day, month and year. If the day or month is missing, 
death will be imputed to the maximum of the full (non-imputed) last contact date (excluding the 
date of death) and the following: 
o Missing day: 15th day of the month and year of death 
o Missing day and month: July 1st of the year of death 
7.1.3 
Dates of Antineoplastic Therapies 
Prior therapies: 
Incomplete start dates will be handled by applying the same imputation rules as described for 
AE/concomitant medications start date (Section 7.8.2) except: 
If only day is missing, and month and year match that of the treatment start date, impute as date 
of randomization (OR first dose of study drug for CSLI patients) -1; 
If both day and month are missing, and the year matches that of the treatment start date, then 
impute as date of randomization (OR first dose of study drug for CSLI patients) - 1. 
Completely missing start date is imputed as date of randomization (OR first dose of study drug 
for CSLI patients) - 1; 
Incomplete end dates and dates of progression on the prior antineoplastic therapies will be 
handled using the following rule: 
If only day is missing, imputed date = min (date of randomization (OR first dose of study drug 
for CSLI patients) -1, last day of the month); 


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If both month and day are missing, imputed date = min (randomization date -1, 31DEC). 
If the end date or the date of progression is not missing and the imputed start date is after the end 
date or after the date of progression, use the min (end date, date of progression) as the imputed 
start date. 
Post-treatment therapies: 
Incomplete subsequent antineoplastic therapy start dates will be imputed using the following 
rules: 
Imputed date = max (End of Treatment Date + 1, first day of the month), if day is missing 
Imputed date = max (End of Treatment Date + 1, 01JAN), if day and month are missing 
Imputed date = End of Treatment Date + 1, if the date is completely missing 
End of Treatment Date is the date of treatment discontinuation as collected from the Disposition 
eCRF page. 
There will be no imputation for missing end dates. 
7.1.4 
Definitions 
Study drug will refer to encorafenib, binimetinib, cetuximab, 5-FU, FA or irinotecan. 
Study treatment will refer to the Triplet Combination (binimetinib + encorafenib + cetuximab), 
Doublet Combination (encorafenib + cetuximab) or Control (irinotecan + cetuximab or FOLFIRI 
+ cetuximab). 
Treatment start date is defined as the first date a non-zero dose of study drug was received. 
For safety assessments, study day is defined in the following manner: 
On or after the start date of study treatment: (date of assessment) – (treatment start date) + 1. 
Study day 1 will therefore be the first day of study treatment. 
Before the start date of study treatment: (date of assessment) – (treatment start date).  
For non-safety assessments, study day is defined in the following manner: 


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On or after the randomization date: (date of assessment) – (randomization rate) + 1. Study day 
1 will therefore be the day of randomization.  
Before the randomization date: (date of assessment) – (randomization rate). 
For safety assessments, Baseline is defined as the last assessment prior to the treatment start 
date/time. If an assessment is planned to be performed prior to the first dose of study drug in the 
protocol and the assessment is performed on the same day as the first administration of study 
drug and the time is unknown, it will be assumed that it was performed prior to study drug 
administration. Unscheduled assessments will be used in the determination of baseline. Data 
reported at the End of Treatment (EOT) visit are not eligible for baseline selection. 
For non-safety assessments, Baseline is defined as the last assessment prior to (or on the day of, 
for ambiguous cases) randomization. 
For analyses of assessments at a specified study visits, each study visit is defined using the 
protocol-specified window for the assessment. 
7.2 
Patient Disposition 
Enrollment and the extent of participation in the study will be summarized by treatment group 
(5 groups and phase 3 total). The number and percent of patients randomized will be presented, 
the number and percent of patients in each analysis set, the number and percent of patients who 
discontinued study treatment and the reason for treatment discontinuation will be presented. 
Number of patients screened and randomized will be summarized respectively by region, 
country, center and treatment group. Number of patients randomized will also be summarized by 
stratification factor [ECOG PS (0 vs. 1), prior use of irinotecan (yes vs. no), cetuximab source 
(US-licensed vs. EU-approved)] and treatment arm, based on the IVRS data used for 
randomization. In addition, separate by-treatment summaries will be generated for the subgroups 
of patients in Japan and in Korea. 
A separate summary of Inclusion/Exclusion criteria not met will be provided for all prescreened 
and screened patients who were not randomized. 
A separate summary of patient disposition will be provided for patients randomized into the 
Phase 3 portion of the study who were never treated. 


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Patient disposition data will be provided in a data listing. A separate listing will describe each 
patient’s inclusion or exclusion status for each of the analysis sets defined in Section 5.0. 
A disposition listing providing date of progression of patients treated past disease progression 
will be provided. 
7.3 
Protocol Deviations 
Protocol deviations will be determined and documented prior to database lock. The source 
document used for protocol deviation reporting will be the Protocol Deviations Tool, a 
comprehensive data set based on protocol deviations collected in 
 
 Protocol deviation terms will be grouped into categories based on Sponsor 
assessment. Frequency counts and percentages of patients in the FAS with any protocol 
deviations will be tabulated by the deviation type, category and treatment group. Protocol 
deviations leading to exclusion of patients from the PPS will be tabulated separately by treatment 
group. 
7.4 
Patient Characteristics 
7.4.1 
Demographics and Pretreatment Characteristics 
All demographic and pretreatment characteristics will be presented in by-patient listings by 
treatment group using the FAS. All summary tables will be presented by treatment group. 
Demographic and Baseline patient characteristics that are measured or assessed prior to the first 
dose of study treatment will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, maximum for continuous variables; n, percent for categorical 
variables); however, no formal comparisons between treatment groups will be performed. 
Stage at study entry; primary tumor location; primary tumor resection status; number of organs 
involved; and the presence of liver, lung, lymph node and peritoneum metastases at baseline will 
be reported. Organ involvement will be based on baseline Target and Non-target lesion 
assessment. There will be a Sponsor assessment to evaluate the number of organs involved. 
 
 
 
 
 
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In addition, separate by-treatment summaries will be generated for the subgroups of patients in 
Japan and in Korea. 
A separate summary will be provided for patients randomized into the Phase 3 portion of the 
study who were never treated. 
Concordance of local versus central BRAF V600E mutation status at baseline will be reported. 
7.4.2 
Medical History, Baseline Signs and Symptoms 
Medical history and Baseline signs and symptoms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) terminology and presented in data listings and summarized 
by treatment group using the FAS.  
A separate summary will be provided for patients randomized into the Phase 3 part portion of the 
study who were never treated. 
7.4.3 
Prior Anticancer Therapy 
Prior anticancer treatments will be coded using World Health Organization (WHO) Drug 
Dictionary (Uppsala Monitoring Centre, Uppsala, Sweden) and summarized and listed by 
Anatomical Therapeutic Chemical (ATC) code (level 4) and PT. The number of prior regimens 
and the types of prior treatments (e.g., medications, radiotherapy, surgery, etc.) will be 
summarized by treatment group using the FAS. There will be a Sponsor assessment to evaluate 
the number of prior regimens. 
In addition, separate by-treatment summaries will be generated for the subgroups of patients in 
Japan and in Korea. 
A separate summary will be provided for patients randomized into the Phase 3 part who were 
never treated. 
7.4.4 
Other Prior Medications 
Other (i.e. non-antineoplastic) prior medications will also be coded using WHO Drug Dictionary 
and presented in a data listing. 


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7.5 
Efficacy Analysis 
Efficacy analyses for the patients in the SLI phase of the study will be performed using the SLI 
Efficacy Set and results will be presented by group (SLI, JSLI and Combined Safety Lead-in 
[CSLI]). The primary analysis of the Phase 3 primary endpoint of Triplet vs. Control ORR will 
be analyzed using the Phase 3 Response Efficacy Set. Unless otherwise stated, other efficacy 
analyses for Phase 3 patients will be performed using the FAS. 
The primary efficacy endpoints are ORR (by BICR; Triplet Arm vs. Control Arm) and OS 
(Triplet Arm vs. Control Arm). 
The key secondary efficacy endpoint is OS (Doublet Arm vs. Control Arm) and other secondary 
endpoints include ORR (by Investigator; Triplet Arm vs. Control Arm); ORR (by BICR and 
Investigator; Doublet Arm vs. Control Arm), and PFS (by BICR and Investigator; Triplet Arm 
vs. Control Arm and Doublet Arm vs. Control Arm), OS (Triplet Arm vs. Doublet Arm), ORR 
(by BICR and by Investigator; Triplet Arm vs. Doublet Arm), DOR (by BICR and by 
Investigator; Triplet Arm vs. Control Arm, Doublet Arm vs. Control Arm, Triplet Arm vs. 
Doublet Arm), and time to response (by BICR and by Investigator; Triplet Arm vs. Control Arm, 
Doublet Arm vs. Control Arm, Triplet Arm vs. Doublet Arm). 
The Type I error rate for the primary endpoints will be controlled using a fallback procedure 
described by Wiens and Dmitrienko (2005). One-sided alpha of 0.005 will be assigned to the 
Triplet vs. Control ORR endpoint. The remaining 0.020 will be assigned to the Triplet vs. 
Control OS endpoint. If the p value of the Triplet vs. Control comparison of ORR at the primary 
analysis is < 0.005, then the Triplet vs. Control OS comparison will be assigned a total one-sided 
alpha of 0.025. Otherwise, alpha will remain at one-sided 0.020. 
The key secondary endpoint and several secondary endpoints may also be formally tested. To 
control the overall Type I error rate, a gatekeeping procedure using hierarchical testing will be 
performed. If the OS of the Triplet Arm vs. Control Arm is found to be significant at either the 
interim analysis or the final analysis, the following tests will then be conducted sequentially, 
each at the same total alpha assigned to the Triplet vs. Control OS endpoint: 
1. 
OS of Doublet Arm vs. Control Arm 
2. 
ORR (by BICR) of Doublet Arm vs. Control Arm 
3. 
PFS (by BICR) of Triplet Arm vs. Control Arm 
4. 
PFS (by BICR) of Doublet Arm vs. Control Arm 


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If any of the above tests is found to not be statistically significant, all subsequent comparisons 
will only be summarized using descriptive statistics along with the nominal p values. 
The overall testing strategy of the study is summarized in Figure 7-1. 
Reported confidence intervals (CIs) will not be adjusted for multiple comparisons. 
 
 


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Figure 7-1: 
Testing Strategy for ARRAY-818-302 
 
7.5.1 
Objective Response Rate 
Best overall response (BOR) is defined as the best response obtained among all tumor 
assessment visits after the date of randomization (or first dose of study drug for SLI) until 
documented disease progression, taking into account the rules as detailed below. The tumor 
Test ORR per BIRC 
(Triplet vs. Control) 
1-sided α = 0.005 
~ 110 pts/arm 
Test OSa 
(Triplet vs. Control) 
1-sided α = 0.020 
~ 205 pts/arm 
[Interim Analysis] 
Test OSa 
(Triplet vs. Control) 
1-sided α = 0.025 
~ 205 pts/arm 
[Interim Analysis] 
Does the p-value surpass the O’Brien-Fleming superiority boundary? 
Test subsequent endpointsb  
in testing hierarchy, using a 
gatekeeping procedure to 
control the overall  
Type I error rate 
~ 205 pts/arm 
Test Triplet vs. Control OS  
at final analysis 
p < 0.005 
p > 0.005 
YES 
NO 
No further testing conducted, 
although the contribution of 
binimetinib to efficacy of the 
Triplet combination may be 
further evaluated at a later 
data cutoff 
No further testing conducted 
No further testing conducted 
Results are positive 
Results are negative 
a A Lan-DeMets spending function that approximates O’Brien-Fleming boundaries will be used to account for the multiple 
(i.e., interim and final) analyses of OS.  
b Subsequent endpoints would be tested in the following order: Doublet vs. Control OS, Doublet vs. Control ORR per BIRC, 
Triplet vs. Control PFS per BIRC, and then Doublet vs. Control PFS per BIRC. 
Test subsequent endpointsb 
in testing hierarchy, using a 
gatekeeping procedure to 
control the overall  
Type I error rate 
~ 205 pts/arm 


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response will be determined according to RECIST v1.1. Only tumor assessments performed 
before the start of any subsequent antineoplastic therapies and not later than 30 days after last 
dose will be considered in the assessment of BOR. Clinical deterioration or clinical progression 
noted on the completion eCRF will not be considered as documented disease progression. 
Two sets of BOR will be summarized by treatment arm, one for confirmed and one for 
confirmed + unconfirmed responses. BOR is determined from the sequence of overall (lesion) 
responses according to the following rules: 
Complete Response (CR) = at least 2 determinations of CR at least 4 weeks apart before disease 
progression, where confirmation required, or one determination of CR prior to disease 
progression, where confirmation not required. 
Partial Response (PR) = at least 2 determinations of PR or better at least 4 weeks apart before 
disease progression (and not qualifying for a CR), where confirmation required, or one 
determination of PR prior to disease progression, where confirmation not required. 
Stable Disease (SD) (applicable only to patient with measurable disease at baseline) = at least 
one SD assessment (or better) ≥ 6 weeks after randomization/start of treatment (and not 
qualifying for CR or PR). 
Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = at least 
one non-CR/non-PD assessment (or better) after date of randomization/start of treatment and 
before progression (and not qualifying for CR or PR). 
Progressive Disease (PD) = disease progression ≤ 9 weeks after date of randomization/ first dose 
of study drug (and not qualifying for CR, PR or SD).  
Not Evaluable (NE) = all other cases (i.e., not qualifying for CR or PR and without SD after at 
least 6 weeks or early progression within the first 9 weeks). Patients with a first tumor 
assessment post-randomization but prior to treatment start will be NE.  
Patients with BOR ‘Not Evaluable’ will be summarized by their reason for having not evaluable 
status. The following reasons will be used (in the following hierarchy): 
o No baseline assessment. 
o SD occurred < 6 weeks after date of randomization (OR first dose of study drug for 
non-randomized studies). 


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o Progression > 9 weeks after date of randomization (OR first dose of study drug for 
non-randomized studies). 
o New antineoplastic therapy started before first post-baseline assessment. 
o All post-baseline assessments have an overall response of “NE”. 
o No adequate post-baseline assessment (defined in Section 7.5.3.2). 
The overall best response (i.e., CR or PR) as assessed both by BICR and Investigator per 
RECIST v1.1 will be determined for each patient. The ORR will be calculated within each 
treatment arm, where ORR is defined as the number of patients achieving an overall best 
response of CR or PR divided by the total number of patients in that treatment arm.  
The ORR by BICR will be tested for the primary endpoint of Triplet Arm vs. Control Arm based 
on the Phase 3 Response Efficacy Set and using the Cochran-Maentel-Haenzel test at a one-sided 
alpha of 0.005. Both confirmed and unconfirmed ORR will be summarized but, for purposes of 
formal testing, the analysis of the confirmed responses will be used. The stratification factors 
used in the test will be those used for randomization and will be based on the actual 
randomization (interactive web response system [IWRS]) information. For the primary analysis, 
ORR will be presented by arm, along with 95% and 99% CIs. A similar analysis for ORR 
(Triplet Arm vs. Control Arm) will be done on the FAS at the final analysis. The secondary ORR 
endpoints (including Investigator-assessed ORR) will be analyzed in a similar manner based on 
the Phase 3 Response Efficacy Set and the FAS. The Doublet Arm vs. Control Arm comparison 
of ORR will be formally tested using the Phase 3 Response Efficacy Set if the preceding 
endpoints in the testing hierarchy (i.e., Triplet vs. Control ORR, Triplet vs. Control OS, and 
Doublet vs. Control OS) are observed to be statistically significant.  
Waterfall plots will be generated to display the maximum change from baseline in sum of 
diameters by treatment arm, for both BICR and Investigator determined tumor measurements. 
Patients who had measurable disease and had a baseline and at least one post-baseline tumor 
assessment will be presented in the waterfall plots. Waterfall plots will be produced for the SLI 
Efficacy Set and for the Phase 3 Response Efficacy and Full Analysis Sets.  
As all patients in this analysis set will be assumed to have sufficient follow-up for response, the 
full alpha assigned to the OS endpoints (i.e., one-sided 0.025 or one-sided 0.020) will be applied 
to the Doublet vs. Control ORR comparison regardless of whether it is tested at the initial 
analysis or the final analysis. 


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Response Rate Sensitivity Analyses 
7.5.1.1
The following sensitivity analyses will be conducted to support the analyses of ORR. Because 
the p values that will be displayed for the supportive and sensitivity analyses are nominal, they 
should be considered descriptive only. 
For the Phase 3 patients, analyses of ORR will be repeated for patients in the Phase 3 Response 
Efficacy Set who had measurable disease at baseline. 
The ORR will also be compared between treatment arms using an unstratified Chi-squared test.  
 
Other Supportive Analyses for Response Rate 
7.5.1.2
Using the Phase 3 Response Efficacy Set, a multivariate logistic regression model that includes 
the same covariates as the OS supportive analysis will be used to further assess ORR by BICR. 
Subgroup analyses will also be performed. A forest plot representation of the odds ratios from 
the logistic regression models will be provided. 
7.5.2 
Overall Survival 
For the Phase 3 portion of the study, the primary and key secondary efficacy endpoints are OS, 
defined as the time from randomization to death due to any cause. Patients who do not have a 
death date by the data cutoff date will be censored for OS at their last contact date. Overall 
survival will be calculated for all patients in the FAS and summarized by treatment arm using the 
Kaplan-Meier (KM) method. In the SLI portion of the study, 
 
 
 
 
Overall treatment arm estimates as well as treatment arm estimates by stratum will be provided 
for the randomized Phase 3 patients.  
For the OS primary endpoint, the null hypothesis of the primary objective is that the OS for the 
Triplet combination is less than or equal to the OS of the Control Arm, i.e., 
H0: SOS,A (t) ≤ SOS,C (t) 
where SOS,A (t) is the OS survival distribution function for the Triplet combination and SOS,C (t) is 
the OS survival distribution function for the Control Arm. The null hypothesis will be tested 
using a stratified log-rank test against the alpha assigned to the endpoint based on the Fallback 
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approach. The stratification factors used in the test will be precisely those used for 
randomization, and will be based on the actual randomization (IWRS) information. 
The distribution of OS will be described in tabular and graphical format by treatment group 
using KM methods, reporting estimated median (in months) with 95% CI, 25th and 75th 
percentiles (Brookmeyer and Crowley 1982; Klein and Moeschberger 1997) and KM estimated 
probabilities with corresponding 95% CIs (Kalbfleisch and Prentice 2002) at several time points 
(including at least 2, 4, 6, 8, 10, 12 and 14 months). 
For the randomized Phase 3 portion of the study, a Cox regression model stratified by 
randomization stratification factors will be used to estimate the HR of OS, along with 95% CI 
based on the Wald test. The PHREG procedure in SAS with option TIES=EXACT will be used 
to fit the Cox proportional hazards model. 
Schoenfeld residuals, including a LOESS curve, will be plotted to investigate graphically 
violations of the proportional hazards assumption. Schoenfeld residuals will be computed in SAS 
using the PHREG procedure and using the OUTPUT statement and the keyword RESSCH. With 
proportional hazards the LOESS curve should be parallel to the x-axis. 
In addition, the proportional hazards assumption will be checked visually by plotting 
log(-log(S(t))) versus log(t) , 
where S(t) is the estimated survival function (OS) at time t. Neither of the above 2 plots will be 
included in the clinical study report. 
At the initial analysis, an interim analysis for superiority or (non-binding) futility of the Triplet 
vs. Control OS endpoint will be performed based on all available data (i.e., using the FAS). 
Futility and superiority boundaries for both the OS interim and final analyses will be determined 
using a Lan-DeMets spending function (Lan and DeMets 1983) that approximates O’Brien-
Fleming stopping boundaries (see Section 7.11). 
For the purposes of the final analysis of the primary endpoint (i.e., Triplet Arm vs. Control Arm 
OS), only the first 268 OS events will be included in the analysis. 
The same method of analysis, including the application of the Lan-DeMets spending function 
and supportive analyses, as for the primary endpoint will be used for the key secondary OS 
endpoint.  


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In addition, the analyses for OS will also be conducted at the end of study. 
A separate OS summary will be provided for patients randomized into the Phase 3 portion of the 
study who were never treated. 
 
OS Sensitivity Analyses 
7.5.2.1
The following sensitivity analyses will be conducted for the Phase 3 randomized part to support 
the analyses of OS. Because p-values that will be displayed for the supportive and sensitivity 
analyses are nominal, they should be considered descriptive only. The analyses of OS will be 
repeated using the PPS. 
As the Triplet Arm and Control Arm will likely have more than 268 combined OS events by the 
time the required number of OS events are observed in the Double Arm and Control Arm, the OS 
analysis of the Triplet vs. Control Arms will be repeated using all available OS events. 
The distribution of OS in the FAS will be compared between treatment arms using an 
unstratified log-rank test and the HR (with associated 95% CI) resulting from an unstratified Cox 
model will be presented.  
 
Other Supportive Analyses for OS 
7.5.2.2
For the randomized Phase 3 part, the effect of potential prognostic factors will be investigated by 
using multivariate stratified Cox regression. In addition to stratifying by the stratification factors 
considered for randomization (ECOG status, prior irinotecan, cetuximab source), the following 
factors measured at baseline might be included as covariates: 
1. Gender (male vs. female) 
2. 
Age (< 65 vs. ≥ 65 years) 
 
 
4. 
Removal status of primary tumor (no resection/ partial resection, complete resection) 
 
 
6. 
Side of tumor (left/right vs. left vs. right) 
7. 
Number of organs involved based on Target and Non-target lesion assessment (<=2 vs. 
3+) 
8. 
Presence of liver metastases at baseline, based on Target and Non-target lesion 
assessment (yes vs. no) 
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9. 
Number of prior regimens (1 vs. 2) 
10. 
Prior oxaliplatin (yes vs. no) 
To avoid model instabilities, the above categorized covariates will only be included in the model 
if the number of observations allows i.e., if there are at least 10 events in each category for 
binary covariates. 
 
 Region (North America, Europe, Rest of the World) will not be evaluated in the 
the multivariate model because it is highly correlated with the stratification factor of cetuximab 
source (US, Europe). 
Subgroup analyses will be performed for each of the 3 baseline stratification factors and other 
relevant baseline variables provided the number of patients randomized with these particular 
covariates allows (i.e., at least 10 events are available in the considered sub-group). Section 7.13 
describes the subgroups that will be considered. For the Japan and Korea subset analyses the 
minimum of 10 event criteria is not required. The analyses will include KM summaries and HRs 
(together with associated 95% CIs) from unstratified Cox models. A forest plot representation 
will be provided. While not included in the multivariate model, 
 and 
Region will be evaluated in the subgroup analyses 
In addition, for the entire FAS population, a reverse KM analysis will be performed for OS to 
estimate the median duration of potential follow-up as described by Schemper and Smith (1996). 
A plot of the censoring distributions will also be provided. Patients who had an OS event for the 
purposes of the OS analysis will be censored at the date of the event. Patients who were censored 
(e.g., lost to follow-up, withdrew consent, ongoing, etc.) in the OS analysis will be considered as 
events for the purposes of estimating duration of potential follow-up. The same duration of time 
values used in the OS analysis will be used in this analysis. KM estimated probabilities with 
corresponding 95% CIs (Kalbfleisch and Prentice 2002) will be presented at the same time points 
as in the OS analysis.  This reverse KM analysis for OS will also be repeated for the SLI 
Efficacy Set. 
Furthermore, the pattern of censored data will be examined between the treatment arms by 
summarizing the number of OS observations that are censored and by tabulating the reasons for 
censored observations. Censoring reasons will also be listed. 
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7.5.3 
Efficacy Analyses of Secondary Endpoints 
 
Progression-free Survival 
7.5.3.1
For the Phase 3 portion of the study, progression-free survival (PFS) is defined as the time from 
randomization to the earliest documented progression date or death due to any cause. In the SLI 
portion of the study, PFS is defined as the time from first dose of study drug to the earliest 
documented progression date or death due to any cause. Patients who are alive and event free as 
of the data cutoff date will be censored for PFS at their last contact date. Progression-free 
survival will be calculated for all patients in the FAS and summarized by treatment arm or SLI 
cohort using the KM method. Both, PFS data determined by BICR and by Investigator will be 
analyzed. For the randomized Phase 3 portion, PFS by BICR will be prioritized in the 
hierarchical testing, followed by PFS by Investigator assessment. Overall treatment arm 
estimates as well as treatment arm estimates by stratum will be provided. PFS in the subgroups 
of patients in Japan and in Korea will be examined separately using KM plots. 
For the primary PFS analysis, disease progression and death (from any cause) will be considered 
as events. If death or disease progression is not observed, the PFS will be censored at the date of 
last adequate tumor assessment (i.e., at the date of last tumor assessment of complete response 
[CR], partial response [PR] or stable disease) prior to cutoff date or date a subsequent therapy is 
started (e.g., systemic therapy, surgery, radiotherapy). However, if a PFS event is observed after 
more than 1 missing or inadequate tumor assessment, PFS will be censored at the last adequate 
tumor assessment. If a PFS event is observed after a single missing or non-adequate tumor 
assessment, the actual date of event will be used. 
Censoring rules to be applied to the PFS endpoint are described in Table 7-1. 
Triplet Arm vs. Control Arm PFS and Doublet Arm vs. Control Arm PFS may be formally tested 
using the FAS if all of the preceding endpoints in the testing hierarchy are observed to be 
statistically significant. If PFS is formally tested, a Lan-DeMets spending function that 
approximates O’Brien-Fleming stopping boundaries will be applied. The information fraction for 
these analyses will be calculated relative to the total number of events that are anticipated to 
occur at the final analysis of the study. If PFS is formally tested at the final analysis of the study, 
the critical p value will be calculated using the spending function assuming that an interim 
analysis had occurred based on the number of events observed at the data cutoff date for the 
interim analysis. 


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For Triplet vs. Control PFS, it is estimated that there will be 315 total events at the final analysis. 
This is estimated using the actual enrollment rates of the study while assuming the median PFS 
for Triplet is 8 months and the median PFS for Control is 2 months. It is also assumed that 15% 
of Triplet patients and 25% of Control patients would be permanently censored and the final 
analysis would occur approximately 30 months after randomization began. 
For Doublet vs. Control PFS, it is estimated that there will be 330 total events at the final 
analysis. This is estimated using the actual enrollment rates of the study while assuming the 
median PFS for Triplet is 5 months and the median PFS for Control is 2 months. It was also 
assumed that 20% of Doublet patients and 25% of Control patients would be permanently 
censored and the final analysis would occur approximately 30 months after randomization began. 
In addition to the primary analysis, the analyses for PFS will also be conducted at the end of 
study. 
Table 7-1: 
Options for PFS Analysis 
 
Situation 
Event Date 
Outcome 
Aa 
No baseline assessment 
Date of randomization 
Censored 
B 
Progression or death at or before next 
scheduled assessment 
Date of progression (or death) 
Progressed 
C1 
Progression or death after exactly one 
missing assessment 
Date of progression (or death) 
Progressed 
C2 
Progression or death after 2 or more 
missing assessments 
Date of last adequate tumor assessment* 
Censored 
D 
No progression 
Date of last adequate tumor assessment* 
Censored 
E 
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e., clinical 
progression based on investigator claim 
N/A (not considered as an event, patient 
without documented PD should be 
followed for progression after 
discontinuation of treatment) 
Information ignored 
F 
New antineoplastic therapy given 
Date of last adequate tumor assessment* 
Censored 
a Patients with a first tumor assessment post-randomization but prior to treatment start will be considered as “No baseline 
assessment”. If the patient dies no later than the time of the second scheduled assessment as defined in the protocol in which 
case a PFS event at the date of death is counted. 
*  tumor assessment with non-missing and non-unknown overall lesion response 
 


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Determination of Missing Adequate Tumor Assessments 
7.5.3.2
The term ‘adequate Tumor Assessments (TA)’ is defined as TA with overall lesion response 
different from missing and ‘Not All Evaluated’. The term ‘missing adequate TA’ is defined as 
TA not done or TA with overall lesion response equal to ‘Not All Evaluated’. For the sake of 
simplicity, the ‘missing adequate TA’ will also be referred as ‘missing TA’. An exact rule to 
determine whether there is one or 2 missing TAs is therefore needed. 
As per protocol, tumor assessments are expected to be performed every 6 weeks (± 7 days) for 
the first 24 weeks and every 12 weeks (± 7 days) thereafter. 
The threshold D1 will be defined as the protocol-specified interval between the tumor 
assessments plus the protocol allowed window around the assessments. Similarly, the threshold 
D2 is defined as 2 times the protocol-specified interval between the tumor assessments plus the 
protocol allowed window around the assessments. If the distance is larger than threshold D1 or 
D2 then the analysis will assume one or 2 missing tumor assessments, respectively. 
Therefore: 
• 
if the last adequate tumor assessment is performed on or before study day 21 then 
D1 = 49 days and D2 = 91 days; 
ο 
This accounts for the scenario where the last adequate tumor assessment is the 
baseline assessment. This also allows for the rare instance where an additional 
assessment occurred early in the study. 
• 
if the last adequate tumor assessment is performed between study day 22 and study day 
105 then D1 = 56 days and D2 = 98 days; 
ο 
This accounts for the scenario where both of the next 2 scheduled assessments occur 
prior to week 24. 
• 
if the last adequate tumor assessment is performed between study day 106 to study day 
147 then D1 = 56 days and D2 = 140 days; 
ο 
This accounts for the scenario where next scheduled assessment occurs prior to week 
24, but the second subsequent assessment occurs after week 24. 
• 
otherwise, when the last adequate tumor assessment is performed after study day 148, 
then D1 = 98 days and D2 = 182 days. 
ο 
This accounts for the scenario where both scheduled assessments occur after week 24. 


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Using the D2 definition above, an event is censored as occurring after ≥ 2 missing tumor 
assessments if the distance between the last adequate tumor assessment date and the PFS event 
date is larger than D2. 
 
PFS Sensitivity Analyses 
7.5.3.3
The following sensitivity analyses will be conducted to support the analyses of PFS by BICR. 
Because the p values that will be displayed for the supportive and sensitivity analyses are 
nominal, they should be considered descriptive only. 
• 
The analyses for PFS will also be repeated for the PPS. 
• 
The distribution of PFS in FAS will be compared between the treatment arms using an 
unstratified log-rank test and the HR (together with associated 95% CI) resulting from an 
unstratified Cox model will be presented. 
• 
The analyses for PFS will be repeated to assess bias due to the evaluation time in two 
ways: 
ο 
If a PFS event does not occur exactly on or within the 7-day window of the scheduled 
day of assessment, the event date will be moved to the next scheduled assessment.  
ο 
If a PFS event does not occur exactly or on within the 7-day window of the scheduled 
day of assessment, the event date will be moved to the next scheduled assessment. If 
a patient is censored on a day that does not coincide with the scheduled assessment 
day, the censoring date will be moved back to the previous scheduled assessment. 
• 
The analyses for PFS will be repeated to assess early censoring and the impact of any 
imbalances in censoring distribution. Patients will be defined as being censored early if 
they were censored for PFS > 2 months prior to data cutoff date. The following 
cumulative analyses will be performed: 
ο 
Early censored patients who progressed or died after ≥ 2 missed assessments will be 
imputed as having an event at the next scheduled assessment. All other early censored 
patients will remain censored. The HR, 95% CI, and p-value will be calculated. 
ο 
Of the remaining early censored patients, those who progressed per local assessment 
will be imputed as having an event per BICR at the next scheduled assessment. All 
other early censored patients will remain censored. An updated HR, 95% CI, and p-
value will be calculated that reflects both this and the previous step. 
ο 
Of the remaining early censored patients, those who had an EOT reason of PD will be 
imputed as having an event per BICR at the next scheduled assessment.  All other 
early censored patients will remain censored. An updated HR, 95% CI, and p-value 
will be calculated that reflects this and the previous steps. 


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ο 
Of the remaining early censored patients, those who were not treated will be imputed 
as having an event at 42 days after randomization.  All other early censored patients 
will remain censored. An updated HR, 95% CI, and p-value will be calculated that 
reflects this and the previous steps. 
ο 
Of the remaining early censored patients, those who received subsequent therapy 
within 6 weeks of stopping treatment will be imputed as having an event at the next 
scheduled assessment.  All other early censored patients will remain censored. An 
updated HR, 95% CI, and p-value will be calculated that reflects this and the previous 
steps. 
ο 
If any patients remain, additional categories may be added. 
• 
The analyses for PFS will be repeated with a censoring rule that includes a PFS event 
even if the event is recorded after 2 or more missing tumor assessments (i.e., counting 
events for line C2 of Table 7-1). 
• 
The analyses for PFS will be repeated with a censoring rule that backdates events 
occurring after one or more missing tumor assessments (i.e., backdating events for line 
C1 and C2 of Table 7-1). This backdating analysis assumes PD occurs at the next 
assessment, so the PFS event date will be set to be at 6 weeks (or 12 weeks) after the last 
adequate tumor assessment for events occurring after one or more missing assessments.  
• 
If at least 15 patients have tumor assessments that occurred after the start of another 
anticancer therapy, an additional sensitivity analysis for PFS will be performed to include 
these tumor assessments (Table 7-1 situation F). 
 
Other Supportive Analyses for PFS 
7.5.3.4
Similar to OS, the effect of potential prognostic factors will be investigated by using stratified 
multivariate Cox regression. The same covariates will be used as the OS analysis. The same 
subgroup analyses will be performed as the OS analysis. 
The censoring distribution for PFS will be summarized using the same methods as OS. 
To assess the balance of the timing of the tumor assessment between the treatment arms, the 
timing of all tumor assessments will be depicted graphically by treatment arm. 
7.5.4 
Duration of Response 
Duration of response is defined as the time from first radiographic evidence of response to the 
earliest documented progressive disease (PD) or death, and is calculated for responders only. 
Responders who do not have a PD or death date by the data cutoff date will be censored for DOR 
at their last adequate radiological assessment (i.e., at the date of last tumor assessment of CR, PR 


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or SD) prior to cutoff date or date a subsequent anticancer therapy for mCRC is started. Duration 
of response will be summarized by arm based on both the Phase 3 Response Efficacy Set and the 
FAS using the KM method in a tabular format. 
The proportion of patients with a DOR of 6 months or more will be summarized by treatment 
arm. 
The DOR by BICR and by Investigator’s assessment will be summarized as secondary 
endpoints. 
7.5.5 
Time to Response 
Time to response (TTR) is the time between date of randomization until first documented 
response of CR or PR. Patients who do not achieve a PR or CR will be censored as follows: 
o Censored at the last adequate tumor assessment date when they do not have a PFS event. 
In this case, patients have not yet progressed so they theoretically still have a chance of 
responding; 
o Censored at maximum follow-up (i.e., FPFV to LPLV used for the analysis) when they 
have a PFS event (i.e., progressed or died due to any cause). In this case, the PFS event is 
the worst possible outcome as it means the patient cannot subsequently respond. Since 
the statistical analysis makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e., time from FPFV to LPLV). 
TTR will be described in tabular format by treatment arm based on both the Phase 3 Response 
Efficacy Set and the FAS using KM methods including estimated median (in months) with 95% 
CI and 25th and 75th percentiles (Brookmeyer and Crowley 1982; Klein and Moeschberger 1997) 
and KM estimated probabilities with corresponding 95% CIs (Kalbfleisch and Prentice 2002) at 
several timepoints (including at least 2, 4, 6, 8, 10 and 12 months). 
Using the same summaries described above, TTR for responders only (i.e., patients achieving at 
least one CR or PR) will also be presented. 
The primary analysis of time to response will be by BICR. Time to response by Investigator’s 
assessment will also be summarized as a supportive analysis. 
No formal statistical test will be performed. 


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7.6 
Assessment of the Binimetinib Contribution to Efficacy 
In order to adequately assess the efficacy benefit that binimetinib contributes to the Triplet 
combination, comparisons of the Triplet Arm to the Doublet Arm will be conducted for each 
efficacy endpoint using the FAS. 
A comparison of the OS distributions for the Triplet Arm and the Doublet Arm will be described 
in tabular and graphical format by treatment arm using KM methods. A Cox regression model 
stratified by randomization stratification factors will be also used to estimate the HR of OS, 
along with 95% CI based on the Wald test. Nominal p values will be provided. 
In addition to the response rates reported by treatment arms with exact binomial CIs, the 
Cochran-Mantel-Haenszel test will be used to compare ORR in the Triplet and Doublet Arms. 
The stratification factors used in the test will be those used for randomization, and will be based 
on the actual randomization (IWRS) information. Nominal p values will be provided. Separate 
summaries for confirmed responses and all responses (confirmed and unconfirmed) will be 
generated. 
The PFS of the Triplet Arm and the Doublet Arm will be summarized using the KM method. 
Nominal p values will be provided. The TTR and DOR of the 2 arms will also be summarized 
using the KM method. 
The ORR and PFS analyses will be conducted on both BICR and Investigator tumor assessment 
data. In addition to the primary analysis, the analyses described here will also be conducted at the 
end of study. 
7.7 
Progression After Next Line of Therapy (PFS2) 
Progression after next line of therapy (PFS2) will be calculated for all randomized Phase 3 
patients in the FAS. PFS2 is defined as time from randomization to the earlier of death at any 
time after randomization or PD after the start of subsequent anticancer therapy; patients alive and 
without progression on their subsequent anticancer therapy will be censored at the time last 
known alive. In addition, patients who die after missing 2 or more tumor assessments while on 
the Study ARRAY-818-302 will remain censored for PFS2. PFS2 will be summarized by 
treatment arm (as randomized) using the KM method. 
Time to second subsequent therapy (TSST) will be calculated as a supportive analysis to PFS2 
for patients who receive subsequent anticancer therapy. TSST is defined as time from 
randomization to start of second subsequent anticancer therapy or death any time after 


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randomization; patients alive without starting a second subsequent anticancer therapy will be 
censored at the time of data cutoff. 
7.8 
Safety Analysis 
All safety analyses will be performed using the appropriate data for all patients in the SS. 
Key safety analyses will also be conducted at the end of study. 
7.8.1 
Extent of Study Drug Exposure 
Definitions: 
Definitions, as well as intermediate calculations of duration of exposure, cumulative dose, 
average daily dose, actual dose intensity (DI) and relative dose intensity (RDI), are provided 
below. These definitions will be applied for each study drug individually. For drugs administered 
intravenously (IV), the dose in mg will be taken from the CRF. 
Duration of exposure: 
This is the duration that the patient was exposed to the drug and is summarized in the exposure 
tables. The duration will be reported in weeks. 
For daily dosing of binimetinib and encorafenib: 
• 
duration of exposure = ([Date of last (non-zero) dose of study drug] – [date of first dose 
of study drug] + 1)/7 
For intermittent dosing of IV drugs, such as cetuximab: 
• 
duration of exposure = ([Date of last (non-zero) dose of study drug] – [date of first dose 
of study drug] + [days until next dose])/7 
As an example, for drugs that are dosed weekly, duration of exposure = ([Date of last (non-zero) 
dose of study drug] – [date of first dose of study drug] + 7)/7 
Relative Dose Intensity 
• 
Duration of planned exposure (this is not summarized in any exposure table) = ([Date of 
EOT or data cutoff (the earlier one)] – [date of first dose of study drug] + 1)/7 


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For daily dosing of binimetinib and encorafenib: 
• 
Dose intensity (DI)= (Cumulative actual dose)/(duration of planned exposure) 
• 
Cumulative planned dose = sum (protocol-specified dose across each day of planned 
exposure) 
• 
Planned dose intensity (PDI) = (Cumulative planned dose)/(duration of planned 
exposure) 
• 
Relative dose intensity (RDI) = 100 x (Dose intensity)/(Planned dose intensity) 
For intermittent dosing of IV drugs, such as cetuximab: 
• 
Number of planned doses = number of non-zero doses plus the number of interrupted 
doses.  
ο 
May be calculated from the duration of planned exposure as floor([duration of 
planned exposure – 1]/[days between doses]) + 1 
• 
Dose intensity (DI) = (Cumulative actual dose)/(number of planned doses) 
• 
Cumulative planned dose = sum (protocol-specified dose across each planned day of 
dosing) 
• 
Planned dose intensity (PDI) = (Cumulative planned dose)/(number of planned doses) 
• 
Relative dose intensity (RDI) = 100*(Dose intensity)/ (number of planned doses) 
A dose interruption will be indicated in the eCRF by a dosing record with a total daily dose of 
0 mg for one or more days. 
To avoid over-counting interruptions, dosing records with 0 mg entered as last dosing record will 
not be counted as interruptions. Those represent the reason for permanent discontinuation and 
will therefore be presented in the reason for treatment discontinuation analysis. 
A dose reduction is defined as a decrease in dose from the protocol-planned dose and a decrease 
from the previous non-zero dose, even if this decrease has been directly preceded by an 
interruption. For example, for encorafenib, in the sequence of total daily dose 300 mg – 0 mg – 
200 mg, the 200 mg dose will be counted as a reduction. 
If a patient moves from a higher than protocol-planned dose down to the planned dose then this 
is not to be counted as a reduction, however if they move directly from a higher than planned 
dose down to a lower than protocol-planned dose or the planned dose on a less frequent regimen, 
then this is counted as a reduction. 


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If the dose on the first dosing record is lower than protocol-planned dose this is also counted as a 
reduction. 
Reporting 
Information about administration of each study drug (encorafenib, binimetinib, cetuximab, 5-FU, 
FA, irinotecan) will be presented in a data listing. For patients who have not discontinued study 
drug prior to the data cutoff date, the patient’s last dose date will be the date of the last 
administration or infusion. 
Duration of exposure to study drug, average daily dose, DI and RDI will be summarized by study 
drug and treatment arm. Duration of exposure will also be categorized by time intervals (e.g., 
< 1 months, 1-3 months, etc. as appropriate for the protocol) for which frequency counts and 
percentages of patients will be provided. Duration of exposure to study treatment (i.e., Triplet 
Arm, Doublet Arm, or Control Arm) will also be presented. 
Frequency counts and percentages of patients who have dose reductions or interruptions, and 
corresponding reasons, will be summarized by study drug and treatment arm. Dose reductions 
and interruptions will be tabulated both separately and in a combined fashion. 
The percentages of days between the first and last non-zero dose with reduced dose i.e., below 
the protocol-planned dose will be summarized. Note, in this calculation a dose of 0 mg will also 
be considered a reduced dose. The percentages of days between the first and last non-zero dose 
with dose interruption will also be summarized. 
Total subject time, expressed in patient-months, will be provided. Total subject time will be 
calculated as the sum of the duration of exposure (in days) for each patient divided by 30.4375 
(i.e., the average number of days per month). 
For each patient, listings of each dose of the study drug administered along with dose 
change/interruption reasons will be produced. 
7.8.2 
Concomitant Medications 
Concomitant therapies are defined as any medications (excluding study drug and antineoplastic 
treatments) administered in the study. 


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Concomitant medications will be coded using the WHO Drug Dictionary and presented in a data 
listing. Concomitant medications will be summarized by ATC code (level 4), PT and treatment 
group. 
For partial concomitant medication start dates, the date imputation will be based on the temporal 
relation between the partial date and start of treatment date. No imputation will be performed 
when the year is missing for the concomitant start date. 
For partial concomitant medication end dates or completely missing end dates (concomitant 
medication is ongoing), the date imputation will be based on the temporal relation between the 
partial date, the last contact date and the 30-day follow-up date. 
Table 7-2 and Table 7-3 provide examples of the different imputations considered for 
concomitant medication start and end dates, respectively. 
Table 7-2: 
Concomitant Medication Start Date Imputation Example Scenarios 
Partial 
conmed start date 
Treatment 
start date 
Temporal relationship 
compared to treatment 
start  
Imputed Date 
12mmyyyy 
20OCT2001 
Uncertain 
<blank> 
ddmmm2000 
20OCT2001 
Before 
01JUL2000 
ddmmm2002 
20OCT2001 
After 
01JAN2002 
ddSEP2001 
20OCT2001 
Before 
15SEP2001 
ddNOV2001 
20OCT2001 
After 
01NOV2001 
 
Table 7-3: 
Concomitant Medication End Date Imputation Example Scenarios 
Partial 
conmed end date 
Minimum (Last contact 
date, 30-day FU date) 
Ongoing  
Imputed Date 
Missing 
20OCT2001 
Yes 
20OCT2001 
ddmmm2000 
20OCT2001 
No 
31DEC2000 
ddmmm2002 
20OCT2001 
No 
31DEC2002 
ddmmm2001 
20OCT2001 
No 
20OCT2001 
ddmmm2001 
20OCT2001 
Yes 
31DEC2001 
ddSEP2001 
20OCT2001 
No 
30SEP2001 
ddOCT2001 
20OCT2001 
No 
20OCT2001 
ddOCT2001 
20OCT2001 
Yes 
31OCT2001 
 


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7.8.3 
Subsequent Anticancer Therapies 
Subsequent anticancer therapies include anticancer systemic therapies, anticancer radiation or 
anticancer surgery. 
Subsequent anticancer systemic therapies will be coded using the WHO Drug Dictionary and 
presented in a data listing. Subsequent anticancer systemic therapies will be summarized by ATC 
code (level 4), PT and reason, by treatment group. In addition, subsequent anticancer systemic 
therapy will be summarized based on specific regimen group categories, as determined by 
Sponsor assessment. 
Subsequent radiation therapy will be summarized according to reason and site of radiation, by 
treatment group. 
Subsequent surgery will be summarized according to reason and type, by treatment group. 
Patients with any subsequent anticancer therapy will be also listed. 
End of Treatment Date is the date of treatment discontinuation as collected from the disposition 
eCRF page. 
There will be no imputation for missing end dates. 
A separate summary of subsequent anticancer systemic therapies will be provided for patients 
randomized into the Phase 3 part who were never treated in Study ARRAY-818-302. 
7.8.4 
Adverse Events 
Adverse events (AEs) and serious adverse events (SAEs) will be coded by Lowest Level Term 
(LLT) using the most recent version of the Medical Dictionary for Regulatory Activities 
(MedDRA) at the time of the database lock (Northrop Grumman Corporation, Chantilly, VA 
USA). 
The severity of an AE will be assessed by the Investigator using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. For patients 
with more than 1 AE within a SOC or PT, only the highest grade will be included in by-severity 
summaries. 
The imputation of the start date and end date of AEs will follow the same conventions as for 
concomitant medication start date and end date. 


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For summaries by SOC and PT, each patient will be counted at most once per SOC and at most 
once per PT. For summaries by PT, each patient will be counted at most once per PT. 
Treatment-emergent AEs (AEs) will be defined as: 
• 
Any new event that starts after administration of study drug and ≤ 30 days after treatment 
discontinuation. 
• 
Any event that was ongoing when treatment with study drug started and the 
severity/grade after treatment was higher than the Baseline value (fluctuations below the 
Baseline severity/grade are not considered as treatment emergent). 
• 
Any new event that starts > 30 days after treatment discontinuation and is assessed by the 
Investigator as related to study treatment. 
Unless otherwise stated, only AEs will be presented in summary tables. 
All AEs (treatment emergent or not) and their attributes will be presented in data listings sorted 
by treatment group, patient identifier, AE and date of onset of the AE. AEs starting after 30 days 
of last dose of study drug will be flagged All deaths will be listed and deaths within 30 days of 
last dose of study drug will be flagged. 
An overall summary of safety table will be presented separately for all patients, patients 
< 65 years old, patients 65 - 74 years old, and patients ≥ 75 years old and will include numbers 
and percentages of the following: 
o Patients who had a Grade 5 AE on study or within 30 days of last treatment. 
o Patients with at least 1: 
• AE, regardless of causality 
• AE with suspected study drug relationship 
• SAE, regardless of causality 
• SAE with suspected any study drug relationship 
• AE leading to discontinuation of any study drug regardless of causality 
• AE leading to discontinuation of any study drug with suspected study drug 
relationship 
• AE leading to discontinuation of all study treatment regardless of causality 


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• AE leading to discontinuation of all study treatment with suspected study drug 
relationship 
• AE requiring dose reduction of any study drug regardless of causality 
• AE requiring dose reduction of any study drug with suspected study drug relationship 
• AE requiring dose interruption of any study drug regardless of causality 
• AE requiring dose interruption of any study drug with suspected study drug 
relationship 
• AE requiring additional therapy regardless of causality 
• AE requiring additional therapy with suspected study drug relationship 
Individual summary tables showing the incidence of patients with the following subsets of AEs 
will be generated: 
o AEs, regardless of causality (all grades and Grade 3+) 
• By SOC and PT 
• By PT 
o AEs, regardless of causality, by PT (all grades and maximum grade). 
o AEs, with suspected study drug relationship (all grades and Grade 3+) 
• By SOC and PT 
• By PT 
o SAEs, regardless of causality (all grades and Grade 3+) 
• By SOC and PT 
• By PT 
o SAEs, with suspected study drug relationship (all grades and Grade 3+) 
• By SOC and PT 
• By PT 
o Non-serious AEs, regardless of causality, by SOC and PT (all grades and Grade 3+) 
The following summaries will be generated separately, for 1) any study drug, 2) binimetinib, 
3) encorafenib, and 4) cetuximab: 
o AEs that led to discontinuation, regardless of causality (all grades and Grade 3+) 


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• By SOC and PT 
• By PT 
o AEs that led to dose reduction, regardless of causality (all grades and Grade 3+) 
• By SOC and PT 
• By PT 
o AEs that led to dose interruption, regardless of causality (all grades and Grade 3+) 
• By SOC and PT 
• By PT 
In addition, AEs that led to discontinuation of all study treatment [defined as discontinuation of 
any study drug within 7 days of decision to discontinue study treatment per end-of-treatment 
form], regardless of causality (all grades and Grade 3+) will be summarized: 
• By SOC and PT 
• By PT 
o AEs that required additional therapy, regardless of causality (all grades and Grade 3+) 
• By SOC and PT 
• By PT 
o AEs, regardless of study drug relationship, adjusted for patient-month exposure, by PT 
and treatment (i.e., number of patients with at least one occurrence of an AE per 
100 patient-months exposure). Patient-months of exposure will be calculated as the sum 
of the duration of exposure up to the time of first occurrence of a PT.   
o Adverse events, regardless of study drug relationship, occurring within the first 3 months 
of study treatment by PT and treatment (overall and maximum Grade 3 or higher). Repeat 
for 6 and 12 months. 
AEs that resulted in death on treatment or within 30 days of last study treatment, regardless of 
causality, by SOC and PT. 
In addition, on-treatment deaths occurring within 30 days of first dose of study treatment will be 
summarized for each arm by SOC and PT. A summary of on-treatment deaths by PT adjusted for 
patient-month exposure (i.e., number of patients with at least one occurrence of a PT resulting in 
death per 100 patient-months exposure) will also be presented. 
Selected tables may be presented for specific subsets of AEs. 


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Time to onset (i.e., first occurrence) of an AE is defined as time from start of study treatment to 
the date of first occurrence of an AE within the grouping, i.e., time in days is calculated as (start 
date of first occurrence of AE) – (date of first dose of study treatment) +1. In the absence of an 
event, the censoring date applied will be the earliest from the following dates: end of treatment + 
30 days, analysis cut-off, new anticancer therapy start date, death and last contact date. 
Ascending KM curves will be constructed by treatment arm. Median together with 95% CI will 
be presented for each treatment arm. Hazard ratio will be obtained from an unstratified Cox 
model. 
Analysis of the time to onset and the duration of AEs will be performed for all patients in the 
Safety Set and also for only those with an event for: 
o first SAE 
o first Grade 3 or above AE 
o AEs resulting in discontinuation of any study drug 
o AEs resulting in discontinuation of all study treatment 
A listing of AEs with start date on or after subsequent anti-neoplastic therapy will be provided. 
A listing of AEs for patients not included in the Safety Set will be provided. 
7.8.5 
Adverse Events of Special Interest 
Specific groupings of AEs of special interest will be considered and the number of patients with 
at least one event in each grouping will be reported. Such groups consist of AEs for which there 
is a specific clinical interest in connection with encorafenib and/or binimetinib treatment 
(i.e., where encorafenib and/or binimetinib may influence a common mechanism of action 
responsible for triggering them) or AEs which are similar in nature (although not identical). 
All AEs of special interest (AESI) groupings are defined through the use of Preferred Terms 
(PT), High Level Terms (HLT), System Organ Classes (SOC), Standardized MedDRA Queries 
(SMQ) or through a combination of these components. The MedDRA terms that define each 
AESI grouping will be outlined in the Case Retrieval Strategy (CRS), which will be used to map 
reported AEs to the notable AEs groupings. The list of AESIs may be updated during the course 
of the trial based on accumulating safety data. Therefore, each clinical study report will list the 
AESI groupings used and provide a listing of the corresponding case retrieval terms. 


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All events occurring between the start of study treatment and last treatment + 30 days will be 
taken into account. Separate summaries will be generated for AESIs attributed to encorafenib 
and those attributed to binimetinib. AESIs will be summarized, as follows: 
o AESIs, regardless of causality, by grouping and PT (overall and Grade 3+) 
o AESIs, regardless of causality, by grouping and PT (overall and maximum Grade) 
o AESIs, with suspected study drug relationship, by grouping and PT (overall and 
Grade 3+) 
o Serious AESIs, regardless of study drug relationship, by grouping and PT (overall and 
Grade 3+) 
o AESIs that led to discontinuation of study drug, regardless of causality, by grouping and 
PT (overall and Grade 3+) 
o AESIs that led to dose reduction of study drug, regardless of causality, by grouping and 
PT (overall and Grade 3+) 
o AESIs that led to dose interruption of study drug, regardless of causality, by grouping and 
PT (overall and Grade 3+) 
o AESIs that required additional therapy, regardless of causality, by grouping and PT 
(overall and Grade 3+) 
o AESIs, regardless of causality, adjusted for patient-month exposure, by grouping and PT 
(i.e., number of patients with at least one occurrence of an AE per 100 patient-months 
exposure). Patient-months of exposure will be calculated as the sum of the duration of 
exposure up to the time of first occurrence of a PT. 
In addition, an overall summary for each AESI grouping will be provided (i.e., number of 
patients having at least one AE, study-drug related AE, SAE, etc). 
The CRS grouping terms and corresponding MedDRA elements will be listed. 
7.8.6 
Clinical Laboratory Evaluations 
Required hematology, coagulation, clinical chemistry and urinalysis tests are described in the 
protocol. Hematology, coagulation, clinical chemistry, and urinalysis test results will be 
presented using the International System of Units (SI units) and, where appropriate, will be 
graded using NCI CTCAE, Version 4.03.21 
Graded hematology, coagulation, clinical chemistry and urinalysis, and test results will be 
summarized in shift tables from Baseline to worst grade on study. For shift tables, the number of 


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patients with missing data at Baseline or on study will be displayed. Separate shift tables will be 
generated for the subgroups of patients in Japan and in Korea. 
Incidence of newly occurring hematology, coagulation, clinical chemistry and urinalysis by 
overall and maximum Grade 3+ will be summarized. 
Incidence of clinically notable shifts in laboratory parameters based on CTCAE grade for 
specific laboratory evaluations will be summarized, where clinically notable is defined as 
worsening from baseline by at least 2 grades or to ≥ Grade 3. 
A listing of patients with newly occurring or worsening (by 1 grade or more) laboratory 
abnormalities with all values for those particular laboratory assessments. 
Laboratory parameters not graded by NCI CTCAE (e.g., basophils, hematocrit, etc.), will be 
summarized by normal range. 
All lab test results will be presented in listings sorted by treatment group, patient identifier, lab 
test and date/time of collection. Values outside laboratory normal ranges will be flagged where 
appropriate. Separate listings will be provided for patients with any clinically notable shifts in 
laboratory parameters as defined above. 
 
Hepatic Toxicity 
7.8.6.1
Possible Hy’s Law and drug-induced liver injury (DILI) cases will be summarized by treatment 
group. 
Hepatic toxicity will be assessed based on the following liver function tests (LFTs): ALT, AST, 
alkaline phosphatase (ALP) and total bilirubin (TBL). For these parameters, CTCAE grades are 
defined. 
LFTs will be summarized by treatment arm and liver metastasis at baseline (overall and yes vs. 
no). Frequency counts and percentages of patients having a newly occurring hepatic value in the 
categories presented in Table 7-4 will be provided. 


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Table 7-4: 
Hepatic Toxicity Criteria 
Parameter 
Criterion 
Albumin 
< LLN 
ALT 
>3×ULN; >5×ULN; >8×ULN;>10×ULN;>20×ULN 
AST 
>3×ULN; >5×ULN; >8×ULN >10×ULN;>20×ULN 
AT (ALT or AST) 
>3×ULN; >5×ULN; >8×ULN >10×ULN;>20×ULN  
TBL 
>1.5×ULN, >2×ULN 
ALP 
>2×ULN, >3×ULN 
AT & TBL 
AT >3×ULN & TBL >2×ULN; 
AT >5×ULN & TBL >2×ULN; 
AT >10×ULN & TBL >2×ULN 
ALP & TBL 
ALP >3×ULN & TBL >2×ULN 
AT & TBL & ALP (i.e., 
Hy’s Law) 
AT >3×ULN & TBL >2×ULN & ALP <2×ULN 
 
LFTs will also be listed. 
 
Creatine Kinase Elevation 
7.8.6.2
A shift table summarizing the worst post-baseline creatine kinase (CK) CTCAE grade vs. 
baseline CTCAE grade will be generated. 
A scatter plot of normalized CK versus normalized creatinine will be provided for all 
on-treatment assessments. Normalized CK is defined as the observed value divided by the ULN. 
Since the CTCAE grade for creatinine is either based on the ULN or the baseline value, the 
normalized creatinine will be derived as the maximum value from creatinine/ULN and 
creatinine/baseline. 
An overall summary of CK elevation will be provided to present myopathy/rhabdomyolysis PTs 
(defined from AEs), dose reduction and dose interrupted for patients with CK elevation 
(laboratory value Grade 4 or > 10,000 IU/L) and creatinine ≥ 2×baseline and ≥ 1.5×ULN. 
Myopathy/rhabdomyolysis events within -15 to 30 days of first creatine kinase elevation by PT 
will also be summarized. 
The CK, creatinine and myoglobin laboratory parameters will be listed for patients with CK 
elevation (i.e., Grade 4 or CK > 10,000 IU/L) and creatinine ≥ 2×baseline and 1.5×ULN. 


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7.8.7 
Pregnancy Tests 
Results of all pregnancy tests will be presented in a data listing. 
7.8.8 
Physical Examinations 
Physical examination dates will be presented in a data listing. Any abnormal findings were to 
have been reported as AEs and will be reported in the appropriate AE listings and summary 
tables. 
7.8.9 
ECOG Performance Status 
ECOG performance status is used to assess the physical health of patients, and ranges from 0 
(most active) to 5 (dead). 
Frequency counts and percentages of patients in each score category will be provided by 
treatment arm and assessment visit. 
ECOG PS at each time point will be listed. 
7.8.10 
Vital Signs 
The following criteria define clinically notable abnormalities: 
o Clinically notable elevated values 
• Systolic blood pressure (BP): ≥ 160 mmHg and an increase ≥ 20 mmHg from 
baseline; 
• Diastolic BP: ≥ 100 mmHg and an increase ≥ 15 mmHg from baseline; 
• Heart rate (collected as pulse rate in the vital signs eCRF): ≥ 120 bpm with increase 
from baseline of ≥15 bpm; 
• Weight: increase from baseline of ≥ 10%; 
• Body temperature [C]: ≥ 37.5 C. 
o Clinically notable low values 
• Systolic BP: ≤ 90 mmHg with decrease from baseline of ≥ 20 mmHg; 
• Diastolic BP: ≤ 50 mmHg with decrease from baseline of ≥ 15 mmHg; 
• Heart rate (collected as pulse rate in the vital signs eCRF): ≤ 50 bpm with decrease 
from baseline of ≥ 15 bpm; 


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• Weight: ≥ 20% decrease from baseline; 
• Body temperature [C]: ≤ 36 C. 
Number and percentage of patients with at least one post-baseline vital sign abnormality will be 
summarized by treatment arm. 
In addition, BP (systolic, diastolic and both combined) shift table based on CTCAE grade for 
hypertension at baseline and worst post-baseline will be produced. 
Patients with clinically notable vital sign abnormalities will be listed by treatment arm. All vital 
sign assessments will be listed by treatment arm, patient and vital sign parameter. 
In the listings, clinically notable values will also be flagged. 
7.8.11 
Electrocardiograms 
As per protocol, baseline ECG will be obtained as the mean of the triplicate measurements 
collected at Cycle 1 Day 1 predose. 
The following summaries will be produced for QT, QTcF and heart rate by treatment arm: 
o Frequency counts and percentages of patients having clinically notable ECG values 
(Table 7-5) 
Patients with clinically notable ECG values will be listed by treatment arm including the 
corresponding notable values and abnormality findings. All ECG values will be listed by 
treatment arm, patient and ECG parameter. 
Table 7-5: 
Clinical Notable ECG Criteria 
Parameter 
Criterion 
QT, QTcF 
increase from baseline > 30 ms 
 
increase from baseline > 60 ms 
 
new > 450 ms 
 
new > 480 ms 
 
new > 500 ms 
Heart rate 
Increase from baseline > 25% to a value > 100 bpm 
 
Decrease from baseline > 25% and to a value < 50 bpm 
 


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7.8.12 
MUGA/Echocardiogram 
Left ventricular ejection fraction (LVEF) abnormalities are defined according to CTCAE version 
4.03. Patient will be considered as having a LVEF abnormality if the worst post-baseline value is 
Grade 2, 3 or 4 according to the following classification: 
o Grade 0: Non-missing value below Grade 2 
o Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% 
and < -20% 
o Grade 3: LVEF between 20% and 39% or absolute change from baseline lower than or 
equal to -20% 
o Grade 4: LVEF lower than 20%. 
The following summaries will be produced for LVEF by treatment arm: 
o Incidence of worst post-baseline LVEF value with CTC grades 
o Shift tables using CTC grades to compare baseline to the worst post-baseline LVEF value 
with CTC grades. 
The number of patients with a decrease in LVEF between 0-9% from baseline, 10-19% from 
baseline, and ≥ 20% from baseline will be summarized. All LVEF assessments will be listed. 
Patients with Grade 2 or above CTCAE abnormalities will be listed by treatment arm. 
Different modalities to assess LVEF might be used for the same patient, change from baseline 
and shift table will be provided regardless of the modality. 
Kaplan-Meier plots of time to LVEF abnormalities (below 50% and absolute decrease of 10% or 
more in LVEF from baseline) will be presented by treatment for all patients for all patients in the 
Safety Set (in the absence of an LVEF abnormality, the censoring date applied will be the 
earliest from the following dates: end of treatment + 30 days, analysis cut-off, new anticancer 
therapy start date, death and last contact date) and for patients with an event. 
7.8.13 
Ophthalmic Examination 
All ophthalmic examination results (i.e., tonometry, visual acuity, visual field, fundoscopy, slit 
lamp, optical coherence tomography (OCT), fluorescein angiography) will be listed. 


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Visual Acuity 
Visual acuity will be measured using the Snellen visual acuity conversion chart. This is 
determined by establishing the smallest optotypes that can be identified correctly by the patient 
at a given observation distance. Snellen visual acuity can be reported as a Snellen fraction (m/M) 
in which the numerator (m) indicates the test distance and the denominator (M) indicates the 
distance at which the gap of the equivalent Landolt ring subtends 1 minute of arc. 
For each timepoint, the LogMAR score will be calculated as –log(m/M). 
Total visual acuity score will also be assessed identifying clinically meaningful deterioration in 
visual acuity (LogMAR increase). The maximum increase in score of ≤ 0, 0 to < 0.1, 0.1 to 
< 0.2, 0.2 to < 0.3 and ≥ 0.3 relative to baseline in LogMAR will be summarized in a shift table. 
All Snellen fraction and logMAR scores will be listed by eye and treatment arm. 
Optical Coherence Tomography (OCT) and Fluorescein Angiography (FA) 
The clinical outcome presented in the listing combines the clinical observation (not present, 
clinically insignificant and clinically significant) and the eye involvement (unilateral or 
bilateral). Since these are optional assessments, all the patients are considered at risk at baseline 
of developing a new abnormality. 
7.8.14 
Dermatologic Examination 
All dermatologic examination data will be listed. 
7.8.15 
Follow-up 
Information obtained during a Follow-up Visit that is not otherwise captured in data listings will 
be presented in a data listing. A summary of subsequent anticancer therapies will be provided. 
7.8.16 
Comments 
All comments entered into the electronic data capture (EDC) system by personnel at the study 
sites will be presented in a data listing. Comments will be separately provided for patients in the 
FAS and patients not in the FAS. 
7.9 
Pharmacokinetic Analysis 
Systemic concentrations and PK parameters will be determined for cetuximab, encorafenib, 
binimetinib and the primary metabolite for binimetinib, AR00426032. PK summaries will be 
presented by treatment arm for patients in the PK set. In the following, Day y of Cycle x will be 


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abbreviated as CxDy. C1D1 is defined as single dose (i.e., first dose) and C2D1 is defined as 
steady-state. 
7.9.1 
Concentrations of Cetuximab, Encorafenib, Binimetinib, and AR00426032 
Plasma concentrations of encorafenib, binimetinib and AR00426032 will be quantitated at the 
time points indicated in the schedules of assessments in the protocol. Serum concentrations of 
cetuximab will be quantitated at equivalent time points with respect to the start of the cetuximab 
infusion. All concentration values for each patient in the PK set will be included in the 
bioanalytical concentration listings. 
The concentrations of cetuximab, encorafenib, binimetinib and AR00426032 will be summarized 
for all nominal time points, including predose (trough) concentrations, using the following 
descriptive statistics: n, arithmetic mean, SD, coefficient of variation (CV), geometric mean, 
geometric SD, geometric CV, minimum, median and maximum. Detailed information regarding 
handling of data with respect to the collection time window specified in the protocol, dose 
reductions, presentation and handling of data below the limit of quantitation (BLQ) and 
additional issues related to PK collection and analysis will be discussed in detail in a standalone 
Pharmacokinetic Analysis Plan (PAP). Separate outputs of concentration summaries will be 
generated for the Safety Lead-In and Phase 3 portions of the study. 
Due to sparse PK sample collection of the randomized Phase 3 portion of the study, the graphical 
evaluation of PK data described below will only be conducted for the Safety Lead-In portion of 
the study. The geometric mean with geometric SD concentration-versus-time profiles will be 
presented graphically for each analyte using both linear and semi-logarithmic scales by treatment 
arm on C1D1 and C2D1. Individual plasma concentration-time profiles will also be presented 
graphically using linear and semi-logarithmic scales by treatment arm and study day. For ease of 
presentation, nominal times will be used to present results in summary and individual figures. 
Handling of plotted data where BLQ values are present will be specified in a standalone PAP. 
7.9.2 
Pharmacokinetic Parameters for Cetuximab, Encorafenib, Binimetinib, and 
AR00426032 
Pharmacokinetic parameters for patients in the PK set will be determined by treatment arm for 
cetuximab, encorafenib, binimetinib and AR00426032 when possible and appropriate. 


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PK Analysis for Safety Lead-In 
7.9.2.1
The individual concentration-time data for each analyte will be evaluated with 
noncompartmental analysis (NCA) using 
. Actual 
blood collection times and doses will be used for PK calculations. Additional details regarding 
the handling of data and presentation of parameters for the NCA analysis will be provided in a 
standalone PAP. 
The following parameters will be calculated for cetuximab, encorafenib, binimetinib and 
AR00426032 on C1D1 and C2D1: 
PK Parameter 
Definition 
AUCext 
Percentage of AUCinf due to extrapolation from Tlast to infinity, calculated as: 
AUCinf - AUClast 
× 100 
AUCinf 
AUCinf 
Area under the plasma concentration-time curve extrapolated to infinity 
AUClast 
Area under the plasma concentration-time curve from zero to the last measurable 
time point 
AUCtau 
Area under the plasma concentration-time curve over the dosing interval 
AUC/D 
Dose-normalized AUC, calculated as: 
AUC 
Dose 
Note: an appropriate AUC parameter for use in this calculation will be specified 
depending on data quality and will be discussed in the final report. 
Cmax 
Observed maximum plasma concentration 
Cmax/D 
Dose-normalized Cmax, calculated as: 
Cmax 
Dose 
Clast 
Last measured concentration 
Tmax 
Observed time of Cmax 
Tlast 
Observed time of Clast 
kel 
Terminal elimination rate constant 
t1/2 
Terminal elimination half-life, calculated as: 
ln(2) 
kel 
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PK Parameter 
Definition 
CL/F (oral) or 
CL (intravenous) 
Apparent systemic clearance, calculated as: 
Dose 
for single dose and 
Dose 
at steady state 
AUCinf 
AUCtau 
Vss (intravenous) 
Apparent steady-state volume of distribution, calculated as: 
Dose x AUMCinf 
 
 
(AUCinf)2 
Vz/F (oral) or 
Vz (intravenous) 
Apparent volume of distribution, calculated as: 
Dose 
for single dose and 
Dose 
at steady state 
AUCinf × kel 
AUCtau × kel 
MRAUC, MRCmax 
(binimetinib only) 
Metabolite ratios, calculated as: 
AUCmetabolite 
, 
Cmax, metabolite 
AUCparent 
Cmax, parent 
Note: an appropriate AUC parameter for use in this calculation will be specified 
depending on data quality and will be discussed in the final report. 
RAUC, RCmax 
Accumulation ratios, calculated as: 
AUCtau, steady state 
, 
Cmax, steady state 
AUCtau, single dose 
Cmax, single dose 
Note: an appropriate AUC parameter for use in this calculation will be specified 
depending on data quality and will be discussed in the final report. 
 
The AUC parameters will be calculated according to the linear-up log-down trapezoidal rule. All 
AUC and Cmax values will also be provided as dose-normalized values based on the actual dose 
administered prior to PK sampling. Additional PK parameters may be calculated at the discretion 
of the pharmacokineticist; reporting of PK parameters listed above is subject to data quality. 
All PK parameter values will be presented in data listings by analyte, treatment arm, cycle and 
study day. Each parameter will be summarized in tables by analyte, treatment arm, cycle and 
study day using the following descriptive statistics: n, arithmetic mean, standard deviation, CV, 
geometric mean, geometric standard deviation, geometric CV, minimum, median and maximum. 
Summary descriptive statistics for in-text summary tables will include geometric mean with 
geometric CV for AUC, AUC/D, Cmax, Cmax/D, RAUC, MRAUC, CL, CL/F, Vss and Vz/F values as 
appropriate. For Tmax and t1/2 values, median, minimum and maximum will be presented. If either 
the extent of extrapolation for an AUCinf is not acceptable and/or the goodness of fit value for 


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terminal phase regression is not acceptable, then only AUCtau or AUClast may be presented in the 
summary statistics rather than any terminal phase-derived parameters. 
Differences in PK parameter estimates for the SLI and JSLI cohorts will be assessed by 
generating separate summary tables of PK parameters for in the 2 cohorts. An additional 
comparison of the SLI and JSLI cohorts will be conducted using dose-normalized AUC and Cmax 
values pooled across dose levels. Assessments of dose-normalized AUC and Cmax between the 
SLI and JSLI cohorts will be conducted for cetuximab, encorafenib, binimetinib and 
AR00426032 based on geometric mean ratios and 90% CIs for Cycles 1 and 2 (Day 1). 
 
PK Analysis for Randomized Phase 3 Portion 
7.9.2.2
An analysis based on population PK modeling will be performed and described in a separate 
stand-alone modeling plan and a specific report will be produced. 
 
Drug-drug Interactions 
7.9.2.3
The potential effect of co-administration of one study drug on the PK of another study drug will 
be assessed (1) by comparison of PK results to historical PK results and (2) by covariate analysis 
using nonlinear mixed effects analysis (i.e., population PK analysis). Comparisons to historical 
PK results will be qualitative and only done as data permit. Covariate analysis will be conducted 
as appropriate for the following potential interactions: (1) the effect of coadministration of 
encorafenib on the PK of cetuximab, (2) the effect of coadministration of encorafenib + 
binimetinib on the PK of cetuximab and (3) the effect of coadministration of binimetinib on the 
PK of encorafenib. The source of cetuximab drug product may also be included as a covariate. 
Analyses will be described in a separate stand-alone modeling plan and a specific report will be 
produced. 
 
Exposure-response Analysis 
7.9.2.4
Relationships between exposure of study drugs and response or safety will be conducted using 
post hoc exposure estimates (e.g., Cmax, AUC or Cmin) from population PK modeling, if possible 
and appropriate. Measures of efficacy may include but are not limited to OS, PFS and ORR. 
Selection of safety measures will be based on frequency of observations or by selection of safety 
measure of interest. Analyses will be described in a separate stand-alone modeling plan and a 
specific report will be produced. 


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7.11 
Patient-reported Outcomes 
Quality-of-life data will be analyzed on the FAS. 
The EORTC QLQ-C30, FACT-C, EQ-5D-5L, and PGIC will be used to assess QoL. For 
EORTC-QLQ-C30, the global health status/QoL scale score is identified as the primary 
patient-reported outcome variable of interest; physical functioning, emotional functioning and 
social functioning scale scores of the QLQ-C30 are considered as secondary. For FACT-C, the 
functional well-being score is the primary patient-reported outcome variable of interest; the 
physical well-being, social/family well-being, emotional well-being, and additional concern 
scores are considered as secondary. The EQ-5D-5L contains 1 item for each of 5 dimensions 
health-related quality of life (i.e., mobility, self-care, usual activities, pain or discomfort, and 
anxiety or depression). Response options for each item vary from having no problems, moderate 
problems or extreme problems. 
The EORTC QLQ-C30, FACT-C, EQ-5D-5L, and PGIC will be scored according to their 
respective scoring manuals. The number of patients completing the questionnaires and the 
number of missing or incomplete assessments will be summarized by each treatment arm for 
each scheduled assessment time point. 
Descriptive statistics will be used to summarize the scored scales at each scheduled assessment. 
Additionally, change from baseline in the domain scores at the time of each assessment will be 
summarized. Patients with an evaluable baseline score and at least 1 evaluable post-baseline 
score during the treatment period will be included in the change from baseline analyses. In 
addition, a repeated measurement analysis model may be used to compare the treatment arms 
with respect to changes in the domain scores longitudinally over time. 
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Time to definitive deterioration in the QoL domains will be assessed in the 3 treatment arms in 
the FAS. The time to definitive deterioration is defined as the time from the date of 
randomization to the date of event, which is defined as at least 10% worsening relative to 
Baseline of the corresponding scale score with no later improvement above this threshold 
observed during the course of the study or death due to any cause. If a patient has not had an 
event prior to analysis cutoff or start of another anticancer therapy, time to deterioration will be 
censored at the date of the last adequate QoL evaluation. The distribution will be presented 
descriptively using KM curves. Median time to definitive deterioration along with two-sided 
95% CI will be provided. A Cox model will be fit with treatment arm and stratification factors as 
the covariates to obtain a HR estimate of the treatment effect along with 95% CI. The 
stratification factors used in the test will be precisely those used for randomization, and will be 
based on the actual randomization (IWRS) information. 
7.12 
Interim Safety Reviews 
The independent DMC will review the available safety information during the SLI part and also 
after the first 30 patients in the randomized Phase 3 portion of the study (i.e., approximately 10 
patients in each arm) have had the opportunity to complete at least 1 cycle of treatment to 
confirm tolerability. Subsequent DMC safety data reviews will occur at regular intervals. 
Additional details will be outlined in the DMC Charter. 
7.13 
Initial Efficacy Analyses 
An initial analysis of the study will be performed when all 3 of the following criteria have been 
met: 
• 
approximately 9 months after randomization of the 330th patient (i.e., approximately 
110 patients per arm), to allow a majority of responders among the 330 Phase 3 patients 
to have the opportunity to be followed for approximately 6 months or longer after their 
first response 
• 
at least 188 OS events have occurred in the Triplet and Control arms combined 
(i.e., approximately 70% information) 
• 
at least 169 OS events have occurred in the Doublet and Control arms combined 
(i.e., approximately 50% information) 
The primary endpoint of Triplet vs. Control ORR (by BICR) will be formally tested first at this 
analysis and will be based on the first approximately 330 randomized patients (any additional 
patient[s] randomized on the same day as the 330th randomized patient will be included in the 


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analysis). If the Triplet vs. Control ORR comparison is positive (i.e., p < 0.005), then based on 
the fallback procedure, the OS endpoint of Triplet vs. Control will be assigned a total one-sided 
alpha = 0.025. Otherwise, the Triplet vs. Control OS will be assigned a total one-sided 
alpha = 0.020. 
An interim analysis for superiority or (non-binding) futility of the Triplet vs. Control OS 
endpoint will be also performed at the time of the primary ORR analysis based on all available 
data. Futility and superiority boundaries for both the OS interim and final analyses will be 
determined using a Lan-DeMets spending function that approximates O’Brien-Fleming stopping 
boundaries. 
For the Triplet vs. Control comparison, if the entire alpha = 0.025 can be applied to the OS 
endpoint and the interim analysis occurs at 70% of information, the overall power will be 88.7%. 
The critical HR for efficacy at the interim analysis is 0.701. The critical HR for futility at the 
interim analysis is 0.842. At the final analysis, the critical HR is 0.783. If alpha = 0.020 is 
applied to the OS endpoint and the interim analysis, the overall power will be 86.6%. The critical 
HR for efficacy at the interim analysis is 0.690. The critical HR for futility at the interim analysis 
is 0.828. At the final analysis, the critical HR is 0.775. 
For the Doublet vs. Control comparison, if the entire alpha = 0.025 can be applied to the OS 
endpoint and the interim analysis occurs at 50% of information, the overall power will be 90.5%. 
The critical HR for efficacy at the interim analysis is 0.634. At the final analysis, the critical HR 
is 0.807. If alpha = 0.020 is applied to the OS endpoint, the overall power will be 88.9%. The 
critical HR for efficacy at the interim analysis is 0.622. At the final analysis, the critical HR is 
0.799. 
The estimated power and critical values described above assume an exponential survival 
distribution in each arm. In addition, the actual alpha spent will be determined by the observed 
information fraction at the interim OS analysis, and the alpha remaining will be adjusted 
accordingly for final analyses. 
If the p value for the Triplet Arm vs. Control Arm OS comparison exceeds the superiority 
boundary at the interim analysis, testing of the endpoints included in the hierarchical approach 
described in Section 7.5 will be conducted. For each endpoint in the hierarchy, a Lan-DeMets 
spending function that approximates the O’Brien-Fleming stopping boundaries will be used with 
data from all available patients as described in Glimm (2010). The total alpha assigned to each 
endpoint will be either 0.025 (if the Triplet Arm vs. Control Arm ORR comparison was 
p < 0.005) or 0.020 (if the Triplet Arm vs. Control Arm ORR comparison was p ≥ 0.005). 


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If the p value for the Triplet Arm vs. Control Arm OS comparison does not exceed the 
superiority boundary at the interim analysis, OS of Triplet Arm vs. Control Arm will be tested 
again at the final analysis (i.e., when at least 268 OS events in Triplet and Control and at least 
338 OS events in Doublet and Control have occurred). Table 7-6 provides the number of 
expected events, the cumulative alpha spent and the cumulative power to reject the null 
hypothesis at the expected analysis timepoints for the Triplet vs. Control OS analysis. 
Table 7-6: 
Expected Number of OS Events and Cumulative Power at Expected OS 
Analysis Timepoints for the Triplet vs. Control Comparison 
 
 
OS Analysis 
 
 
Triplet vs. 
Control OS 
Analysis 
Cumulative 
Number of OS 
Events 
Cumulative 
Alpha Spent on 
OS 
Cumulative 
Power to Reject 
H0 for OS (%) 
Triplet vs. Control ORR is 
statistically significant  
(i.e., one-sided p<0.005) 
Interim 
188 
0.0074 
61.5 
Final 
268 
0.0250 
88.3 
Triplet vs. Control ORR is not 
statistically significant  
(i.e., one-sided p>0.005) 
Interim 
188 
0.0055 
57.4 
Final 
268 
0.0200 
86.3 
Note: All values were calculated using East® v6.4, assuming 70% information at the OS interim analysis. Boundaries will be 
adjusted according to the actual information fraction observed at the interim analysis. Cumulative power values were estimated 
using simulations within East® under the alternative hypothesis. 
Efficacy and futility are determined using Lan-DeMets approximation of O’Brien-Fleming alpha- and (non-binding) 
beta-spending boundaries, respectively. 
 
7.14 
Subgroup Analyses 
The following subgroup analyses will be performed for efficacy endpoints for Phase 3 patients: 
For OS and PFS by BICR on the FAS, and for ORR by BICR on the Phase 3 Response Efficacy 
Set: 
o ECOG PS (0 vs. 1) 
o Prior use of irinotecan (yes vs. no) 
o Cetuximab source (US-licensed vs. EU-approved) 
o Region (North America vs. Europe vs. Rest of World) 
o Number of prior regimens (1 vs. 2) 
o Race (Caucasian vs. non-Caucasian) 


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o Race (Asian vs. non-Asian) 
o Age (< 65 vs. ≥ 65 years) 
o Gender (male vs. female) 
o Number of organs involved at baseline (≤ 2 vs. ≥ 3) 
o 
 
o BRAF V600E mutation per central assessment (positive vs. negative/indeterminate) 
o 
 
 
 
o Removal status of primary tumor (no resection/partial resection, complete resection) 
o Side or tumor (left vs. right) 
o Presence of liver metastases at baseline, based on Target and Non-target lesion 
assessment (yes vs. no) 
For OS and PFS (by BICR and Investigator) on the FAS, and for ORR (by BICR and 
Investigator) on the Phase 3 Response Efficacy Set: 
o Japanese subgroup (patients randomized in Japan) 
o Korean subgroup (patients randomized in Korea) 
For analyses (by BICR and Investigator) of PFS, ORR, DOR and TTR on the FAS: 
o Japanese subgroup (patients randomized in Japan) 
o Korean subgroup (patients randomized in Korea) 
The following subgroup analyses will be performed for the AE analyses: 
o Race (Asian, White, Other) 
• Note that any patient with multiple races selected will be categorized as “Other” 
o Age category (< 65, ≥ 65, <75, ≥ 75 years) at screening visit 
o Gender (Male, Female) 
o Number of prior regimens (1 vs. 2) 
o Removal status of primary tumor (no resection/partial resection, complete resection) 
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o Liver metastases at baseline based on either disease characteristics or tumor lesion 
eCRFs: 
• No liver metastases 
• Liver metastases and both AST and ALT < 3 x ULN 
• Liver metastases and AST and/or ALT ≥ 3 x ULN 
o Japanese subgroup (patients randomized in Japan) 
o Korean subgroup (patients randomized in Korea) 
The following subgroup analyses will be performed for the duration of exposure analyses: 
o Age category (< 65, 65-74,75-84, ≥ 85 years) at screening visit 
o Race category (Asian, White, Other) 
• Note that any patient with multiple or races selected will be categorized as “Other” 
o Gender (Male, Female) 
o Number of prior regimens (1 vs. 2) 
o Removal status of primary tumor (no resection/partial resection, complete resection) 
o Liver metastases at baseline based on either disease characteristics or tumor lesion 
eCRFs: 
• No liver metastases 
• Liver metastases and both AST and ALT < 3 × ULN 
• Liver metastases and AST and/or ALT ≥ 3 × ULN 
o Baseline cardiac risk (Yes, No) 
• If the patient reports history of hypertension, diabetes, hyperlipidemia, cardiac 
disorders, arteriosclerosis and/or ischemic heart disease in the Medical History eCRF 
(Table 7-7), the patient is considered to have baseline cardiac risk. 


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Table 7-7: 
Medical History Terms for Cardiac Risk 
Disease 
Terms 
Hypertension 
SMQ: Hypertension 
Diabetes 
PT: Diabetic vascular disorder 
HLT: Diabetes mellitus (incl. subtypes) 
HLT: Diabetic complications cardiovascular 
Hyperlipidemia 
SMQ: Dyslipidaemia [broad] 
Cardiac Disorders 
SOC: Cardiac disorders 
Arteriosclerosis 
 
PT: Aortic arteriosclerosis 
PT: Arteriosclerosis 
PT: Peripheral arterial occlusive disease 
Ischaemic heart disease 
SMQ: Ischaemic heart disease [narrow] 
 
o Ethnicity (Hispanic or Latino, Non-Hispanic or Latino) 
o Baseline renal impairment based on estimated creatinine clearance (CrCl): 
• Normal (CrCl > 90 mL/min) 
• Mild impairment (CrCl between 60 and 90 mL/min) 
• Moderate impairment (CrCl between 30 and < 60 mL/min) 
• Severe impairment (CrCl < 30 mL/min) 
o Japanese subgroup (patients randomized in Japan) 
o Korean subgroup (patients randomized in Korea) 
The following subgroup analyses will be performed for newly occurring notable hepatic 
toxicities, based on baseline data (collected on disease characteristics or tumor lesion eCRFs): 
o No liver metastases 
o Liver metastases and both AST and ALT < 3 × ULN 
o Liver metastases and AST and/or ALT ≥ 3 × ULN 


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DATA AND ANALYSIS QUALITY ASSURANCE 
8.0
This protocol was conducted under the sponsorship of Array BioPharma. Personnel within Array 
BioPharma provided statistical and data management input for the design of the clinical trial 
protocol; data management, statistical analysis and generation of tables, listings and figures; and 
medical writing support for the clinical study report. 
All parties mentioned above will work diligently and collaboratively to ensure that data 
collection and analysis for this study are of the highest quality. This will be accomplished 
through programmed edit checks, quality control processes, and clinical and statistical review of 
data displays. Quality and accuracy of statistical analyses will be verified though established 
statistical programming validation processes. 


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9.0
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De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA 
mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory 
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East® version 6.3 manual (2014). Cytel Inc. Cambridge, MA USA. 
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East® version 6.4 manual (2016). Cytel Inc. Cambridge, MA USA. 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. 
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Fayers PM. (2001) The EORTC QLQ-C30 Scoring Manual (3rd Edition). Brussels: 
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10. Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group‐sequential 
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11. Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarryhthmic Drugs, Center for Drug Evaluation and 
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12. IMPACT® Harmony version 14.5 Main (2017). PAREXEL International Corp. Waltham, 
MA USA. 
13. Kalbfleisch JD, Prentice RL. (2002) The Statistical Analysis of Failure Time Data. Wiley 
Series in Probability and Statistics. 
14. Klein J. P. and Moeschberger, M. L. (1997), Survival Analysis: Techniques for Censored 
and Truncated Data, New York: Springer-Verlag. 
15. Kopetz S, McDonough SL, Lenz H-J et al. Randomized trial of irinotecan and cetuximab 
with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). 
J Clin Oncol. 2017;35:4s (suppl abstr 3505). 
16. Lan KKG, DeMets DL (1983). Discrete sequential boundaries for clinical trials. Biometrika 
70: 649-53. 


Encorafenib (LGX818)/Binimetinib (MEK162) 
Array BioPharma Inc.
ARRAY-818-302 (BEACON) Statistical Analysis Plan 
 
 
Version 6.0 FINAL 
75 
Confidential
23April 2019 
 
17. Morris V, Overman MJ, Jiang Z-Q, et. al. Progression-free survival remains poor over 
sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin 
Col Cancer Res 2014;13:164-71. 
18. Peeters M, Oliner KS, Price TJ, et al. Updated analysis of KRAS/NRAS and BRAF 
mutations in study 20050181 of panitumumab (pmab) plus FOLFIRI for second-line 
treatment (tx) of metastatic colorectal cancer (mCRC). J Clin Oncol 32:15s, 2014 (suppl; 
abstr 3568). 
19. Schemper M, Smith TL (1996). A note on quantifying follow-up in studies of failure time. 
Controlled Clinical Trials; 17: 343-346. 
20. Seymour MT, Brown SR, Middleton G et al. Panitumumab and irinotecan versus irinotecan 
alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer 
(PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013;14:749-59. 
21. U.S. Department of Health and Human Services. Common Terminology Criteria for 
Adverse Events (CTCAE). Revised May 29, 2009. Accessed July 14, 2009. 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf. 
22. Wiens BL, Dmitrienko A. The fallback procedure for evaluating a single family of 
hypotheses. J Biopharm Stat. 2005; 15:929-42. 
 


Encorafenib (LGX818)/Binimetinib (MEK162) 
Array BioPharma Inc.
ARRAY-818-302 (BEACON) Statistical Analysis Plan 
 
 
Version 6.0 FINAL 
76 
Confidential
23April 2019 
 
 
CHANGES TO THE STATISTICAL ANALYSIS PLAN 
10.0
Major changes in Version 2 include: 
• 
Addition of the secondary endpoint of PK modeling for drug interactions between 
encorafenib, cetuximab, and binimetinib to the Phase 3. 
• 
 
 
• 
Addition of a Japanese SLI cohort of 6 patients. 
Major changes in Version 3 include: 
• 
 
• 
Subgroup analyses for Japan added. 
Major changes in Version 4 include: 
• 
Addition of a primary objective and endpoint of confirmed ORR by BICR of Triplet Arm 
vs. Control Arm to the randomized portion of the study. 
• 
Modification of the planned interim analysis of OS (Triplet vs. Control) to include 
boundaries for both superiority and (non-binding) futility; the timing of this analysis was 
modified to occur at the same time as the primary analysis of the ORR endpoint specified 
above. 
• 
Addition of BICR of patients’ tumor imaging data to support the Phase 3 primary 
endpoint of confirmed ORR by BICR (Triplet Arm vs. Control Arm) as well as secondary 
efficacy analyses of ORR, progression-free survival (PFS), duration of response (DOR) 
and time to response. 
• 
Addition of PFS (by BICR and Investigator assessment) as a secondary objective and 
endpoint in the SLI portion of the study. 
• 
Modification of the threshold for requiring central laboratory confirmation of BRAF 
V600E mutation status prior to randomization. 
• 
Modification of algorithm to determine number of missing tumor assessments required 
for PFS analyses. 
• 
Updated format of summary tables. 
• 
Clarified analysis sets to be used for efficacy analyses. 
• 
Updated variables to be included in multivariate regression models of efficacy. 
CCI
CCI


Encorafenib (LGX818)/Binimetinib (MEK162) 
Array BioPharma Inc.
ARRAY-818-302 (BEACON) Statistical Analysis Plan 
 
 
Version 6.0 FINAL 
77 
Confidential
23April 2019 
 
• 
Updated AESI analyses. 
• 
Subgroup analyses for Korea added. 
Major changes in Version 5 include: 
• 
Provided more detail for the initial analysis and added Table 7-7 to further clarify 
calculations. 
• 
Clarified that OS and ORR are primary endpoints. 
• 
Included additional subset analyses and covariates for MV modeling. 
• 
Included additional detail for BOR definition. 
Major changes in Version 6 include: 
• 
Further updated the univariate and multivariate regression models of efficacy. 
• 
Further updated the details of the subgroup analyses. 
• 
Clarified data imputation rules. 
• 
Added summary reports for prescreened and screened patients not randomized and 
patients randomized but not treated. 
• 
Added detail on the BOR “Not Evaluable” category. 
• 
Specified analyses to be conducted to check the proportional hazards assumption for the 
Cox proportional hazards models. 
• 
Included additional sensitivity analyses for PFS. 
• 
Added analyses for PFS2 and TSST. 
• 
Sponsor assessments were specified where applicable. 
• 
AE summaries were further clarified. 
• 
Hepatic toxicity and CK elevation analyses were further refined. 
 

Prot_000.pdf: 
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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
3 
 
11 July 2019 
PRINCIPAL INVESTIGATOR AGREEMENT 
I have read and understand the contents of the clinical protocol for Clinical Study 
ARRAY-818-302 dated 11 July 2019 and will adhere to the study requirements as presented, 
including all statements regarding confidentiality. In addition, I will conduct the study in 
accordance with the requirements of this protocol and also protect the rights, safety, privacy and 
well-being of study patients in accordance with the following: 
• International Conference on Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) E6(R1) 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations 
• Requirements for reporting serious adverse events (SAEs) defined in Section 10.9 of this 
protocol 
• Terms outlined in the Clinical Study Site Agreement 
My signature also acknowledges that: 
• Neither my subinvestigators nor I are members of the Ethics Committee (EC) reviewing 
this protocol, or 
• I and/or my subinvestigators are members of the EC, but I/we will not participate in the 
initial review or continuing review of this study 
 
 
 
 
 
Name of Principal Investigator 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
4 
 
11 July 2019 
PROTOCOL SYNOPSIS 
Title 
A Multicenter, Randomized, Open-label, 3-Arm Phase 3 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 
Protocol Number 
ARRAY-818-302 
Phase 
3 
Study Centers 
Approximately 300 international study centers  
Objectives 
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 blinded independent central review (BICR)-
determined and Investigator-determined objective response 
rate (ORR), duration of response (DOR), progression-free 
survival (PFS) and time to response  
• Characterize the pharmacokinetics (PK) of encorafenib, 
cetuximab, binimetinib and the active metabolite of 
binimetinib (AR00426032) 
Exploratory:  
• Assess the activity of encorafenib + binimetinib + cetuximab 
as measured by overall survival (OS) 
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) 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
5 
 
11 July 2019 
• Compare the activity of encorafenib + binimetinib + cetuximab 
(Triplet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab 
(Control Arm) as measured by ORR per BICR 
Key Secondary: 
• Compare the activity of encorafenib + cetuximab (Doublet 
Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab 
(Control Arm) as measured by OS 
Other Secondary: 
• Compare the Investigator-determined ORR of encorafenib + 
binimetinib + cetuximab (Triplet Arm) vs. 
irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) 
• Compare the BICR-determined and Investigator-determined 
ORR of encorafenib + cetuximab (Doublet Arm) vs. 
irinotecan/cetuximab or FOLFIRI/ cetuximab (Control Arm) 
• Compare the BICR-determined and Investigator-determined 
progression-free survival (PFS) of encorafenib + binimetinib + 
cetuximab (Triplet Arm) vs. irinotecan/cetuximab or 
FOLFIRI/cetuximab (Control Arm) 
• Compare the BICR-determined and Investigator-determined 
PFS of encorafenib + cetuximab (Doublet Arm) vs. 
irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) 
• Compare the activity of Triplet Arm vs. Doublet Arm as 
measured by OS 
• Compare BICR-determined and Investigator-determined ORR 
of Triplet Arm vs. Doublet Arm 
• Compare the BICR-determined and Investigator-determined 
PFS of Triplet Arm vs. Doublet Arm 
• Compare BICR-determined and Investigator-determined DOR 
of Triplet Arm vs. Control Arm, of Doublet Arm vs. Control 
Arm and of Triplet Arm vs. Doublet Arm 
• Compare BICR-determined and Investigator-determined time 
to response of Triplet Arm vs. Control Arm, of Doublet Arm 
vs. Control Arm and of Triplet Arm vs. Doublet Arm 
• Assess the safety/tolerability of Triplet Arm, of Doublet Arm 
and of Control Arm 
• Compare the effect on quality of life (QoL) of Triplet Arm vs. 
Control Arm, of Doublet Arm vs. Control Arm and of Triplet 
Arm vs. Doublet Arm  


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CCI


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
7 
 
11 July 2019 
• PK parameters of encorafenib, cetuximab, binimetinib and the 
active metabolite of binimetinib (AR00426032) 
Exploratory: 
• OS, defined as the time from first dose to death due to any 
cause 
 
Randomized Phase 3 
Primary:  
• OS, defined as the time from randomization to death due to 
any cause, of Triplet Arm vs. Control Arm 
• Confirmed ORR (by BICR) per RECIST, v1.1 of Triplet Arm 
vs. Control Arm 
Key Secondary: 
• OS of Doublet Arm vs. Control Arm 
Other Secondary: 
• Confirmed ORR (by Investigator) per RECIST, v1.1 of Triplet 
Arm vs. Control Arm 
• Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 
of Doublet Arm vs. Control Arm 
• PFS (by BICR and Investigator), defined as the time from 
randomization to the earliest documented disease progression 
or death due to any cause, of Triplet Arm vs. Control Arm 
• PFS (by BICR and Investigator) of Doublet Arm vs. Control 
Arm 
• OS of Triplet Arm vs. Doublet Arm 
• Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 
of Triplet Arm vs. Doublet Arm 
• PFS (by BICR and Investigator) of Triplet Arm vs. Doublet 
Arm 
• DOR (by BICR and Investigator) of Triplet Arm vs. Control 
Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. 
Doublet Arm 
• Time to response (by BICR and Investigator), defined as the 
time from randomization to first radiographic evidence of 
response, of Triplet Arm vs. Control Arm, of Doublet Arm vs. 
Control Arm and of Triplet Arm vs. Doublet Arm 


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CCI


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
9 
 
11 July 2019 
from first dose of study treatment.  
In cases where there is discordance between the local assay and 
central laboratory results, or if the central laboratory is not able to 
confirm presence of a BRAFV600E mutation due to inadequate or 
poor sample condition within 30 days of initiating study therapy, 
patients may only continue treatment if there is no clinical 
indication of deterioration or disease progression and the 
investigator determines that the patient is deriving benefit. In such 
instances, patients must be informed that the BRAF mutation status 
is unconfirmed and must sign a separate informed consent form 
that includes this information and describes alternative treatment 
options.  
Central laboratory BRAF mutation tests with a definitive result 
(positive or negative) cannot be repeated to resolve a discordant 
result. Patients whose sample is determined to be inadequate or 
who have an indeterminate result on central testing may have 
samples resubmitted for testing. Lack of BRAFV600E confirmation 
by the central laboratory may be due to discordance between the 
local assay and central laboratory results (potential false positive 
local assay results), or due to inadequate or poor sample condition 
for central testing (indeterminate results). If at any time in the 
study there is lack of BRAFV600E confirmation in a total of 37 
patients (6% of the total planned enrollment of the randomized 
portion of the trial) or discordance between the local assay and the 
central laboratory in 18 patients (3% of the total planned 
enrollment), all subsequent patients will be required to have 
BRAFV600E determined by the central laboratory for treatment (i.e., 
local BRAF testing will no longer be accepted for trial eligibility). 
Information regarding sites and laboratories associated with 
discordant results will be maintained and results from laboratories 
with more than 1 prior discordant result will not be accepted. Sites 
with more than 2 randomized patients having indeterminate results 
after initiation of protocol version 6 will be required to enroll all 
subsequent patients based only on central laboratory assay results. 
Molecular Prescreening 
Prior to eligibility assessment for study enrollment/randomization, 
patients may undergo molecular tumor prescreening with the 
central laboratory BRAF mutation assay at any time prior to 
Screening as long as they meet all the Molecular Prescreening 
inclusion/exclusion criteria. Note that tumor samples previously 
determined to be BRAFwild-type (BRAFwt) by local assessment 
may be submitted to the central laboratory. In particular, tumors 
with clinicopathological features of BRAF mutations may be 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
10 
 
11 July 2019 
considered for testing by central laboratory regardless of the 
results of prior local BRAF mutation testing.   
Safety Lead-in 
The Safety Lead-in will be conducted at a limited number of sites. 
Dose-limiting toxicities will be evaluated and the tolerability of 
the binimetinib, encorafenib, and cetuximab combination will be 
assessed by the Sponsor and the Investigator in (approximately) 
weekly communications. The Data Monitoring Committee (DMC) 
will evaluate the safety data at pre-specified intervals and at 
additional points during the conduct of the Safety Lead-in, if 
necessary. The first 9 evaluable patients will be enrolled on a 
rolling basis in a single cohort to evaluate the combination of 
encorafenib 300 mg once daily (QD) + binimetinib 45 mg twice 
daily (BID) + cetuximab 400 mg/m2 followed by 250 mg/m2 IV 
weekly. Additional patients will be enrolled based on assessments 
of the safety data by the DMC during the Safety Lead-in. 
Following study treatment discontinuation, patients who provide 
informed consent for survival follow-up will continue to be 
assessed to determine survival status until withdrawal of consent, 
patient is lost to follow-up, death or defined end of study. 
If informed consent cannot be obtained due to the patient being 
lost to follow-up or previous withdrawal of consent, attempts to 
determine survival status will be made via access to public records 
where permitted by local laws. 
The doses for the Triplet Arm in the randomized Phase 3 portion 
of the study will be determined after a total of 25-30 patients have 
been treated at the proposed doses and their data evaluated by the 
DMC. 
In the Japanese Safety Lead-in portion of the study, a separate 
cohort of patients will be evaluated at a limited number of sites in 
Japan. Six patients will be enrolled on a rolling basis in a single 
cohort to evaluate the triplet dose. The starting dose in Japanese 
patients will be the dose assessed to be tolerable in the Safety 
Lead-in for non-Japanese patients. Similar to the Safety Lead-in 
for non-Japanese patients, the DMC will evaluate the safety data 
to confirm tolerability. 
Phase 3 
Once the tolerability of the proposed doses for the Triplet Arm has 
been established, the Phase 3 portion of the study will begin and 
eligible patients will be randomized in a 1:1:1 ratio to the Triplet 
Arm, Doublet Arm or Control Arm. The number of 3rd-line 
patients (those having received 2 prior regimens) will be limited to 
215 (35% of the total randomized) after which only patients with 


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1 prior regimen will be 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. Patients randomized to the 
Control Arm may be treated with either irinotecan + cetuximab or 
FOLFIRI + cetuximab as per Investigator’s choice. The choice of 
irinotecan or FOLFIRI must be declared prior to randomization.  
Randomization will be stratified by baseline Eastern Cooperative 
Oncology Group performance status (ECOG PS; 0 vs. 1), prior use 
of irinotecan (yes vs. no) and cetuximab source (US-licensed vs. 
EU-approved). The DMC will review the available safety 
information after the first 30 patients in the randomized Phase 3 
portion of the study (i.e., approximately 10 patients in each arm) 
have had the opportunity to complete at least 1 cycle of treatment 
to confirm tolerability. 
Treatment will be administered in 28-day cycles until disease 
progression, unacceptable toxicity, withdrawal of consent, 
initiation of subsequent anticancer therapy or death. In special 
circumstances (defined in Section 4.5), continuation of treatment 
beyond disease progression may be allowed. After treatment is 
discontinued, randomized Phase 3 patients will continue to be 
followed for OS unless consent for survival follow-up is 
withdrawn.  
Upon implementation of protocol v8.0, patients randomized to the 
Control arm who meet crossover eligibility criteria may cross over 
to receive the triplet regimen. Crossover patients will undergo 
study activities and assessments similar to those performed for 
patients randomized to the Triplet arm and will be treated until 
disease progression, unacceptable toxicity, withdrawal of consent, 
initiation of subsequent anticancer therapy or death. In special 
circumstances (defined in Section 4.5), continuation of treatment 
beyond disease progression may be allowed. After treatment is 
discontinued, patients will continue to be followed for OS unless 
consent for survival follow-up is withdrawn. 
End of Study 
End of study will be defined as the point when all patients have 
the opportunity to be followed for at least 1 year after the 
randomization date of the last patient enrolled and at least 80% of 
patients have an OS event (or are lost to follow-up). Any patients 
still receiving study drugs at the end of the study will be allowed 
to continue at the discretion of the Investigator and as long as none 
of the treatment discontinuation criteria are met. After the end of 
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with local regulations and requirements. 
Treatment Regimens 
The investigational products in this study are encorafenib and 
binimetinib, which will be administered orally (PO) in 
combination with cetuximab (i.e., encorafenib + binimetinib + 
cetuximab [Safety Lead-in and Triplet Arm] and encorafenib + 
cetuximab [Doublet Arm]). The comparator combination treatment 
will be the Investigator’s choice of either irinotecan/cetuximab or 
FOLFIRI/cetuximab (Control Arm).  
Patients will receive the following per 28-day cycle: 
Safety Lead-in and Triplet Arm: 
• Encorafenib: 300 mg (4 × 75 mg oral capsule) QD PO 
• Binimetinib: 45 mg (3 × 15 mg oral tablet) BID PO 
• Cetuximab: 400 mg/m2 initial dose (120-minute intravenous 
[IV] infusion on Cycle 1 Day 1), then 250 mg/m2 (60-minute 
IV infusion) once weekly thereafter 
Doublet Arm: 
• Encorafenib: 300 mg (4 × 75 mg oral capsule) QD PO 
• Cetuximab: 400 mg/m2 initial dose (120-minute IV infusion on 
Cycle 1 Day 1), then 250 mg/m2 (60-minute IV infusion) once 
weekly thereafter 
Control Arm: 
• Irinotecan: 180 mg/m2 IV on Days 1 and 15 
• Cetuximab: 400 mg/m2 initial dose (120-minute IV infusion on 
Cycle 1 Day 1), then 250 mg/m2 (60-minute IV infusion) once 
weekly thereafter 
OR 
• Irinotecan: 180 mg/m2 IV on Days 1 and 15 
• FA: 400 mg/m2 IV on Days 1 and 15 
• 5-FU: 400 mg/m2 IV on Day 1 and 15, then 1200 mg/m2/d x 
2 days (total 2400 mg/m2 over 46-48 hours) continuous 
infusion 
• Cetuximab: 400 mg/m2 initial dose (120-minute IV infusion on 
Cycle 1 Day 1), then 250 mg/m2 (60-minute IV infusion) once 
weekly thereafter 
For an individual patient, the dose of study drug(s) may be 
reduced or interrupted as appropriate based on protocol-defined 
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In the Phase 3 portion of the study, patients must receive their first 
dose of study drug within 5 days of randomization. 
Crossover 
Patients crossing over to the triplet regimen will receive study 
treatments as described above, although the cetuximab dose will 
be 250 mg/m2 IV weekly or the last tolerated dose level the patient 
received in the Control Arm. 
Study Population 
Approximately 646 to 651 patients (includes 31 to 36 patients for 
the non-Japanese and Japanese Safety Lead-in study portions; 
additional patients may be included if lower dose levels are 
evaluated during the Safety Lead-in) with BRAFV600E mCRC 
whose disease has progressed after 1 or 2 prior regimens in the 
metastatic setting.   
Duration of Study 
Participation 
Patients may enter into the Molecular Prescreening Phase of the 
study to determine the BRAF mutation status of their tumor using 
the central laboratory assay at any time prior to the Screening 
Period of the study. The study consists of a 28-day Screening 
Period, followed by 28-day treatment cycles until disease 
progression, unacceptable toxicity, withdrawal of consent, 
initiation of subsequent anticancer therapy or death. After 
discontinuation of study treatment, there will be a 30-day safety 
follow-up period and a survival follow-up period.  
Eligibility Criteria  
 
Eligibility will be determined separately for molecular tumor 
testing during a Prescreening Phase and for 
enrollment/randomization in the study during a Screening Phase. 
Inclusion and Exclusion 
Criteria for Molecular 
Prescreening 
Patients may undergo molecular tumor prescreening at any time 
prior to Screening as long as they meet all the following 
inclusion/exclusion criteria:  
Inclusion Criteria for Molecular Prescreening 
All the following inclusion criteria must be met for a patient to be 
eligible to undergo molecular tumor prescreen: 
1. 
Provide a signed and dated prescreening informed consent 
document 
2. 
Age ≥ 18 years at time of informed consent 
3. 
Histologically- or cytologically-confirmed CRC that is 
metastatic 
4. 
Eligible to receive cetuximab per locally approved label 
with regard to tumor RAS status  


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5. 
Able to provide a sufficient amount of representative tumor 
specimen (primary or metastatic, archival or newly obtained) 
for central laboratory testing of BRAF and KRAS mutation 
status (minimum of 6 slides; optimally up to 15 slides). 
Exclusion Criteria for Molecular Prescreening 
Patients meeting any of the following criteria at Prescreening are 
not eligible to undergo molecular tumor prescreen: 
1. Leptomeningeal 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. Known history of acute or chronic pancreatitis 
4. History of chronic inflammatory bowel disease or Crohn’s 
disease requiring medical intervention (immunomodulatory 
or immunosuppressive medications or surgery) ≤12 months 
prior to randomization 
5. Concurrent neuromuscular disorder that is associated with 
the potential of elevated creatine kinase (CK) (e.g., 
inflammatory myopathies, muscular dystrophy, 
amyotrophic lateral sclerosis, spinal muscular atrophy) 
6. Known history of human immunodeficiency virus (HIV) 
infection 
7. 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 
8. Known contraindication to receive cetuximab or irinotecan 
at the planned doses; refer to the most recent cetuximab 
and irinotecan summary of product characteristics (SPC) or 
local label as applicable 
9. Prior anti-epidermal growth factor receptor (EGFR) 
treatment 
10. More than 2 prior regimens in the metastatic setting 
Note: 
a. Disease relapse during treatment or within 6 months 
following adjuvant therapy will be considered 


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metastatic disease.  
b. Maintenance therapy given in the metastatic setting 
will not be considered a separate regimen. 
Patient Eligibility 
 
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, 
additional samples may be submitted.   
d) If at any time in the Phase 3 portion of the study there 
is lack of BRAFV600E confirmation by the central 
laboratory (for any reason including discordance and 
inadequate available tissue) in 37 total patients or 
discordance (a valid result of “no BRAFV600E mutation” 
as determined by the central laboratory) between the 
local assay and the central laboratory in 18 patients, all 
subsequent patients will be required to have BRAFV600E 
determined by the central laboratory prior to 
enrollment (see Section 7.1.1). 
e) Results from local laboratories with more than 1 
discordant result leading to patient enrollment will not 


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be accepted for further patient enrollment. 
f) Sites with more than 2 randomized patients having 
indeterminate results after initiation of protocol version 
6 will be required to enroll all subsequent patients 
based only on central laboratory assay results.    
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 6 slides; 
optimally up to 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. Patients who have received 2 prior regimens (i.e. 
those entering the study in the 3rd line setting), must 
have received or have been offered and refused 
prior oxaliplatin unless it was contraindicated due 
to underlying conditions. 
c. Maintenance therapy given in the metastatic setting 
will not be considered a separate regimen. 
d. 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.   
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disease per RECIST, v1.1 
9. ECOG PS of 0 or 1 
10. Adequate bone marrow function characterized by the 
following at screening: 
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L; 
• Platelets ≥ 100 × 109/L; 
• 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 electrolytes at Baseline, defined as serum 
potassium and magnesium levels within institutional 
normal limits (Note: replacement treatment to achieve 
adequate electrolytes will be allowed) 
13. Adequate hepatic function characterized by the following 
at screening: 
• 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 
• Alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) ≤ 2.5 × ULN, or 
≤ 5 × ULN in presence of liver metastases 
14. Adequate cardiac function characterized by the following 
at screening: 
• Left ventricular ejection fraction (LVEF) ≥ 50% as 
determined by a MUGA scan or ECHO; 
• Mean triplicate QT interval corrected for heart rate 
using Fridericia's formula (QTcF) value ≤480 msec 
15. Able to take oral medications 


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16. Willing and able to comply with scheduled visits, 
treatment plan, laboratory tests and other study procedures 
17. 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 contraceptive methods listed in 
Section 5.3.1 should be communicated to the patients and 
their understanding confirmed. For all females, the 
pregnancy test result must be negative at screening. 
18. Males must agree to take appropriate precautions to avoid 
fathering a child from screening through 90 days following 
end of therapy. 
Note: Permitted contraceptive methods listed in 
Section 5.3.1 should be communicated to the patients and 
their understanding confirmed. 
19. Patients under guardianship or partial guardianship will be 
eligible unless prohibited by local laws or by local/central 
ethic committees (e.g., France, Germany). Where allowed, 
all procedures prescribed by law must be followed. 
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 


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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) at the time of screening 
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) 
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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: 
• 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 
• 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 
• Bevacizumab or aflibercept therapy ≤ 3 weeks prior 
to starting study treatment 
• 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. 
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at the planned doses; refer to the most recent cetuximab 
and irinotecan SPC or local label as applicable.  
22. 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. 
23. Concomitant use of St. John’s Wort (hypericum 
perforatum). 
24. 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. 
25. Pregnant, confirmed by a positive human chorionic 
gonadotropin (hCG) laboratory test result, or nursing 
(lactating). 
26. Prior enrollment into this clinical study. 
Inclusion and Exclusion 
Criteria for Treatment 
Crossover 
Inclusion Criteria for Treatment Crossover 
All of the following inclusion criteria must be met within 28 days 
prior to initiation of crossover treatment.  
1. Patient was randomized to the Control arm and: 
• Discontinued Control arm treatment for any reason 
on or after 13 June 2019 (i.e., 4 weeks before the 
date of protocol version 8.0), 
• Received no systemic anticancer therapy after 
discontinuation of Control arm treatment, and  
• Remains in survival follow-up. 
2. Provide a signed and dated Crossover informed consent 
document. 
3. ECOG PS of 0 or 1. 
4. Adequate bone marrow function characterized by the 
following: 


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• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L; 
• Platelets ≥ 100 × 109/L; 
• 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 these criteria.  
5. 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. 
6. Adequate electrolytes defined as serum potassium and 
magnesium levels within institutional normal limits (Note: 
replacement treatment to achieve adequate electrolytes will 
be allowed). 
7. Adequate hepatic function characterized by the following: 
• 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 
• Alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × 
ULN in presence of liver metastases. 
8. Adequate cardiac function characterized by the following: 
• Mean triplicate QT interval corrected for heart rate 
using Fridericia's formula (QTcF) value ≤480 msec. 
9. Able to take oral medications. 
10. Willing and able to comply with scheduled visits, 
treatment plan, laboratory tests and other study procedures. 
11. 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 
through follow-up if of childbearing potential. 
Note: Permitted contraceptive methods listed in Section 
5.3.1 should be communicated to the patients and their 
understanding confirmed. For all females, the pregnancy 
test result must be negative at crossover screening and at 


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the time of crossover. 
12. Males must agree to take appropriate precautions to avoid 
fathering a child through 90 days following end of therapy. 
Note: Permitted contraceptive methods listed in Section 
5.3.1 should be communicated to the patients and their 
understanding confirmed. 
13. Patients under guardianship or partial guardianship will be 
eligible unless prohibited by local laws or by local/central 
ethic committees (e.g., France, Germany). Where allowed, 
all procedures prescribed by law must be followed. 
Exclusion Criteria for Treatment Crossover 
Patients randomized to the Control arm who meet any of the 
following criteria within 28 days prior to initiation of crossover 
treatment will not be eligible for crossover. 
1. Patients for whom cetuximab was permanently 
discontinued due to cetuximab-related toxicity in the 
randomized Phase 3 portion of the study. 
2. 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., MRI or CT) demonstrating no current evidence of 
progressive brain metastases.  
3. Leptomeningeal disease. 
4. 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 
crossover. 
5. Known history of acute pancreatitis. 
6. History of chronic inflammatory bowel disease or Crohn’s 
disease requiring medical intervention (immunomodulatory 
or immunosuppressive medications or surgery) ≤ 12 
months prior to crossover. 
7. Impaired cardiovascular function or clinically significant 
cardiovascular diseases, including any of the following: 
• History of acute myocardial infarction, acute 


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coronary syndromes (including unstable angina, 
CABG, coronary angioplasty or stenting) 
≤ 6 months prior to start of crossover; 
• 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 crossover, except 
atrial fibrillation and paroxysmal supraventricular 
tachycardia. 
8. Impaired hepatic function, defined as Child Pugh class B 
or C. 
9. 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). 
10. Treatment with irinotecan within 3 weeks prior to Day 1 of 
crossover treatment.  
11. Residual CTCAE ≥ Grade 2 toxicity from any prior 
anticancer therapy, with the exception of Grade 2 alopecia 
or Grade 2 neuropathy.  
12. Concomitant use of St. John’s Wort (hypericum 
perforatum). 
13. 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 
crossover treatment. 
14. Pregnant, confirmed by a positive hCG laboratory test 
result, or nursing (lactating) at time of crossover. 
15. Left ventricular ejection fraction (LVEF) < 50% as 
determined by a MUGA scan or ECHO. 
16. Current evidence or history of RVO or current risk factors 
for RVO (e.g., uncontrolled glaucoma or ocular 
hypertension, history of hyperviscosity or 


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hypercoagulability syndromes). 
17. Uncontrolled hypertension defined as persistent systolic 
blood pressure ≥ 150 mmHg or diastolic blood pressure 
≥ 100 mmHg despite current therapy. 
18. History of thromboembolic or cerebrovascular events 
≤ 6 months prior to crossover, including transient ischemic 
attacks, cerebrovascular accidents, deep vein thrombosis or 
pulmonary emboli. 
19. Concurrent neuromuscular disorder that is associated with 
the potential of elevated CK (e.g., inflammatory 
myopathies, muscular dystrophy, amyotrophic lateral 
sclerosis, spinal muscular atrophy) 
Assessments 
Efficacy assessments include radiological imaging (e.g., CT, MRI, 
X-ray, different methods of whole body bone scans) and with 
tumor response will be determined locally by the Investigator and 
restrospectively by BICR according to RECIST, v1.1. Tumor 
assessments will be performed every 6 weeks from randomization 
(or from first dose in Safety Lead-in) for the first 24 weeks, then 
every 12 weeks until disease progression, withdrawal of consent 
for treatment, initiation of subsequent anticancer therapy, patient is 
lost to follow-up, or death. After patients have discontinued 
treatment for any reason, they will be followed every 3 months, or 
more frequently as needed, until withdrawal of consent, the patient 
is lost to follow-up, death or end of study as defined in 
Section 4.6. If patients withdraw consent, they will be asked if 
they are willing to be contacted via telephone for survival status. If 
the patient refuses to be contacted, attempts to determine survival 
status should be made via access to public records where permitted 
by local laws. 
Safety assessments include monitoring of AEs, clinical laboratory 
tests (chemistry, hematology, coagulation and urinalysis), vital 
signs, physical examinations, ophthalmic examinations, 
dermatologic examinations, ECGs and ECHO/MUGA scans. 
Other assessments include ECOG PS and QoL questionnaires 
(EORTC QLQ-C30, FACT-C, EQ5D-5L and PGIC).  
Serial blood samples for characterization of the PK of encorafenib, 
cetuximab, binimetinib and the active metabolite of binimetinib 
(AR00426032) will be collected from all patients in the Safety 
Lead-in and from a subset of patients (approximately the first 50 
enrolled in the Triplet Arm and in the Doublet Arm from any site 
and approximately the first 100 enrolled in the Control Arm from 


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CCI


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
27 
 
11 July 2019 
• at least 188 OS events have occurred in the Triplet and 
Control arms combined (i.e., approximately 70% 
information) 
• at least 169 OS events have occurred in the Doublet and 
Control arms combined (i.e., approximately 50% 
information) 
This analysis will be conducted by the DMC and will serve as both 
the primary analysis of Triplet vs Control ORR and an interim 
analysis of Triplet vs Control OS. The Type I error rate for the 
primary endpoints will be controlled using a fallback procedure 
described by Wiens and Dmitrienko (2005). A 1-sided alpha value 
of 0.005 will be assigned to the Triplet vs Control ORR endpoint. 
The remaining alpha of 0.020 will be assigned to the Triplet vs 
Control OS endpoint.  
The primary endpoint of Triplet vs Control ORR (per BICR) will 
be formally tested first and will be based on the first 
330 randomized patients. A sample size of 110 patients per arm 
provides 88% power to detect a 20% absolute difference in ORR, 
assuming an ORR of 10% in the Control Arm and an ORR of 30% 
in the Triplet Arm at a 1-sided alpha of 0.005. 
If the Triplet vs. Control ORR comparison is positive (p < 0.005), 
then, based on the fallback procedure, the OS endpoint of Triplet 
vs. Control will be assigned a total 1-sided alpha = 0.025. 
Otherwise, the Triplet vs. Control OS will be assigned a total 
1-sided alpha = 0.020.  
An interim analysis for superiority or (non-binding) futility of the 
Triplet vs Control OS endpoint will then also be performed using 
data from all available patients. Futility and superiority boundaries 
for both the OS interim and final analyses will be determined 
using a Lan-DeMets spending function that approximates 
O’Brien-Fleming stopping boundaries.  
If the p-value for the Triplet Arm vs Control Arm OS comparison 
exceeds the superiority boundary at the interim analysis, the 
following endpoints will be tested at that time in the following 
order: 
1. OS of Doublet Arm vs. Control Arm  
2. ORR (per BICR) of Doublet Arm vs. Control Arm 
3. PFS (per BICR) of Triplet Arm vs. Control Arm 
4. PFS (per BICR) of Doublet Arm vs. Control Arm 
For each endpoint in the hierarchy, a Lan-DeMets spending 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
28 
 
11 July 2019 
function that approximates the O’Brien-Fleming stopping 
boundaries will be used with data from all available patients. The 
total alpha assigned to each endpoint will match the total alpha 
assigned to Triplet vs Control OS comparison (either 1-sided 0.025 
or 1-sided 0.020). If any of the above tests is found to not be 
statistically significant, all subsequent comparisons will only be 
summarized using descriptive statistics.  
If the p-value for the Triplet Arm vs Control Arm OS comparison 
does not exceed the superiority boundary at the OS interim 
analysis, OS of Triplet Arm vs. Control Arm will be tested again at 
the final analysis (i.e., when at least 268 OS events in Triplet and 
Control and at least 338 OS events in Doublet and Control have 
occurred). If the results are positive, the four remaining endpoints 
will be tested using the hierarchy and method specified above. If 
the results of the OS of Triplet Arm vs. Control Arm comparison 
are negative, no further formal testing will be conducted and all 
remaining endpoints will be summarized using descriptive 
statistics. 
The OS of Triplet Arm vs. Doublet Arm will be assessed as a 
secondary endpoint, but this will not be included in the 
hierarchical sequence that controls the overall Type I error rate. If 
the interim analysis for OS of Triplet vs. Control exceeds the 
superiority boundary, patients in the Triplet and Doublet arms may 
continue to be followed for a more mature comparison. 
Additional analyses will be performed for PFS, ORR, DOR and 
time to response (CR or PR).  
Plasma concentrations of encorafenib, binimetinib and the active 
metabolite of binimetinib (AR00426032) and serum 
concentrations of cetuximab will be determined using validated 
assays. Descriptive statistics of concentrations will be reported and 
summarized graphically.  
Pharmacokinetic parameters from the Safety Lead-in will be 
generated by noncompartmental and/or compartmental approaches 
as appropriate. No noncompartmental PK parameters will be 
estimated in the Phase 3 portion of the study due to sparse 
sampling. Phase 3 PK parameters will be estimated for 
encorafenib, cetuximab, binimetinib and the active metabolite of 
binimetinib (AR00426032) as appropriate using a population 
model-based approach for patients in the Safety Lead-in, Triplet, 
Doublet, and Control Arms, as appropriate, to determine 
appropriate model-based PK parameters and their respective 
variability, if deemed appropriate. 
Assessments of potential drug-drug interactions for encorafenib, 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
29 
 
11 July 2019 
cetuximab, binimetinib and the active metabolite of binimetinib 
(AR00426032) will be conducted by comparison to historical PK 
results for all 3 study drugs and by covariate modeling as part of 
the population PK analysis, as appropriate. 
Safety data will be presented in tabular and/or graphical format 
and summarized descriptively by treatment arm and study day, as 
appropriate.  
Results of QoL questionnaires (EORTC QLQ-C30, FACT-C, 
EQ-5D-5L, PGIC) will be summarized for each visit using 
descriptive statistics. Additionally, changes from baseline in the 
domain scores at the time of each assessment will be summarized. 
A repeated measurement analysis model may be used to compare 
the treatment groups with respect to longitudinal changes over 
time. Additional details regarding analysis of QoL results will be 
included in the statistical analysis plan. 
Sponsor 
Array BioPharma Inc. 
 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
30 
 
11 July 2019 
TABLE OF CONTENTS 
1.0 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ....................... 43 
2.0 INTRODUCTION ........................................................................................................... 44 
2.1 
Metastatic Colorectal Cancer....................................................................................... 44 
2.2 
BRAFV600E Colorectal Cancer ...................................................................................... 44 
2.2.1 
Inhibition of BRAF, MEK, and EGFR in BRAF-V600E Colorectal Cancer 
Cells .................................................................................................................... 45 
2.2.2 
Effects of Encorafenib and Cetuximab in BRAF-V600E Colorectal Cancer .......... 46 
2.2.3 
Effects of Encorafenib, Binimetinib, and Cetuximab in BRAF-V600E 
Colorectal Cancer ................................................................................................ 47 
2.2.4 
Encorafenib in Colorectal Cancer ........................................................................ 48 
2.2.5 
Other BRAF Inhibitors ........................................................................................ 51 
2.3 
Overview of Encorafenib ............................................................................................ 52 
2.3.1 
Nonclinical Safety Pharmacology and Toxicology ............................................... 52 
2.3.2 
Pharmacokinetics and Metabolism ....................................................................... 53 
2.3.3 
Clinical Safety ..................................................................................................... 54 
2.4 
Overview of Binimetinib ............................................................................................. 58 
2.4.1 
Nonclinical Safety Pharmacology and Toxicology ............................................... 58 
2.4.2 
Clinical Pharmacokinetics.................................................................................... 58 
2.4.3 
Clinical Experience.............................................................................................. 59 
2.5 
Overview of the Combination of Encorafenib and Binimetinib .................................... 60 
2.5.1 
Nonclinical Pharmacokinetics and Metabolism .................................................... 60 
2.5.2 
Clinical Experience.............................................................................................. 61 
2.6 
Overview of Cetuximab .............................................................................................. 63 
2.6.1 
Clinical Experience.............................................................................................. 63 
2.7 
Overview of Irinotecan................................................................................................ 64 
2.8 
Overview of FOLFIRI................................................................................................. 64 
2.9 
Rationale for the Study ................................................................................................ 64 
2.9.1 
Study Design ....................................................................................................... 65 
2.9.2 
Safety Lead-in ..................................................................................................... 67 
2.9.3 
Dose Selection ..................................................................................................... 68 
2.9.4 
Summary ............................................................................................................. 69 
3.0 STUDY OBJECTIVES AND ENDPOINTS ................................................................... 71 
3.1 
Study Objectives ......................................................................................................... 71 
3.1.1 
Safety Lead-In ..................................................................................................... 71 
3.1.2 
Randomized Phase 3 ............................................................................................ 71 
3.2 
Study Endpoints .......................................................................................................... 73 
3.2.1 
Safety Lead-In ..................................................................................................... 73 
3.2.2 
Randomized Phase 3 ............................................................................................ 74 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
31 
 
11 July 2019 
4.0 STUDY DESIGN ............................................................................................................. 76 
4.1 
Study Design Overview .............................................................................................. 76 
4.2 
Safety Lead-in Phase ................................................................................................... 80 
4.2.1 
Dose-Limiting Toxicities ..................................................................................... 80 
4.2.2 
Tolerability Assessment ....................................................................................... 81 
4.2.3 
Japanese Safety Lead-in ....................................................................................... 83 
4.3 
Randomized Phase 3 ................................................................................................... 84 
4.4 
Measures to Minimize Bias ......................................................................................... 85 
4.5 
Duration of Treatment ................................................................................................. 86 
4.6 
End of Study ............................................................................................................... 87 
4.7 
Data Review Committees ............................................................................................ 87 
4.7.1 
Data Monitoring Committee ................................................................................ 87 
4.7.2 
Steering Committee ............................................................................................. 87 
5.0 PATIENT POPULATION ............................................................................................... 88 
5.1 
Number of Patients ..................................................................................................... 88 
5.2 
Selection of Patients .................................................................................................... 88 
5.2.1 
Eligibility Criteria for Molecular Prescreening ..................................................... 88 
5.2.2 
Patient Eligibility ................................................................................................. 90 
5.2.3 
Eligibility Criteria for Treatment Crossover ......................................................... 95 
5.3 
Lifestyle Guidelines .................................................................................................... 98 
5.3.1 
Contraception ...................................................................................................... 98 
5.3.2 
Photosensitivity ................................................................................................... 99 
6.0 STUDY TREATMENT AND CONCOMITANT MEDICATIONS/THERAPIES ..... 100 
6.1 
Patient Numbering .................................................................................................... 100 
6.2 
Allocation to Treatment ............................................................................................. 100 
6.2.1 
Treatment Crossover .......................................................................................... 100 
6.3 
Doses and Schedule of Administration ...................................................................... 101 
6.3.1 
Administration of Encorafenib or Encorafenib + Binimetinib ............................ 102 
6.3.2 
Administration of Cetuximab ............................................................................. 103 
6.3.3 
Administration of Irinotecan .............................................................................. 104 
6.3.4 
Administration of FOLFIRI ............................................................................... 104 
6.4 
Dose Modifications ................................................................................................... 104 
6.4.1 
Dose Modifications for Encorafenib and/or Binimetinib .................................... 106 
6.4.2 
Dose Modifications for Cetuximab .................................................................... 117 
6.4.3 
Dose Modifications for FOLFIRI Treatment ...................................................... 118 
6.4.4 
Dose Modifications for Irinotecan When Given Without 5-FU and FA ............... 121 
6.5 
Concomitant Medications/Therapies ......................................................................... 122 
6.5.1 
Permitted Concomitant Medications/Therapies .................................................. 122 
6.5.2 
Permitted Concomitant Therapy Requiring Caution and/or Action ..................... 123 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
33 
 
11 July 2019 
8.2 
Screening .................................................................................................................. 160 
8.2.1 
Screening for Treatment Crossover .................................................................... 162 
8.3 
Cycle 1...................................................................................................................... 162 
8.3.1 
Cycle 1 Day 1 .................................................................................................... 162 
8.3.2 
Cycle 1 Day 8 .................................................................................................... 164 
8.3.3 
Cycle 1 Day 15 .................................................................................................. 165 
8.3.4 
Cycle 1 Day 22 .................................................................................................. 165 
8.4 
Subsequent Cycles .................................................................................................... 166 
8.4.1 
Subsequent Cycles Day 1 ................................................................................... 166 
8.4.2 
Subsequent Cycles Day 8 ................................................................................... 168 
8.4.3 
Subsequent Cycles Day 15 ................................................................................. 168 
8.4.4 
Subsequent Cycles Day 22 ................................................................................. 168 
8.5 
End of Treatment Visit .............................................................................................. 168 
8.6 
Follow-up Visits ........................................................................................................ 170 
8.6.1 
30-Day Safety Follow-up Visit........................................................................... 170 
8.6.2 
Other Follow-up Visits ....................................................................................... 171 
8.7 
Collection of Data for Ongoing Patients Following Database Lock ........................... 172 
9.0 STUDY DISCONTINUATION ..................................................................................... 173 
9.1 
Termination of the Study by the Sponsor ................................................................... 173 
9.2 
Treatment Discontinuation for Individual Patients ..................................................... 173 
9.3 
Study Discontinuation for Individual Patients............................................................ 174 
9.4 
Replacement of Patients ............................................................................................ 175 
10.0 SAFETY MONITORING: DEFINITIONS AND REPORTING ................................ 176 
10.1 Adverse Event ........................................................................................................... 176 
10.2 Events Related to Progression of Disease .................................................................. 176 
10.3 Adverse Events Related to Subsequent Anticancer Therapy ...................................... 176 
10.4 Clinical Laboratory Abnormalities ............................................................................ 176 
10.5 Overdose ................................................................................................................... 176 
10.6 Assessment of Severity ............................................................................................. 176 
10.7 Assessment of Causality............................................................................................ 177 
10.8 Assessment of Seriousness ........................................................................................ 178 
10.9 Reporting of Serious and Nonserious Adverse Events ............................................... 178 
10.10 Reporting of Suspected Unexpected Serious Adverse Events (SUSAR)..................... 179 
10.11 Pregnancy or Drug Exposure during Pregnancy ........................................................ 179 
10.12 Review of Safety Data .............................................................................................. 180 
11.0 STATISTICAL METHODS .......................................................................................... 181 
11.1 Determination of Sample Size ................................................................................... 181 
11.1.1 
Safety Lead-in ................................................................................................... 181 
11.1.2 
Randomized Phase 3 .......................................................................................... 182 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
35 
 
11 July 2019 
LIST OF TABLES 
Table 1: 
Summary of Best Overall Response by Treatment Group for Patients with 
Metastatic Colorectal Cancer in CLGX818X2101 Dose Expansion ....................... 48 
Table 2: 
Summary of Best Overall Response per Investigator Assessment by Treatment 
Group in Phase 1b (Study CLGX818X2103-Dual Combination) ........................... 49 
Table 3: 
Summary of Best Overall Response per Investigator Assessment by Treatment 
Group in Phase 2 (Study CLGX818X2103) .......................................................... 51 
Table 4: 
Adverse Events (≥ 20%), Regardless of Study Drug Relationship, by Preferred 
Term - Study CLGX818X2101 in mCRC Patients in the Dose-Expansion Phase... 55 
Table 5: 
Adverse Events (≥ 20% of Patients) Regardless of Causality by Preferred Term 
in Phase 1b (Study CLGX818X2103, Safety Set - Dual Combination Treatment) . 56 
Table 6: 
Adverse Events Regardless of Causality in ≥ 15% of Patients by Preferred Term 
in the Phase 2 Interim Analysis (Study CLGX818X2103, Safety Set) ................... 57 
Table 7: 
Adverse Events Regardless of Causality in ≥ 10% of Patients by Preferred Term 
in Interim Phase 2 Analysis (Study CLGX818X2109) ........................................... 62 
Table 8: 
Criteria for Defining Dose-limiting Toxicities ....................................................... 80 
Table 9: 
Starting Dose and Treatment Schedule ................................................................ 101 
Table 10: 
Dose Levels for Dose Modification ..................................................................... 106 
Table 11: 
Modified NCI CTCAE, Version 4.03 Grading of Eye Disorders .......................... 107 
Table 12: 
NCI CTCAE, Version 4.03 Grading of Serous Detachment of the Retina ............ 108 
Table 13: 
NCI CTCAE, Version 4.03 Grading of Uveitis .................................................... 108 
Table 14: 
NCI CTCAE, Version 4.03 Grading of Hand-foot Skin Reaction (HFSR)a .......... 108 
Table 15: 
Modified NCI CTCAE, Version 4.03 Grading of Diarrhea .................................. 108 
Table 16: 
Recommended Dose Modifications for Encorafenib-related and/or Binimetinib-
related Adverse Events ........................................................................................ 110 
Table 17: 
Recommended Dose Modifications for Cetuximab-related Adverse Events ......... 117 
Table 18: 
Recommended Dose Modifications for 5-FU and Irinotecan Treatment-related 
Adverse Events During FOLFIRI Treatment ....................................................... 118 
Table 19: 
Recommended Dose Modifications for Irinotecan Treatment-related Adverse 
Events When Given Without 5-FU and FA .......................................................... 121 
Table 20: 
Summary of Clinical Laboratory Tests ................................................................ 132 
Table 21: 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale ........... 137 
Table 22: 
Blood Collection Volumes for Pharmacokinetic and Biomarker Assessments ...... 138 
Table 23: 
Pharmacokinetic Sampling Times for the Safety Lead-in Portion of Study 
ARRAY-818-302 for the Safety Lead-in Patients Who Will Receive 
Encorafenib, Cetuximab and Binimetinib ............................................................ 139 
Table 24: 
Pharmacokinetic Sampling Times for the Randomized Phase 3 Portion of Study 
ARRAY-818-302 for a Subset of the Triplet, Doublet, and Control Arms ............ 140 
Table 25: 
Schedule of Events for Prescreening and Screening ............................................ 149 
Table 26: 
Schedule of Events for Safety Lead-in, Triplet Arm, and Crossover Patients 
(Encorafenib + Binimetinib + Cetuximab) .......................................................... 151 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
36 
 
11 July 2019 
Table 27: 
Schedule of Events for Doublet Arm (Encorafenib + Cetuximab)........................ 154 
Table 28: 
Schedule of Events for Control Arm (Irinotecan/Cetuximab or 
FOLFIRI/Cetuximab) ......................................................................................... 157 
Table 29: 
Operating Characteristics of Safety Lead-In Criteria for 9 Patients Compared to 
3+3 Rules ........................................................................................................... 182 
Table 30: 
Expected Number of OS Events and Cumulative Power at Expected OS 
Analysis Timepoints for the Triplet vs Control Comparison ................................ 197 
 
LIST OF FIGURES 
Figure 1: 
Efficacy of Encorafenib and Cetuximab as Single Agents and in Combination in 
the HT-29 (BRAFV600E, PIK3CαP449T) Human CRC Tumor Xenograft Model 
Grown in Immunocompromised Mice ................................................................... 46 
Figure 2: 
Effects of Encorafenib and Binimetinib in Combination with Cetuximab in the 
HT-29 (BRAFV600E, PIK3CαP449T) Human CRC Tumor Xenograft Model 
Grown in Immunocompromised Mice ................................................................... 47 
Figure 3: 
Best Percentage Change from Baseline in Sum of Diameters in Phase 1b (Study 
CLGX818X2103-Dual Combination) ................................................................... 50 
Figure 4: 
Summary of Time on Study, by Response in Phase 1b (Study CLGX818X2103-
Dual Combination) ............................................................................................... 50 
Figure 5: 
Study Design ........................................................................................................ 79 
Figure 6: 
Safety Lead-in Schema ......................................................................................... 83 
Figure 7: 
BRAF Testing ..................................................................................................... 129 
Figure 8: 
Graphic Representation of Pharmacokinetic Sampling Plan ................................ 141 
Figure 9: 
Testing Strategy for Study ARRAY-818-302 ....................................................... 187 
 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
37 
 
11 July 2019 
LIST OF APPENDICES 
Appendix 1: Recommended Guidelines for the Management of Cetuximab-induced, 
Encorafenib-induced and/or Binimetinib-induced Skin Toxicity .......................... 211 
Appendix 2: Recommended Guidelines for the Management of Encorafenib-induced Hand-
foot skin reactions (HFSR) .................................................................................. 214 
Appendix 3: Recommended Guidelines for the Management of Binimetinib-induced 
Diarrhea .............................................................................................................. 217 
Appendix 4: Snellen Equivalence (Visual Acuity Conversion Chart) ....................................... 220 
Appendix 5: List of Concomitant Medications ........................................................................ 221 
Appendix 6: Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 ................ 227 
Appendix 7: Patient Global Impression of Change .................................................................. 238 
Appendix 8: Recommended Guidelines for the Management of Binimetinib-associated 
Interstitial Lung Disease ..................................................................................... 239 
 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
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11 July 2019 
Abbreviation or  
special term 
Explanation 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vita 
CYP 
cytochrome P450 
DDS 
dose-determining data set 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
EC 
ethics committee (includes institutional review board, research ethics board, and 
institutional ethics committee) 
EC50 
half maximal effective concentration 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
electronic case report form 
EDC 
electronic data capture system 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
end of treatment 
EQ-5D-5L 
EuroQol-5D-5L  
ESMO 
European Society of Medical Oncology 
EU 
European Union 
FA 
folinic acid 
FACT-C 
Functional Assessment of Cancer Therapy-Colon Cancer 
FAS 
full analysis set 
FDA 
United States Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
FOLFIRI 
5-fluorouracil/folinic acid/irinotecan 
FOLFOX 
5-fluorouracil/folinic acid/oxaliplatin 
FOLFOXIRI 
5-fluorouracil/folinic acid/oxaliplatin/irinotecan 
FSH 
follicle-stimulating hormone 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
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11 July 2019 
Abbreviation or  
special term 
Explanation 
5-FU 
5-fluorouracil 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
hCG 
human chorionic gonadotropin 
HDPE 
high-density polyethylene  
hERG 
human ether-a-go-go-related gene 
HFSR 
rash, hand foot skin reaction 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICF 
informed consent form 
IC50 
half maximal inhibitory concentration 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
IWRS 
interactive web response system 
KA 
keratoacanthoma 
KM 
Kaplan-Meier  
KRAS 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LH 
luteinizing hormone 
LLN 
lower limit of the normal reference range 
LVEF 
left ventricular ejection fraction  
mCRC 
metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
MUGA 
multi-gated acquisition  
NaF PET 
sodium fluoride positron emission tomography 
NCCN 
National Comprehensive Cancer Network 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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Protocol Version 8.0 
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Abbreviation or  
special term 
Explanation 
NCI  
National Cancer Institute  
NGS 
next generation sequencing 
OAT 
organic anionic transporter 
OATP 
organic anion-transporting peptide 
OCT 
optical coherence tomography 
OCT 
organic cationic transporter 
ORR 
objective response rate (overall response rate) 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression-free survival 
PGIC 
Patient Global Impression of Change 
P-gp 
P-glycoprotein 
pH 
hydrogen ion concentration 
PK 
pharmacokinetic(s) 
PO 
oral(ly) 
PPS 
per-protocol set 
PR 
partial response 
QD 
once daily 
QLQ-C30 
Quality of Life Questionnaire for Cancer Patients 
QoL 
quality of life  
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPED 
retinal pigment epithelial detachment 
RP2D 
recommended Phase 2 dose 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Steering Committee 
SCC 
squamous cell carcinoma 
SD 
stable disease 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
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11 July 2019 
Abbreviation or  
special term 
Explanation 
SOP 
standard operating procedure 
SPC 
summary of product characteristics 
SS 
safety set 
t1/2 
terminal half-life 
T max 
Time of maximaum plasma concentration 
TdP 
Torsade de Pointes 
UGT 
UDP-glucuronosyl transferase 
ULN 
upper limit of normal  
US 
United States 
v 
version 
wt 
wild-type 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
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1.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
The Principal Investigator is the person responsible for the conduct of the study at the 
investigational site. A subinvestigator is any member of the clinical study team designated and 
supervised by the Principal Investigator to perform critical study-related procedures and/or to 
make important study-related decisions. 
Prior to study initiation, the Principal Investigator at each site must provide to Array BioPharma 
Inc. (Array BioPharma/Sponsor) a signed protocol signature page, a fully executed and signed 
United States (US) Food and Drug Administration (FDA) Form 1572 (or equivalent) and a 
Qualified Investigator Undertaking form for Investigators at Canadian sites, a current curriculum 
vita (CV), medical license and a financial disclosure form. Financial disclosure forms, current 
CVs and medical licenses must also be provided for all subinvestigators listed on Form 1572 
who will be directly involved in the treatment or evaluation of patients in this study. 
The study will be administered and monitored by employees or representatives of Array 
BioPharma and/or a contract research organization (CRO) in accordance with all applicable 
regulations. Clinical research associates (CRAs) will monitor each site on a periodic basis and 
perform verification of source documentation for each patient. The Array BioPharma Drug 
Safety Department (and/or the CRO, if applicable) will be responsible for ensuring timely 
reporting of expedited serious adverse event (SAE) reports to regulatory authorities and 
Investigators. 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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2.0 
INTRODUCTION 
2.1 
Metastatic Colorectal Cancer 
Metastatic colorectal cancer (mCRC) continues to be a serious, life-threatening condition. In the 
US, it is the fourth most common type of cancer with approximately 130,000 new cases 
projected in 2015, and it is the second leading cause of cancer mortality with nearly 
50,000 projected deaths in 2015 (Siegel et al. 2015). It is also the second most common type of 
cancer in men and women in Europe. In 2012, almost 450,000 new cases were diagnosed and 
colorectal cancer (CRC) was responsible for 215,000 deaths. Approximately 25% of patients 
present with metastases and 50% of patients eventually develop metastatic disease 
(Van Cutsem et al. 2014). Standard therapy in patients with unresectable mCRC includes 
combination regimens with cytotoxic and targeted agents. In the last decade, substantial 
advances in the treatment of mCRC have resulted in an improvement in overall survival (OS) 
from 10 to 12 months to more than 20 months (Grothey and Goldberg 2004). This improvement 
has occurred with the addition of irinotecan, oxaliplatin, bevacizumab, cetuximab, and 
panitumumab to the standard treatment with 5-fluorouracil (5-FU)/folinic acid (FA).  
2.2 
BRAFV600E Colorectal Cancer 
BRAF mutations, which lead to constitutive activation of BRAF kinase and sustained 
RAS/RAF/MEK/ERK pathway signaling resulting in increased cell proliferation and survival 
(Corcoran et al. 2012), are found in up to 20% of patients with CRC with lower prevalence in 
more advanced patient populations (De Roock et al. 2010, Sorbye et al. 2015). 
The presence of a BRAF mutation is considered a marker for poor prognosis in patients with 
mCRC and is associated with a median survival of approximately 12 to 14 months relative to 
21 to 25 months for patients with BRAFwild-type (BRAFwt) tumors (Van Cutsem et al. 2011, 
Sorbye et al. 2015). In a retrospective analysis of patients with chemo-refractory mCRC treated 
with chemotherapy and an anti-epidermal growth factor receptor (EGFR) agent, the median 
progression-free survival (PFS) and OS in patients with BRAF-mutant tumors was 8 weeks and 
26 weeks, respectively, compared with a PFS of 26 weeks and an OS of 54 weeks in patients 
with BRAFwt tumors (De Roock et al. 2010). In a study evaluating 5-FU/FA/irinotecan 
(FOLFIRI) plus panitumumab in a pure second-line setting, patients with BRAF-mutant mCRC 
had a median PFS of 2.5 months and an OS of 4.7 months, compared with a PFS and an OS of 
6.9 and 18.7 months, respectively, in patients with BRAFwt tumors (Peeters et al. 2014). Finally, 
in 71 patients with BRAFV600E mCRC treated at MD Anderson Cancer Center between 2003 and 
2012, the median PFS with second-line therapy was 10 weeks in the overall group (n=58) and 
12 weeks in patients who were treated with an irinotecan-based regimen (n=39), 28 of whom had 
received panitumumab or cetuximab concomitantly with irinotecan. The median PFS in patients 
receiving 2nd- or 3rd-line therapy corresponded to the timing of the first restaging scan 
(Morris et al. 2014) suggesting that more efficacious therapies are urgently needed. Currently, 
there are no agents specifically indicated for patients with BRAFV600E mCRC. However, since 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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BRAF and KRAS mutations are almost always mutually exclusive, patients with BRAFV600E 
mCRC have typically been treated with standard-of-care regimens for KRASwild-type (KRASwt) 
mCRC. Patients with KRASwt mCRC typically receive infusional 5-FU/FA/oxaliplatin 
(FOLFOX) with or without bevacizumab as initial therapy. Common regimens following 
progression on first-line therapy include infusional FOLFIRI or irinotecan with or without 
cetuximab or panitumumab. Recent data suggests that the combination of 5-FU/FA, oxaliplatin 
and irinotecan (FOLFOXIRI) with bevacizumab may be more efficacious than FOLFIRI plus 
bevacizumab in patients with BRAFV600 mCRC (Cremolini et al. 2015). 
While data suggest BRAF mutation status has clear prognostic value in mCRC, the predictive 
value of BRAF mutation status for response and benefit from EGFR-directed treatments, such as 
cetuximab, remain controversial. Retrospective analyses of recent trials have suggested that 
BRAF mutations are not predictive of outcome with EGFR-directed therapies (Tol and Punt 
2010, Van Cutsem et al. 2011, Bokemeyer et al. 2012, Oliner et al. 2013) in certain settings 
whereas other analyses have suggested that cetuximab and panitumumab are most active in 
patients with BRAFwt mCRC (Di Nicolantonio et al. 2008, De Roock et al. 2010). In a recent 
meta-analysis of 7 randomized control trials in which patients received panitumumab or 
cetuximab in different lines of therapy, and with a range of background chemotherapy, no 
significant interaction was noted between the benefits of anti-EGFR therapy (measured as OS 
and PFS) and the presence of BRAF mutation (Rowland et al. 2015). These results suggest that 
anti-EGFR therapy may have benefit for patients with BRAFV600E CRC. Consistent with this 
recent publication, a joint committee of the American Society for Clinical Pathology (ASCP), the 
College of American Pathologists (CAP), the Association for Molecular Pathology (AMP), and 
the American Society of Clinical Oncology (ASCO) issued draft guidelines for the evaluation of 
molecular markers for colorectal cancer which stated that there is insufficient evidence to 
recommend BRAFV600 mutation status as a predictive molecular marker for response to 
anti-EGFR inhibitors (ASCP/CAP/ASCO/AMP Draft Recommendations Summary 2015). Based 
on these data and recommendations, EGFR-directed therapies remain an appropriate component 
of therapy for patients with BRAFV600E mCRC. 
2.2.1 Inhibition of BRAF, MEK, and EGFR in BRAF-V600E Colorectal Cancer Cells 
Cancer cells with BRAF mutations are highly dependent on MEK/ERK signaling. As 
demonstrated in melanoma cells, MEK-dependent activation of MAPK signaling occurs 
following BRAF inhibition and near-complete inhibition of phospho-ERK is required for tumor 
responses (Corcoran et al. 2012). The combination of a BRAF inhibitor and a MEK inhibitor has 
been shown to be more active than either agent alone presumably due to delaying or preventing 
resistance (Thakur and Stuart 2014). Nonclinical work in CRC cells has shown that BRAF 
inhibition causes a rapid feedback activation of EGFR that supports continued proliferation of 
BRAFV600E CRC tumor cells (Corcoran et al. 2012, Prahallad et al. 2012). Activation of EGFR 
can be effectively prevented by the combination of vemurafenib with anti-EGFR agents such as 
the small-molecule kinase inhibitor, erlotinib, or the monoclonal antibody, cetuximab. These 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
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11 July 2019 
reports suggest that activation of EGFR may partially explain the limited therapeutic effect of 
BRAF inhibitor monotherapy in patients with BRAFV600E mCRC and that this can be overcome 
with concomitant EGFR inhibition. The dependence of BRAF-mutant CRC cells on MAPK 
signaling provides a compelling rationale for inhibiting MEK in addition to BRAF and EGFR to 
achieve more robust inhibition of the pathway. 
2.2.2 Effects of Encorafenib and Cetuximab in BRAF-V600E Colorectal Cancer 
Consistent with the published literature, encorafenib in combination with cetuximab has 
demonstrated robust and synergistic anti-proliferative effects in a human xenograft model of 
BRAFV600E CRC (Figure 1).  
In this experiment, encorafenib was administered 20 mg/kg BID and cetuximab was 
administered 20 mg/kg biweekly. The same concentration and dosing schedule was used for 
single agents and the combination. Dosing was stopped 29 days following the initiation of 
treatment. No signs of toxicity or mortality were observed. 
Figure 1: 
Efficacy of Encorafenib and Cetuximab as Single Agents and in Combination 
in the HT-29 (BRAFV600E, PIK3CαP449T) Human CRC Tumor Xenograft 
Model Grown in Immunocompromised Mice 
 
 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
52 
 
11 July 2019 
patients and was marked with no activity (0 CR or PR) and increased toxicity, especially skin 
toxicity (Van Cutsem et al. 2015). In a separate trial, the combination of dabrafenib plus 
trametinib without an EGFR inhibitor yielded a response rate of 12% (Corcoran et al. 2015).   
Vemurafenib was initially tested as a single agent in a total of 21 patients, 19 of whom were 
evaluable for response. Among these 19 patients, there was 1 partial response (PR) (5%) and the 
median PFS was 3.7 months (Kopetz et al. 2010). When combined with panitumumab in 15 total 
patients of whom 12 were evaluable for response, PRs were observed in 2 (13%) patients 
(Yeager et al. 2015). In another Phase 1b/2 study (n=19), vemurafenib at doses of 480 mg BID, 
720 mg BID, and 960 mg BID was also combined with panitumumab and irinotecan. Of 
17 response-evaluable patients, responses were observed in 6 (35%) patients with a median DOR 
of 8.8 months and median PFS of 7.7 months. The most common adverse events (AEs) (≥ 30%) 
observed in 19 patients included fatigue 17 (89%), diarrhea 16 (84%), rash 15 (74%), nausea 
15 (74%), anemia 14 (74%), myalgia 10 (53%), leukopenia 9 (47%), arthralgia 8 (42%), 
vomiting 6 (32%), and neuropathy 6 (32%) (Hong et al. 2015).  
2.3 
Overview of Encorafenib 
Encorafenib is a highly selective adenosine triphosphate (ATP)-competitive small-molecule RAF 
kinase inhibitor, which suppresses the RAS/RAF/MEK/ERK pathway in tumor cells expressing 
BRAFV600E. Similar to other selective small-molecule RAF kinase inhibitors, encorafenib inhibits 
CRAF (half maximal inhibitory concentration [IC50]=0.30 nM), BRAF (IC50=0.47 nM), as well 
as BRAFV600E (IC50=0.35 nM) in cell-free assays. However, this class of inhibitor does not 
inhibit RAS/RAF/MEK/ERK signaling in cells expressing BRAFwt. In the human melanoma cell 
line A375, which expresses BRAFV600E, encorafenib potently inhibits phospho-MEK (half 
maximal effective concentration [EC50]=2 nM), phospho-ERK (EC50=3 nM), and proliferation 
(EC50=4 nM), resulting in cell cycle arrest and apoptosis. Given the high-degree of selectivity 
against other kinases, encorafenib has no antiproliferative activity in tumor cell lines that express 
BRAFwt and is highly selective for BRAF mutations in cell lines containing V600E/D/K, with the 
greatest sensitivity observed in BRAFV600E melanoma and CRC lineages. 
Encorafenib has been evaluated in multiple human tumor xenograft models grown in nude mice. 
Similar to the in vitro profile, the antitumor activity was restricted to tumors expressing 
BRAFV600E, while there was no antitumor effect in xenograft models expressing BRAFwt or 
CRAFwt. Nonclinical in vivo data suggest that encorafenib has a wide therapeutic index and that 
regression of BRAFV600E human melanoma tumor xenografts is associated with a strong and 
sustained inhibition of the RAF/MEK/ERK pathway. 
2.3.1 Nonclinical Safety Pharmacology and Toxicology 
In 1- to 4-week toxicology studies in rats and cynomolgus monkeys, encorafenib was well 
tolerated at systemic exposures which result in tumor regression in mouse xenograft studies. 
Findings included hyperplasia and hyperkeratosis in the skin (plantar surface of feet) and 


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non-glandular stomach in the rat. An absence of the later stages of spermatid maturation in male 
rats was also observed. Significant mortality/morbidity was observed mostly in female rats at the 
highest dose of 400 mg/kg/day, a dose well above the maximum tolerated dose (MTD) in rats. 
In the 13-week toxicology study in monkeys, the only test article-related finding was blister-like 
lesions identified over the macular region of the retina, observed in 2 monkeys treated at a dose 
of 60 mg/kg/day. Exposure (maximum AUC0-24 achieved in the study at any time point) in the 
2 affected monkeys was 5 to 8-fold and 4 to 6-fold that achieved at the 300 and 450 mg QD dose 
levels, respectively, in humans at steady state in Clinical Study CLGX818X2101. One of the 
animals with this finding showed evidence of recovery. Histopathology examination of the 
affected eyes suggested that the findings were similar to the retinopathy associated with MEK 
inhibitors. 
Nonclinical safety pharmacology results did not indicate a risk for corrected QT interval (QTc) 
prolongation based on: the findings of the Good Laboratory Practice (GLP) human ether-a-go-
go-related gene (hERG) assay, on electrocardiogram (ECG) evaluations in the GLP monkey 
cardiovascular telemetry study, and the GLP 4- and 13-week toxicology studies in monkeys.). 
Also, there were no clinical signs in the 4-or 13-week GLP-compliant studies in the rat and 
monkey that would indicate an effect on the central nervous system or respiratory system. 
The GLP Ames and chromosomal aberration assays as well as a rat micronucleus study indicated 
that encorafenib is not genotoxic.  
Encorafenib showed a potential for phototoxicity in a screen 3T3 neutral red uptake (NRU) 
in vitro assay. In patients treated with encorafenib, as a single-agent, in the range of doses of 300 
to 450 mg QD, the incidence of photosensitivity was 2.9% and 5.6% in the melanoma and 
colorectal cohorts, respectively (Study CLGX818X2101). 
2.3.2 Pharmacokinetics and Metabolism 
Encorafenib is a relatively potent reversible inhibitor of cytochrome P450 (CYP)2B6, CYP2C9, 
and CYP3A4/5 and a weak (IC50 ≥ 20 µM) reversible inhibitor of CYP1A2, CYP2C8, 
CYP2C19, and CYP2D6. Encorafenib is also a time-dependent inhibitor and at high 
concentrations (≥ 10 to 50 µM), a potential inducer of CYP3A4 based on an in vitro pregnane X 
receptor (PXR) reporter gene assay. Furthermore, encorafenib inhibits UDP-glucuronosyl 
transferase (UGT)1A1 and is a substrate of P-glycoprotein with high apparent passive 
permeability. It is also an inhibitor of breast cancer resistance protein (BCRP) (IC50=10 to 
25 µM). Finally, encorafenib inhibits the renal transporters OAT1, OAT3, and OCT2 and the 
hepatic transporters, organic anion-transporting polypeptide (OATP)1B1 and OATP1B3.  
Encorafenib is primarily metabolized by CYP3A4 (> 50%) and to lesser degrees by CYP2D6 
and CYP2C19.  


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In a Phase 1 study in patients with locally advanced or metastatic BRAFV600E melanoma 
(Study CLGX818X2101, dose escalation phase), encorafenib exposures on Cycle 1 Day 15 were 
consistently decreased by 30% to 60% compared with those at Day 1, probably due to induction 
of CYP450 enzymes. Area under the concentration-time curve (AUC) and maximum 
concentration (Cmax) ratios at steady-state concentrations (Day 15) relative to Day 1 did not 
appear to change with dose. The trough concentration on and after Cycle 2 Day 1 did not show a 
trend of further decline, suggesting that Cycle 1 Day 15 was close to or at the time of 
steady-state concentration. At doses tested in the study (50, 100, 150, 200, 300, 450, 550 or 
700 mg once daily [QD] and 75, 100, and 150 mg BID), the average concentrations of 
encorafenib were above the predicted efficacious concentrations based on nonclinical xenograft 
models (0.135 μg/mL). The terminal half-life of encorafenib is approximately 4 hours. 
Additional details are provided in the encorafenib Investigator’s Brochure. 
2.3.3 Clinical Safety 
2.3.3.1 Single-agent Encorafenib 
Single-agent encorafenib was evaluated in a first-in-human, Phase 1 dose-escalation/dose-
expansion study (Clinical Study CLGX818X2101) in adult patients with BRAFV600E locally 
advanced or metastatic melanoma (dose-escalation and dose-expansion phases) or mCRC 
(dose-expansion phase only). A total of 107 patients were treated at doses ranging from 50 mg to 
700 mg QD. 
In the dose-expansion phase of Study CLGX818X2101, the first 34 patients received encorafenib 
450 mg QD (i.e., MTD). Nine of these patients experienced a dose-limiting toxicity (DLT) 
during Cycle 1, leading to a dose reduction to 300 mg QD in 6 patients and discontinuation of 
encorafenib for the remaining 3 patients. Among the patients who did not have a DLT, the 
encorafenib dose was reduced to 300 mg QD in 8 patients, and 1 patient discontinued due to an 
AE. Based on these findings, 300 mg QD was identified as the recommended Phase 2 dose 
(RP2D).  
Eighteen patients with mCRC received encorafenib in the dose-expansion phase of the study. 
Twelve patients received encorafenib 450 mg QD and 6 patients received 300 mg QD. 
Dose-limiting toxicities were reported in 3 patients treated at the 450 mg QD dose and in none of 
the patients treated at the 300 mg QD dose. The most common (occurring in ≥ 20% of patients) 
AEs, regardless of causality, observed at the MTD of 450 mg QD and the RP2D of 300 mg QD 
in the mCRC patients in the dose-expansion phase are shown in Table 4. 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
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2.4 
Overview of Binimetinib 
Binimetinib (also known as MEK162 or ARRY-438162) is a potent and selective allosteric, 
ATP-uncompetitive inhibitor of MEK1/2 that is active in inhibiting pERK and growth of 
BRAF-mutant cancer cells in the low nanomolar range. In oncology settings, binimetinib is 
currently being investigated both as a single agent and in combination with RAF or PI3K or 
inhibitors in patients with selected advanced or metastatic solid tumors, including biliary cancer, 
CRC and melanoma.  
2.4.1 Nonclinical Safety Pharmacology and Toxicology  
Acute, subchronic, chronic and reproductive toxicity, genotoxicity and phototoxicity studies 
were completed in rats and monkeys to support the chronic administration of binimetinib to adult 
patients. There was no evidence of a genotoxic potential in vitro or in vivo. The adverse effects 
of MEK inhibitors in humans are similar to those observed in rats and monkeys, with the 
exception of ocular findings. These adverse effects include gastro-intestinal intolerance and 
diarrhea, rash (skin findings in rats only), retinal events (only seen in humans) and retinal vein 
occlusion (rarely seen in humans). In vitro and in vivo phototoxicity studies conducted in mice 
indicate that binimetinib has a low risk of weak phototoxic potential at therapeutic doses. 
Furthermore, there has been no evidence of phototoxicity or photosensitivity in humans being 
treated with binimetinib for cancer or for rheumatoid arthritis. 
Given the embryo-lethal effects seen in rats and rabbits and the teratogenic effects seen in 
rabbits, binimetinib should not be used in pregnant women. Women of child-bearing potential 
must be advised to use highly effective contraception methods. 
For further details, please refer to the current binimetinib Investigator’s Brochure. 
2.4.2 Clinical Pharmacokinetics 
Nonclinical in vitro and in vivo data indicated that binimetinib is metabolized by multiple routes 
but primarily by glucuronidation pathways (mainly via UGT1A1, 1A3 and 1A9) and to a lesser 
extent by oxidation pathways (mainly via CYP1A2 and 2C19). In vitro, binimetinib has the 
potential to inhibit CYP2B6. It is not considered a time dependent inhibitor of CYP1A2, 
CYP2C9, CYP2D6 and CYP3A. 
Binimetinib is rapidly absorbed after oral administration with a median time (Tmax) to reach Cmax 
around 1.5 hours at steady-state. The mean terminal half-life (t1/2) in healthy subjects is 
approximately 10 hours. 
For further details on non-clinical pharmacokinetics (PK) and metabolism, please refer to the 
current binimetinib Investigator’s Brochure. 


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2.4.3 Clinical Experience 
2.4.3.1 Clinical Safety 
As of 20 January 2016, a total of 2555 healthy subjects and patients have received at least 1 dose 
of binimetinib and are therefore eligible for inclusion in the overall safety population of 
binimetinib, which comprises 220 healthy subjects, 164 patients with rheumatoid arthritis, 
12 patients with hepatic dysfunction and 2159 patients with advanced cancer. 
For further details, please refer to the current binimetinib Investigator’s Brochure. 
2.4.3.1.1 Single-agent Binimetinib 
The single agent safety of binimetinib in oncology patients is based on data from 884 patients 
across 7 clinical trials. The recommended single-agent dose is 45 mg PO BID. The most 
frequently reported AEs considered related to single-agent binimetinib, regardless of grade and 
binimetinib dose, have been dermatologic events (rash, dermatitis acneiform), gastrointestinal 
(GI) events (nausea, vomiting, diarrhea), edema peripheral, fatigue and increased CK. The 
majority of these AEs have been Grade 1 or 2, with the exception of increased blood CK, which 
was reported as Grade 3/Grade 4 for 24% of patients in Clinical Study CMEK162X2201 and for 
17.2% and 16.6% of patients in the dose-escalation and dose-expansion portions of Clinical 
Study CMEK162X1101.  
Additional AEs which require monitoring include ejection fraction decreases and retinal 
toxicities. Cardiac events, in particular events related to asymptomatic ejection fraction decrease 
as detected by protocol-specified echocardiogram (ECHO)/multi-gated acquisition (MUGA) 
scans and cardiac failure, are a class effect of MEK inhibitors. In Clinical Study 
CMEK162X2201 of binimetinib as a single agent, at the recommended dose of 45 mg BID (N = 
158 patients), the incidence of left ventricular ejection fraction (LVEF) decreases reported as 
AEs were observed in 10 patients (6.3%). Nine of these patients presented with an LVEF above 
50% at Baseline, and 1 patient had an LVEF of 48% at Baseline. These AEs were reversible in 
6 patients (60.0%) and were ongoing in 4 patients at the time of cutoff. Five patients (3.2%) had 
Grade 3 events; all considered related to study treatment. No Grade 4 events were observed. Four 
patients discontinued the study treatment due to decreased LVEF, of whom 2 patients 
experienced Grade 3 events.   
Retinopathy is also a well-known MEK inhibitor-associated class effect. The most common 
retinal events that have been reported are retinal detachment, detachment of retinal pigment 
epithelium and chorioretinopathy. In Clinical Study CMEK162X2201 of binimetinib as a single 
agent, at the recommended dose of 45 mg BID (N = 158), observations related to retinal events 
(retinopathy, retinal detachment, detachment of retinal pigment epithelium, chorioretinopathy, 
retinal disorder, retinal edema, macular edema, maculopathy, and retinal cyst) were as follows. 
Forty-nine of the 158 patients (31%) reported retinal events. The majority of patients presented 


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with low severity retinal events; maximum severity was Grade 1 (n = 31, 19.6%), Grade 2 (n = 
15, 9.5%), Grade 3 (n = 3, 1.9%). All Grade 3 retinal events were considered related to the study 
drug. No retinal events observed in patients receiving 45 mg BID led to study drug 
discontinuation and no Grade 4 retinal events were reported. Events occurred early in treatment, 
with a median time to onset of 15 days. 
Among the preferred terms reported by the 49 patients with retinal events, chorioretinopathy 
(n = 6; 10.1%) was the most commonly observed, followed by retinopathy and retinal 
detachment (n = 13 each, 8.2%). In the majority of patients, retinal events were transient with a 
median duration of 29 days. Most patients continued the planned treatment without treatment 
modification. Sixteen patients (10.1%) had either dose reduction or temporary study drug 
interruption. 
Analyses of retinal events confirmed by optical coherence tomography (OCT) in cancer patients 
treated with binimetinib as a single-agent monotherapy at the recommended dose of 45 mg BID, 
revealed that most of the events were bilateral, early onset, mild or moderate (Grade 1/2) in 
severity, transient and reversible, and in most of the cases, did not lead to treatment 
discontinuation. 
2.4.3.1.2 Binimetinib in Combination with Anti-EGFR Agents 
The combination of binimetinib and panitumumab was evaluated in patients with mCRC in the 
Phase 1b/2 Clinical Study CMEK162X2116. Ten patients were treated in the Phase 1b portion of 
the study with binimetinib (45 mg BID) and the labeled dose of panitumumab (6 mg/kg IV 
biweekly) which was declared the MTD/RP2D. An additional 40 patients were enrolled in the 
Phase 2 portion of the study. In the Phase 2 portion, AEs, regardless of causality, reported in 
≥ 15% of patients included all grade (%)/Grade 3-4 (%): diarrhea (70.0/12.5), vomiting 
(55.0/2.5), rash (50.0/12.5), nausea (47.5/5.0), fatigue (35.0/5.0), abdominal pain (32.5/2.5), 
dermatitis acneiform (32.5/5.0), blood creatine kinase (CK) increased (27.5/7.5), dry skin 
(25.0/5.0), anemia (20.0/10.0), asthenia (20.0/2.5), constipation (20.0/0), hypokalemia 
(20.0/12.5), pyrexia (20.0/0), stomatitis (20.0/0), AST increased (17.5/5.0), blood creatinine 
increased (15.0/2.5), chills (15.0/0) and hypomagnesemia (15.0/0). 
2.5 
Overview of the Combination of Encorafenib and Binimetinib  
2.5.1 Nonclinical Pharmacokinetics and Metabolism 
Although the in vitro data suggest a potential for encorafenib to affect the PK of binimetinib-
based inhibition of UGT1A1, no significant drug-drug interaction was observed up to the highest 
doses tested in Clinical Study CMEK162X2110 (800 mg QD encorafenib in combination with 
45 mg BID of binimetinib).  


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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2.5.2 Clinical Experience 
The ongoing Clinical Study CMEK162X2110 is an open label, dose finding, Phase 1b/2 study to 
determine the MTD(s) and/or RP2D(s) of encorafenib in combination with binimetinib (dual 
combination), and in combination with encorafenib and LEE011 (triple combination), in selected 
patient populations (locally advanced or metastatic melanoma, mCRC or any other solid tumor 
positive for either BRAF-V600 mutation). Forty-seven patients have been enrolled (with 
different tumor types, including melanoma, mCRC, papillary thyroid cancer (PTC) and non-
small cell lung cancer (NSCLC) and treated with at least 1 dose of encorafenib and binimetinib 
across several dose levels in the Phase 1b dose escalation, and 79 patients with either melanoma 
or mCRC have been enrolled and treated with at least 1 dose of encorafenib and binimetinib in 
the Phase 2 portion of the study.  
In Phase 1b, 47 patients were treated with binimetinib 45 mg BID and encorafenib at 7 dose 
levels [Dose levels; 50 (n=6), 100 (n=5), 200 (n=4), 400 (n=5), 450 (n=13), 600 (n=8) and 800 
(n=6) mg QD)]. The MTD was not reached up to the highest tested dose of 800 mg + 45 mg 
(encorafenib QD + binimetinib BID). Initially, two RP2Ds were declared for the combinations at 
450 mg + 45 mg and 600 mg + 45 mg dose levels. Based on the occurrence of 3 cases of Grade 3 
creatinine increase suspected to be drug related in the Phase 2 portion of the study at 600 mg + 
45 mg, the confirmed RP2Ds of the combination is 450 mg + 45 mg of encorafenib QD plus 
binimetinib BID, respectively.  
Among the 47 patients treated with the dual combination in Phase 1b, 18 patients were treated at 
an encorafenib starting dose of 400 or 450 mg QD and 14 patients were treated with ≥ 600 mg 
QD. The most common AEs (≥ 20%, all grades) in all patients treated in Phase 1b, regardless of 
causality, were nausea, diarrhea, fatigue, constipation, abdominal pain, vomiting, headache, 
cough, alanine aminotransferase (ALT) increased, and pain in extremity. The most common 
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 3 or 4 AEs (≥ 3.0%), regardless of causality, were increases in serum lipase, liver enzymes 
(ALT, AST), and CK, fatigue, anemia, abdominal pain, and cancer pain.  Hypertension of any 
grade was observed in 6/47 (12.8%) patients and a Grade 3/4 hypertension event was 
documented in 1 (2.1%) patient. 
Among the 79 patients treated with the dual combination in Phase 2, 15 patients were treated at 
an encorafenib starting dose of 400 or 450 mg QD and 64 were treated with ≥ 600 mg QD. The 
most common AEs (≥ 20%, all grades), regardless of causality, were diarrhea, nausea, vomiting, 
arthralgia, fatigue, pyrexia, constipation, aspartate aminotransferase (AST) increased, blood CK 
increased, ALT increased, retinopathy, and cough. The most common CTCAE Grade 3 or 4 AEs 
(≥ 3.0 %), regardless of causality, were increases in serum lipase, liver enzymes (ALT, AST), 
and CK, diarrhea, nausea, vomiting, and anemia. As compared to the respective single-agent 
therapies, there was a decreased occurrence of skin toxicities in the combination. Among the 
29 patients treated with encorafenib 400 or 450 mg, the most common AEs (≥ 20% all grades), 


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The study has been monitored by an independent Data Monitoring Committee (DMC) which has 
not raised any concerns regarding safety/tolerability.   
2.6 
Overview of Cetuximab 
Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically 
to the extracellular domain of human EGFR on both normal and tumor cells, and inhibits 
receptor activation by competing with epidermal growth factor and other ligands. In vitro and in 
vivo assays have shown that binding of cetuximab to EGFR blocks its dimerization and 
phosphorylation and its consequent activation, resulting in inhibition of cell growth, induction of 
apoptosis, and decreased matrix metalloproteinase and vascular endothelial factor production. 
Cetuximab exhibits clinical activity as monotherapy or in combination with chemotherapy and/or 
radiation in head and neck cancer and mCRC (Cunningham et al. 2004, Baselga et al. 2005, 
Bonner et al. 2006, Mendelsohn and Baselga 2006, Vermorken et al. 2008). 
Cetuximab is approved in several countries for the treatment of patients with CRC or head and 
neck squamous cell carcinomas. Cetuximab is approved for the treatment of EGFR-expressing, 
RASwt mCRC in combination with chemotherapeutic agents or as a single agent, in previously 
untreated patients and in patients who have failed irinotecan- and oxaliplatin-based regimens or 
who are intolerant to irinotecan-based regimens (see the locally applicable cetuximab label). 
2.6.1 Clinical Experience 
2.6.1.1 Clinical Pharmacokinetics 
Following the recommended dose regimen (400 mg/m2 initial dose; 250 mg/m2 weekly dose), 
concentrations of cetuximab reach steady-state levels by the third weekly infusion. Although the 
US label for Erbitux® indicates that US-licensed cetuximab (Erbitux) provides approximately 
22% greater exposure relative to cetuximab which is approved in the European Union (EU), the 
dosing and administration guidelines are consistent between the regions. 
2.6.1.2 Clinical Efficacy 
In patients with mCRC whose disease had progressed during or within 3 months after treatment 
with an irinotecan-based regimen, treatment with single-agent cetuximab resulted in an objective 
response rate of 11% and a median time to progression of 1.5 months (Cunningham et al. 2004). 
In patients with EGFR-expressing mCRC treated with cetuximab in combination with irinotecan 
in the second-line setting, the median PFS was 4.0 months (95% confidence interval [CI], 
3.2-4.1 months) and OS was 10.7 months (95% CI, 9.6 -11.3 months) (Sobrero et al. 2008). 
2.6.1.3 Clinical Safety 
Across all studies, cetuximab was discontinued in 3% to 10% of patients because of AEs. The 
main undesirable effects of cetuximab are as follows: 


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• Skin reaction occurring in 76% to 88% of patients, with severe acneiform rash occurring in 
1% to 17% of patients 
• Severe (Grade 3-4 by NCI CTCAE) hypomagnesemia in 6% to 17% of patients 
• Infusion reactions, with mild to moderate symptoms in 15% to 21% of patients, and severe in 
1% to 5% of patients 
• Cardiopulmonary arrest and/or sudden death in 2% of patients receiving cetuximab in 
combination with radiation therapy 
• A case of tumor lysis syndrome reported with single-agent cetuximab within 24 hours of 
administration of the first dose (Krishnan et al. 2008). 
More details are provided in the locally approved cetuximab label. 
2.7 
Overview of Irinotecan 
Irinotecan is a topoisomerase-I inhibitor which has been used in patients with mCRC since the 
late 1990s. In patients with mCRC, it is indicated as a component of first-line therapy or as a 
single agent following progression on an initial fluorouracil-based regimen (see locally approved 
irinotecan label).  
Irinotecan treatment is most commonly associated with GI toxicity and myelosuppression. The 
biweekly regimen is associated with Grade 3 or 4 diarrhea in 10% of patients, Grade 2 nausea 
and Grade 2 vomiting in 10% of patients, and Grade 4 neutropenia in approximately 8% of 
patients (Martín-Martorell et al. 2008, Pfeiffer et al. 2008).  
2.8 
Overview of FOLFIRI 
Irinotecan combined with infusional 5-FU and FA administered biweekly (FOLFIRI) has been 
shown to be more effective than when irinotecan is combined with bolus 5-FU (Fuchs et al. 
2007). The regimen is considered one of the standard-of-care regimens in 2nd line mCRC 
(National Comprehensive Cancer Network [NCCN] Guidelines Version 2, 2016), and has also 
been shown to be effective in previously untreated patients (i.e., 1st line) (Bekaii-Saab and Wu 
2014). The combination of FOLFIRI and cetuximab has been shown to be an active regimen in 
patients with RASwt mCRC (Heinemann et al. 2014, Venook et al. 2014). Adverse events most 
commonly associated with FOLFIRI are typically GI toxicity and myelosuppression with 
Grade 3-4 diarrhea and mucositis occurring in approximately 10% and 3% patients, respectively, 
and Grade 3-4 neutropenia occurring in approximately 20% of patients (Peeters et al. 2010). 
2.9 
Rationale for the Study 
BRAF mutations are found in up to 20% of mCRC cases with lower rates of prevalence in 
patients in later lines of therapy. Patients with BRAFV600E mCRC have a poor prognosis with 
shorter PFS and OS compared with patients with wild-type tumors (Van Cutsem et al. 2011, 


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Modest et al. 2012, Sorbye et al. 2015). There are no specific therapies targeting BRAFV600E 
mCRC, and these patients are treated with combination chemotherapy with or without 
anti-EGFR agents.   
Nonclinical experiments have provided compelling evidence that combining a BRAF inhibitor 
with an EGFR inhibitor results in greater anti-tumor effects than either agent alone in BRAFV600E 
CRC cells (Corcoran et al. 2012, Prahallad et al. 2012, Yang et al. 2012). Consistent with these 
observations, the combination of the selective BRAF inhibitor, encorafenib and cetuximab 
resulted in a strong synergistic antitumor activity (Section 2.2.2).  
There is convincing non-clinical evidence that robust inhibition of MAPK signaling is needed to 
more effectively treat BRAF-mutated tumors (Larkin et al. 2014, Long et al. 2015). This is 
consistent with the observations of the effects of the combination of binimetinib, encorafenib, 
and cetuximab, generated in human colon cancer xenograft model. 
Early clinical data suggests that the combination of encorafenib and cetuximab is a well-tolerated 
regimen in patients with BRAFV600E mCRC with encouraging response rates which are durable 
(Section 2.2.4). Preliminary clinical data with other BRAF and MEK inhibitor combinations have 
also suggested greater activity of the triple combination of a MEK inhibitor, BRAF inhibitor, and 
an anti-EGFR antibody relative to the dual combination of a BRAF and EGFR inhibitor. This 
data also suggests that the combination of a MEK inhibitor and an EGFR inhibitor (without a 
BRAF inhibitor) is only minimally active and associated with increased toxicity in patients with 
BRAFV600E mCRC (Van Cutsem et al. 2015).   
The current study is designed in light of the promising non-clinical and early clinical data of the 
combination of binimetinib, encorafenib, and cetuximab, and of encorafenib and cetuximab in 
patients with BRAFV600E mCRC who have a poor clinical outcome, and for whom no targeted 
therapeutic strategies are effective after failure of standard chemotherapeutic regimens.  
2.9.1 Study Design 
This is a prospective, randomized, open-label, multi-center, parallel group, 3-arm Phase 3 study 
in patients with previously-treated BRAFV600E mCRC comparing the efficacy and safety of 
binimetinib + encorafenib + cetuximab (Triplet Arm), and encorafenib + cetuximab (Doublet 
Arm) to Control Arm (irinotecan/cetuximab or FOLFIRI/cetuximab per Investigator’s choice of 
control treatment), with a Safety Lead-in to assess the tolerability of binimetinib plus encorafenib 
plus cetuximab. The purpose of the study is to initially evaluate the safety/tolerability of the 
triplet combination in the Safety Lead-in and then to assess the efficacy of the triplet 
combination and the doublet combination relative to the control treatment in the randomized 
Phase 3 portion of the study.  
Several lines of evidence suggest that BRAFV600E mCRC is a distinct histological subtype 
associated with a unique clinical phenotype. The predominant BRAF mutations in CRC affect 


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V600E and result in a constitutively active BRAF protein. In the current study, patients may be 
enrolled using local laboratory assessment of BRAF status. All samples will also be tested by the 
central laboratory using the assay being developed as a companion diagnostic in the trial. Lack of 
BRAFV600E confirmation by the central laboratory may be due to discordance between the local 
assay and central laboratory results (potential false positive local assay results), or due to 
inadequate or poor sample condition for central testing (indeterminate results). If at any time 
there is lack of BRAFV600E confirmation by the central laboratory in a total of 37 patients (6% of 
the total planned enrollment of the randomized portion of the trial) or discordance between the 
local assay and the central laboratory in 18 patients (3% of the total planned enrollment), all 
subsequent patients will only be enrolled using central laboratory results. The actual discordance 
rate of 3% reflects the accuracy assessment observed between the central laboratory assay and an 
orthogonal PCR method, and minimizes the number of patients without BRAFV600E mCRC who 
would be exposed to study therapy.   
The trial targets the population of patients whose disease has progressed on 1 or 2 prior regimens 
for mCRC. The number of 3rd-line patients (those having received 2 prior regimens) randomized 
to the Phase 3 portion of the study will be limited to 215 (35% of the total randomized) in order 
to ensure generalizability of the study. 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. Permitting up to 35% of the randomized patients 
to have received 2 prior regimens ensures a sufficient sample size to adequately generalize the 
results across subgroups when incorporating other relevant stratification factors. 
In order to allow for an early assessment of efficacy, an initial analysis for efficacy and futility 
will be conducted on the primary endpoints of OS (interim analysis) and ORR (primary analysis) 
of the Triplet Arm vs the Control Arm. While OS is considered the gold standard for 
demonstrating clinical benefit (Amir et al. 2012), ORR allows for a more rapid assessment of 
potential clinical benefit. Doublet vs Control OS is the key secondary endpoint of the study and 
will be tested in a hierarchical manner if the OS primary endpoint is observed to be statistically 
significant. Other secondary endpoints included in the testing hierarchy will be ORR of Doublet 
vs. Control, PFS of Triplet vs. Control, and PFS of Doublet vs. Control. In addition, a 
comparison of the OS in the Triplet Arm and the Doublet Arm will be a secondary endpoint in 
order to help demonstrate the contribution of binimetinib when added to the combination of 
encorafenib and cetuximab.   
A number of therapeutic options are available following progression of initial therapy for mCRC. 
The combination of cetuximab plus irinotecan is one of the options recommended by the NCCN 
for patients who have previously received irinotecan- or oxaliplatin-based combination regimens 
and its use in this setting is consistent with current labeling of cetuximab. The use of FOLFIRI is 
consistent with European Society of Medical Oncology (ESMO) guidelines which recommend 
the use of cytotoxic doublets containing 5-FU with an EGFR inhibitor in patients with mCRC 
which is RASwt whose disease has progressed on 1 prior regimen (Van Cutsem et al. 2014). It has 


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been used in the control arm of several recent Phase 3 studies in the pure 2nd line setting in 
patients with mCRC (Peeters et al. 2014, Tabernero et al. 2015, Van Cutsem et al. 2015). The 
choice of whether to treat with FOLFIRI or irinotecan in the control arm will be at the discretion 
of the treating Investigator. In one of the few head-to-head comparisons of irinotecan and 
FOLFIRI found in the literature, mCRC patients without specific molecular characterization of 
their disease, the treatment groups did not differ significantly in overall quality of life (QoL) 
changes, response rate or PFS. The authors reported these findings to be consistent with a 
meta-analysis of 29 Phase 2 trials (Clarke et al. 2011).   
2.9.2 Safety Lead-in 
The safety of binimetinib/encorafenib (Section 2.5.2), cetuximab/encorafenib (Section 2.3.3.2), 
and binimetinib/panitumumab (Section 2.4.3.1.2) combinations have already been assessed in 
previous trials. Since the safety of the combination of binimetinib, encorafenib and cetuximab 
has not previously been evaluated, the current study proposes to expeditiously evaluate the 
tolerability of binimetinib/encorafenib/cetuximab in a Safety Lead-in phase to identify the dose 
to be used in the randomized Phase 3 portion of the study. The Safety Lead-in will be conducted 
at a limited number of sites where safety will be assessed by (approximately) weekly 
communication with Investigators to monitor AEs on a continuous basis. Dose-limiting toxicities 
will be evaluated. A DMC will determine tolerability after 9 and 15 patients have been treated at 
the starting doses of binimetinib 45 mg BID, encorafenib 300 mg QD and cetuximab 400 mg/m2 
followed by 250 mg/m2 weekly. The DMC will also assess the tolerability at the end of the 
Safety Lead-in when a total of 25-30 patients have been treated. If it is determined that the MTD 
has been exceeded at any point during the Safety Lead-in, lower doses of binimetinib (30 mg 
BID), or encorafenib (225 mg QD) or both (depending on the observed toxicity), in combination 
with the same dose of cetuximab will be tested in a separate cohort. In considering whether it is 
appropriate to proceed at the recommended dose, the DMC will also have the opportunity to 
review toxicities observed over time, in cycles of treatment beyond the first cycle.   
The proposed design for the run-in in conjunction with additional measures taken to ensure 
patient safety both during and after the Safety Lead-in will provide sufficient information to 
proceed with the randomized portion of the trial while maintaining patient safety within the trial. 
2.9.2.1 Japanese Safety Lead-in 
Prior studies in Japanese patients of binimetinib single agent (clinical trial CMEK162X1101) 
suggested that exposure was increased 1.5 to 2-fold in Japanese patients compared with 
non-Japanese patients. This increase in binimetinib exposure did not however appear to result in 
clinically meaningful differences in tolerability relative to non-Japanese patients. Encorafenib 
exposures, as assessed in clinical trials CLGX818X2101 and CLGX818X2103, appear to be 
similar in Japanese and non-Japanese patients. The safety and tolerability of the combination of 
encorafenib with cetuximab is expected to be consistent with the non-Japanese patients based on 
findings in clinical trial CLGX818X2103. The combination of binimetinib and encorafenib in 


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Japanese patients is currently being evaluated in an ongoing Phase 3 study (CMEK162B2301) 
and no significant differences in safety and tolerability have been observed between the Japanese 
and non-Japanese patients in that study.  
In order to confirm the triplet dose is tolerable in Japanese patients, a separate Japanese Safety 
Lead-in cohort will be conducted in 6 patients. The starting dose in Japanese patients will be the 
dose assessed to be tolerable in the non-Japanese Safety Lead-in. The tolerability assessments 
will be based upon occurrence of DLTs as described in Section 4.2.1. As in the non-Japanese 
Safety Lead-in, the safety data will be reviewed by the DMC. 
2.9.3 Dose Selection 
2.9.3.1 Encorafenib/Cetuximab 
In order to optimize the potential for benefit, while limiting the potential for toxicity, the starting 
encorafenib dose in the current study is 300 mg QD, corresponding to its single-agent RP2D.  
As described in Section 2.3.3.2, the combination of encorafenib and cetuximab are currently 
being evaluated in patients with BRAFV600E mCRC the Phase 1b/2 study CLGX818X2103. In the 
dose exploration of encorafenib and cetuximab, the MTD was not reached through the highest 
dose tested (encorafenib 450 mg QD plus cetuximab 400 mg/m2 initial dose followed by 
250 mg/m2 weekly). In the dose exploration of the triple combination including encorafenib, 
cetuximab and the PI3K inhibitor alpelisib, although an MTD was not formally declared, review 
of safety and tolerability data suggested RP2D regimen of the triplet of encorafenib 200 mg QD, 
alpelisib 300 mg QD and standard doses of cetuximab. Although higher doses of encorafenib 
were tolerated in the doublet combination with cetuximab alone, the 200 mg QD encorafenib 
dose was chosen and is being evaluated in the Phase 2 portion of the study to maintain 
consistency between the dual combination and triple combination arms in order to isolate the 
effect of adding the PI3K inhibitor.  
Given the available safety data up to 450 mg QD for encorafenib combined with standard doses 
of cetuximab, there are no clear safety concerns that would require initiating this study at a dose 
of 225 mg, approximating the Phase 2 dose which was chosen in Clinical Study 
CLGX818X2103 for practical reasons related to a specific scientific question rather than to 
maximize the benefit/risk of the doublet combination of encorafenib and cetuximab. It is not 
surprising that doses even higher than the single agent RP2D of 300 mg would be tolerated in 
combination with cetuximab as reactivation of the RAS/RAF/MEK pathway (i.e., RAS and 
CRAF), observed with single agent encorafenib, which is mediated by EGFR, is effectively 
modulated by the addition of cetuximab.  
The proposed 300 mg starting dose represents an active dose of encorafenib that has been shown 
in clinical studies to lead to tumor regressions and clinical responses as a single agent 
(Dummer et al. 2013, Gomez-Roca et al. 2014). Nonclinical in vitro and in vivo studies using 


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BRAFV600E human melanoma and colon cancer cell lines and xenograft models exploring the 
relationship between dose and efficacy also provide evidence in support of 300 mg being an 
appropriate starting dose in patients. Using the human melanoma xenograft model A375, which 
expresses BRAFV600E, a 20 mg/kg dose was estimated to reduce tumor volume by 85% compared 
to untreated animals. Based on relative free fraction exposure, the 20 mg/kg steady-state mouse 
exposure is equivalent to the average exposure for patients receiving 300 mg QD dosing. This is 
also consistent with the observed inhibitory effects of encorafenib in combination with 
cetuximab using a BRAFV600E CRC cell based system. Inhibition was 70% when studied at a free 
encorafenib concentration that was equivalent to the average daily concentration in patients 
receiving 300 mg QD dosing. 
2.9.3.2 Binimetinib/Encorafenib/Cetuximab 
The safety and tolerability of the relevant doublets of encorafenib plus cetuximab, binimetinib 
plus encorafenib, and binimetinib plus the EGFR inhibitor, panitumumab, have been previously 
evaluated. In these trials, all the agents were tolerated at or above their single agent MTD. These 
data are reviewed in detail in Section 2.2.4, Section 2.4.3.1.2 and Section 2.5.2. 
The Safety Lead-in in this study will assess the safety/tolerability of binimetinib 45 mg BID and 
encorafenib 300 mg QD in combination with the standard weekly cetuximab regimen 
(400 mg/m2 initial dose followed by 250 mg/m2 weekly) for use in the randomized Phase 3 
portion of the study. The binimetinib dose of 45 mg BID is below its single-agent MTD of 60 mg 
BID and represents the dose evaluated in the recently completed Phase 3 registrational trial in 
patients with advanced unresectable or metastatic NRAS mutation-positive melanoma (Clinical 
Study CMEK162A2301). 
The combination of encorafenib and binimetinib was evaluated in Clinical Study 
CMEK162X2110 in which encorafenib 450 mg QD (in combination with binimetinib 45 mg 
BID) was identified as the RP2D (see Section 2.5.2) and is currently being evaluated in the 
ongoing Phase 3 trial (CMEK162XB2301) which has completed enrollment. The finding that 
encorafenib doses above the single agent RP2D are tolerated when combined with binimetinib is 
consistent with previous observations that MEK inhibition may ameliorate BRAF-inhibitor 
mediated toxicities (Menzies and Long 2014). As described below, when combined with 
standard doses of cetuximab, encorafenib doses up to 450 mg QD were tolerated without 
reaching MTD. As described in Section 2.4.3.1.2, Clinical Study CMEK162X2116 has 
demonstrated that binimetinib 45 mg BID plus the standard dose of panitumumab (6 mg/kg IV 
biweekly) was tolerated in patients with mCRC. 
2.9.4 Summary 
In summary, Phase 1/2 clinical data obtained to date have demonstrated that the combinations of 
encorafenib/cetuximab, encorafenib/binimetinib, and binimetinib/an EGFR-inhibitor have 
acceptable safety profiles. In addition, encouraging clinical activity has been observed when 


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MAPK signaling is partially inhibited with the combination of encorafenib and cetuximab in 
patients with previously treated BRAFV600E-mutated mCRC. Preclinical data in-vivo models of 
CRC indicate the addition of a MEK inhibitor to the combination of a BRAF inhibitor and an 
EGFR-directed therapy could improve clinical activity and this has also been observed in 
preliminary clinical data sets. 


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3.0 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 Safety Lead-In 
In patients with BRAFV600E mCRC: 
3.1.1.1 Primary Objective 
• Assess the safety/tolerability of the combination of encorafenib + binimetinib + 
cetuximab 
3.1.1.2 Secondary Objectives 
• Assess the activity of encorafenib + binimetinib + cetuximab as measured by blinded 
independent central review (BICR)-determined and Investigator-determined ORR, DOR, 
PFS and time to response 
• Characterize the PK of encorafenib, cetuximab, binimetinib and the active metabolite of 
binimetinib (AR00426032) 
3.1.1.3 Exploratory Objective 
• Assess the activity of encorafenib + binimetinib + cetuximab as measured by OS 
3.1.2 Randomized Phase 3 
In patients with BRAFV600E mCRC: 
3.1.2.1 Primary Objectives 
• Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. 
irinotecan/cetuximab or 5-FU/FA/irinotecan (FOLFIRI)/cetuximab (Control Arm) as 
measured by OS 
• Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. 
irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) as measured by ORR per 
BICR 
3.1.2.2 Key Secondary Objectives 
• Compare the activity of encorafenib + cetuximab (Doublet Arm) vs. irinotecan/cetuximab 
or FOLFIRI/cetuximab (Control Arm) as measured by OS 


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3.1.2.3 Other Secondary Objectives 
• Compare the Investigator-determined ORR of encorafenib + binimetinib + cetuximab 
(Triplet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) 
• Compare the BICR-determined and Investigator-determined ORR of encorafenib + 
cetuximab (Doublet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control 
Arm) 
• Compare the BICR-determined and Investigator-determined PFS of encorafenib + 
binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab 
(Control Arm) 
• Compare the BICR-determined and Investigator-determined PFS of encorafenib + 
cetuximab (Doublet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control 
Arm) 
• Compare the activity of Triplet Arm vs. Doublet Arm as measured by OS 
• Compare the BICR-determined and Investigator-determined ORR of Triplet Arm vs. 
Doublet Arm 
• Compare the BICR-determined and Investigator-determined PFS of Triplet Arm vs. 
Doublet Arm 
• Compare BICR-determined and Investigator-determined DOR of Triplet Arm vs. Control 
Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm 
• Compare BICR-determined and Investigator-determined time to response of Triplet Arm 
vs. Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm 
• Assess the safety/tolerability of Triplet Arm, of Doublet Arm and of Control Arm 
• Compare the effect on QoL of Triplet Arm vs. Control Arm, of Doublet Arm vs. Control 
Arm and of Triplet Arm vs. Doublet Arm  
• Characterize the PK of encorafenib, cetuximab, binimetinib and the active metabolite of 
binimetinib (AR00426032)  
• Assess for drug interactions between encorafenib, cetuximab, binimetinib and the active 
metabolite of binimetinib (AR00426032) based on PK modeling  


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
74 
 
11 July 2019 
3.2.2 Randomized Phase 3 
3.2.2.1 Primary Endpoints 
• OS, defined as the time from randomization to death due to any cause, of Triplet Arm vs. 
Control Arm 
• Confirmed ORR (by BICR) per RECIST, v1.1 of Triplet Arm vs. Control Arm 
3.2.2.2 Key Secondary Endpoint  
• OS of Doublet Arm vs. Control Arm 
3.2.2.3 Other Secondary Endpoints 
• Confirmed ORR (by Investigator) per RECIST, v1.1 of Triplet Arm vs. Control Arm 
• Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 of Doublet Arm vs. 
Control Arm 
• PFS (by BICR and Investigator), defined as the time from randomization to the earliest 
documented disease progression or death due to any cause, of Triplet Arm vs. Control 
Arm 
• PFS (by BICR and Investigator) of Doublet Arm vs. Control Arm 
• OS of Triplet Arm vs. Doublet Arm 
• Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 of Triplet Arm vs. 
Doublet Arm 
• PFS (by BICR and Investigator) of Triplet Arm vs. Doublet Arm 
• DOR (by BICR and Investigator) of Triplet Arm vs. Control Arm, of Doublet Arm vs. 
Control Arm and of Triplet Arm vs. Doublet Arm 
• Time to response (by BICR and Investigator), defined as the time from randomization to 
first radiographic evidence of response, of Triplet Arm vs. Control Arm, of Doublet Arm 
vs. Control Arm and of Triplet Arm vs. Doublet Arm 
• Incidence and severity of AEs, graded according to NCI CTCAE, v.4.03, and changes in 
clinical laboratory parameters, vital signs, ECGs, ECHO/MUGA scans and ophthalmic 
examinations 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
76 
 
11 July 2019 
4.0 
STUDY DESIGN 
4.1 
Study Design Overview 
This is a multicenter, randomized, open-label, 3-arm, Phase 3 study to evaluate encorafenib + 
cetuximab plus or minus binimetinib versus Investigator’s choice of either irinotecan/cetuximab 
or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has 
progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety 
Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will 
be assessed prior to the Phase 3 portion of the study.   
BRAF Testing 
Patients will be eligible for the study based on identification of a BRAFV600E mutation in the 
tumor as determined by the central laboratory as part of Molecular Prescreening for the trial or 
by a local assay result obtained any time prior to Screening. Only polymerase chain reaction 
(PCR) and next generation sequencing (NGS)-based local assays results will be acceptable. If the 
patient is enrolled based on local assay results, the BRAF mutation status must be confirmed by 
the central laboratory no later than 30 days from first dose of study treatment.  
In cases where there is discordance between the local assay and central laboratory results, or if 
the central laboratory is not able to confirm presence of a BRAFV600E mutation due to inadequate 
or poor sample condition within 30 days of initiating study therapy, patients may only continue 
treatment if there is no clinical indication of deterioration or disease progression and the 
investigator determines that the patient is deriving benefit. In such instances, patients must be 
informed that the BRAF mutation status is unconfirmed and must sign a separate informed 
consent form (ICF) that includes this information and describes alternative treatment options.  
Central laboratory BRAF mutation tests with a definitive result (positive or negative) cannot be 
repeated to resolve a discordant result. Patients whose sample is determined to be inadequate or 
who have an indeterminate result on central testing may have samples resubmitted for testing. 
Lack of BRAFV600E confirmation by the central laboratory may be due to discordance between 
the local assay and central laboratory results (potential false positive local assay results), or due 
to inadequate or poor sample condition for central testing (indeterminate results). If at any time 
in the study there is lack of BRAFV600E confirmation in a total of 37 patients (6% of the total 
planned enrollment of the randomized portion of the trial) or discordance between the local assay 
and the central laboratory in 18 patients (3% of the total planned enrollment), all subsequent 
patients will be required to have BRAFV600E determined by the central laboratory for enrollment 
(i.e., local BRAF testing will no longer be accepted for trial eligibility). Information regarding 
sites and laboratories associated with discordant results will be maintained and results from 
laboratories with more than 1 prior discordant result will not be accepted for patient enrollment. 
Sites with more than 2 randomized patients having indeterminate results after initiation of 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
77 
 
11 July 2019 
protocol version 6 will be required to enroll all subsequent patients based only on central 
laboratory assay results. 
Molecular Prescreening 
Prior to eligibility assessment for study randomization, patients may undergo molecular tumor 
prescreening with the central laboratory BRAF mutation assay at any time prior to Screening as 
long as they meet all the Molecular Prescreening inclusion/exclusion criteria. Note that tumor 
samples previously determined to be BRAFwt by local assessment may be submitted to the central 
laboratory. In particular, tumors with clinicopathological features of BRAF mutations, may be 
considered for testing by central laboratory regardless of the results of prior local BRAF mutation 
testing (see Section 7.1.1). 
Safety Lead-in 
The Safety Lead-in will be conducted at a limited number of sites. Dose-limiting toxicities will 
be evaluated (see Section 4.2.1) and the tolerability of the binimetinib, encorafenib, and 
cetuximab combination will be assessed (see Section 4.2.2) by the Sponsor and the Investigator 
in approximately weekly communications. The DMC will evaluate the safety data at pre-
specified intervals and at additional points during the conduct of the Safety Lead-in, if necessary. 
The first 9 evaluable patients will be enrolled on a rolling basis in a single cohort to evaluate the 
combination of encorafenib 300 mg QD + binimetinib 45 mg BID + cetuximab 400 mg/m2 
followed by 250 mg/m2 IV weekly. Additional patients will be enrolled based on assessments of 
the safety data by the DMC during the Safety Lead-in. The doses for the Triplet Arm in the 
randomized Phase 3 portion of the study will be determined after a total of 25-30 patients have 
been treated at the proposed doses and their data evaluated by the DMC (see Section 4.2). 
In the Japanese Safety Lead-in portion of the study, a separate cohort of patients will be 
evaluated at a limited number of sites in Japan. Six patients will be enrolled on a rolling basis in 
a single cohort to evaluate the triplet dose. The starting dose in Japanese patients will be the dose 
assessed to be tolerable in the Safety Lead-in for non-Japanese patients. Similar to the Safety 
Lead-in for non-Japanese patients, the DMC will evaluate the safety data to confirm tolerability. 
The Phase 3 portion of the trial outside of Japan may be initiated before the completion of the 
Japanese Safety Lead-in (see Section 4.2.3). 
Following study treatment discontinuation, patients who provide informed consent for survival 
follow-up will continue to be assessed to determine survival status until withdrawal of consent, 
patient is lost to follow-up, death or defined end of study (see Section 8.6.2.2). 
Phase 3 
Once the tolerability of the proposed doses for the Triplet Arm has been established, the Phase 3 
portion of the study will begin and eligible patients will be randomized in a 1:1:1 ratio to the 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
78 
 
11 July 2019 
Triplet Arm, Doublet Arm or Control Arm. The number of 3rd-line patients (those having 
received 2 prior regimens) will be limited to 215 (35% of the total randomized) after which only 
patients with 1 prior regimen will be 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. Patients randomized to the Control Arm 
may be treated with either irinotecan + cetuximab or FOLFIRI + cetuximab as per Investigator’s 
choice. The choice of irinotecan or FOLFIRI must be declared prior to randomization.  
Randomization will be stratified by baseline Eastern Cooperative Oncology Group performance 
status (ECOG PS; 0 vs. 1), prior use of irinotecan (yes vs. no) and cetuximab source 
(US-licensed vs. EU-approved). The DMC will review the available safety information after the 
first 30 patients in the randomized Phase 3 portion of the study (i.e., approximately 10 patients in 
each arm) have had the opportunity to complete at least 1 cycle of treatment to confirm 
tolerability. 
Treatment will be administered in 28-day cycles until disease progression, unacceptable toxicity, 
withdrawal of consent, initiation of subsequent anticancer therapy or death. In special 
circumstances (defined in Section 4.5), continuation of treatment beyond disease progression may 
be allowed. After treatment is discontinued, randomized Phase 3 patients will continue to be 
followed for OS unless consent for survival follow-up is withdrawn (see Section 8.6.2.3). 
Upon implementation of protocol version 8, patients randomized to the Control arm who meet 
crossover eligibility criteria (Section 5.2.3) may cross over to receive the triplet regimen. 
Treatment in crossover patients will be administered in 28-day cycles until disease progression, 
unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy or 
death. In special circumstances (defined in Section 4.5), continuation of treatment beyond disease 
progression may be allowed. After treatment is discontinued, patients will continue to be 
followed for OS unless consent for survival follow-up is withdrawn. 
End of Study 
End of study will be defined as the point when all patients have the opportunity to be followed 
for at least 1 year after the randomization date of the last patient enrolled and at least 80% of 
patients have an OS event (or are lost to follow-up). Any patients still receiving study drugs at 
the end of the study will be allowed to continue at the discretion of the Investigator and as long 
as none of the treatment discontinuation criteria are met (see Section 4.6). After the end of the 
study, access to study drugs will be provided in accordance with local regulations and 
requirements. 
A schematic of the study design is presented in Figure 5. 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
79 
 
11 July 2019 
Figure 5: 
Study Design 
 
Note: Upon implementation of protocol version 8, patients randomized to the Control arm who meet crossover eligibility 
criteria (Section 5.2.3) may cross over to receive the triplet regimen. 
Patients with BRAF V600E-mutant metastatic colorectal cancer 
and meeting all elig ibility criteria 
~ 
~ 
r---
~ 
Safety Lead-in 
Japanese Safety Lead-in 
Encorafenib + Binimetinib + Cetuximab 
Encorafenib + Binimetinib + Cetuximab 
6 
N = 25 to 30 
N = 6 
< 
w 
..J 
------------. 1.-----------
>-
1-w 
LL < 
rn 
1 o objective: 
Evaluate safety/tolerability of 
proposed doses for Triplet Arm 
'---
r---
Stratification: 
ECOG PS (0 vs. 1) 
Prior irinotecan (yes vs. no) 
Cetuximab source (US-licen sed vs. EU-approved) 
Randomization 1:1:1 
-------------~ 
Control Arm 
Triplet Arm 
Doublet Arm 
lrinotecan + Cetuximab 
M 
Encorafenib + Binimetinib + Cetuximab 
Encorafenib + Cetuximab 
OR 
w 
N = 205 
N = 205 
FOLFIRI + Cetuximab 
rn < 
N = 205 
:I: 
n. 
-------------- ~ 
1° objectives: 
OS of Triplet Arm vs. Control Arm 
ORR (by BICR) of Triplet Arm vs. Control Arm 
Key 2°objective: 
OS of Doublet Arm vs. Control Arm 
Other 2°objectives: 
ORR (by Investigator) of Triplet Arm vs. Control Arm 
ORR (by BICR and Investigator) of Doublet Arm vs. Control Arm 
PFS (by BICR and Investigator) of Triplet Arm vs. Control Arm 
PFS (by BICR and Investigator) of Doublet Arm vs. Control Arm 
OS of Triplet Arm vs. Doublet Arm 
ORR, PFS (each by BICR and Investigator) of Doublet Arm vs. Control Arm, Triplet Arm vs. Doublet Arm 
DOR, TIR (each by BICR and Investigator) of Triplet Arm vs. Control Arm, Doublet Arm vs. Control Arm, Triplet Arm vs. Doublet Arm 
'---


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
80 
 
11 July 2019 
4.2 
Safety Lead-in Phase 
The Safety Lead-in portion of the study will evaluate the safety and tolerability of the 
combination of encorafenib + binimetinib + cetuximab for 1 cycle (the first 28 days of 
treatment). 
4.2.1 Dose-Limiting Toxicities 
For purposes of tolerability decisions, a DLT is defined as any AE or abnormal laboratory value 
assessed as unrelated to disease, disease progression, intercurrent illness or concomitant 
medications/therapies occurring within the first 28 days of treatment that satisfies at least 1 of the 
criteria listed in Table 8. 
Table 8: 
Criteria for Defining Dose-limiting Toxicities 
DLT Criteria 
• 
Any AE or laboratory value considered unrelated to underlying disease, disease progression, intercurrent illness 
or concomitant medications/therapies resulting in the inability to tolerate at least 75% dose intensity 
[(administered dose in mg/planned dose in mg) x 100] of binimetinib, encorafenib or cetuximab during Cycle 1 
Cardiac disorders 
• 
Absolute decrease of LVEF > 10% compared to Baseline and the LVEF is below the institution’s LLN 
• 
Left ventricular systolic dysfunction Grade ≥ 3 
• 
Other cardiac disorders Grade ≥ 3 
Vascular disorders 
• 
Grade 3 hypertension for > 14 consecutive days  
• 
Grade 4 hypertension 
General disorders and administration site conditions 
• 
Fatigue Grade 3 for > 14 consecutive days 
Respiratory disorders 
• 
Interstitial lung disease/pneumonitis Grade ≥ 2 
Skin and subcutaneous tissue disordersa 
• 
Rash, hand foot skin reaction (HFSR), or photosensitivity CTCAE Grade 3 for > 14 consecutive days despite 
maximal skin toxicity treatment (as per local practice) 
• 
Rash, HFSR, or photosensitivity CTCAE Grade 4 
Gastrointestinal disordersa 
• 
Diarrhea Grade 3 for ≥ 48 hours despite optimal use of antidiarrheal therapy 
• 
Diarrhea Grade 4 
• 
Nausea/vomiting Grade 3 for ≥ 48 hours despite optimal use of antiemetic therapy 
• 
Nausea/vomiting Grade 4 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
81 
 
11 July 2019 
DLT Criteria 
Investigations 
• 
Total bilirubin Grade ≥ 3 
• 
AST or ALT Grade ≥ 3 in conjunction with total bilirubin Grade ≥ 2 of any duration 
• 
AST or ALT Grade 3 for > 7 consecutive days 
• 
AST or ALT Grade 4 
• 
Serum creatinine Grade ≥ 3 
• 
CK elevation ≥ Grade 3 associated with an increase in creatinine ≥ 1.5 × the patient’s Baseline screening 
creatinine 
• 
ANC Grade 4 for > 7 consecutive days 
• 
Platelet count Grade 3 with signs of clinically significant bleeding 
• 
Platelet count Grade 4 
• 
ECG QTcF prolonged ≥ Grade 3b 
Eye disorders-Retinal 
• 
Retinopathy or retinal detachment Grade ≥ 3, confirmed by ophthalmic examination 
• 
Retinal vascular disorder including retinal vein occlusion (RVO), confirmed by ophthalmic examination 
Eye disorders –Visual disturbances without ocular (retinal) changes 
• 
Blurred vision, flashing lights, floaters: Grade ≥ 3 
Eye disorders – (other specify) 
• 
Grade ≥ 3 for > 21 consecutive days 
• 
Grade 4 confirmed by ophthalmic examination 
Other hematologic and nonhematologic toxicitiesc 
• 
Any other Grade ≥ 3 AE except: 
o 
Lymphocyte count decreased (lymphopenia) Grade ≥ 3 unless clinically significant 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; 
AST = aspartate aminotransferase; CK = creatine kinase; DLT = dose-limiting toxicities; ECG = electrocardiogram; 
LLN = lower limit of normal; LVEF = left ventricular ejection fraction; QTcF = QT interval corrected for heart rate 
using Fridericia’s formula.  
a Prophylactic treatment for nausea/vomiting or skin AEs is not required with binimetinib. However, antiemetics 
and treatments for skin AEs should be used at the discretion of the Investigator if the patient experiences 
nausea/vomiting and/or skin AEs Grade ≥ 1. 
b QTc must be prolonged on two separate ECGs.  
c Isolated laboratory changes (e.g. alkaline phosphatase, cholesterol, lipase, serum amylase) or those due to 
sampling or laboratory errors without associated clinical signs or symptoms may be determined to not be DLTs 
upon review and agreement by the Investigator and Sponsor’s Medical Monitor. 
 
4.2.2 Tolerability Assessment 
For the Safety Lead-in, the first 9 patients will be enrolled on a rolling basis in a single cohort to 
evaluate the combination of encorafenib 300 mg QD + binimetinib 45 mg BID + cetuximab 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
82 
 
11 July 2019 
400 mg/m2 followed by 250 mg/m2 weekly (see Figure 6). The tolerability assessment will be 
based upon occurrence of DLTs (see Section 4.2.1) in all patients. Enrollment will be put on hold 
if 3 patients experience DLTs until a discussion with the DMC can occur. If it is determined that 
the MTD has been exceeded, dosing at the current dose will be suspended and the next 9 patients 
will be enrolled on a rolling basis in a separate cohort to test lower doses of binimetinib (30 mg 
BID) or encorafenib (225 mg QD), corresponding to the doses of binimetinib, and encorafenib in 
Dose Level -1 in Table 10, in combination with the standard cetuximab dose. It is possible that 
doses of binimetinib, encorafenib, or both may be reduced depending on the observed pattern of 
toxicity and based on the known AE profiles of both drugs.   
If DLTs are observed in fewer than 3 of 9 evaluable patients, the DMC will review data after the 
9th patient has been followed for at least one 28-day cycle to confirm tolerability of the doses. 
As the initial 9 patients will be enrolled over time, the DMC will have available information 
beyond the first 28 days of treatment on several patients, and this information will also be 
reviewed and incorporated into decisions regarding tolerability of the regimen. If the DMC 
determines the doses to be tolerable in the first 9 evaluable patients based on observing DLTs in 
< 33% of patients and evaluation of the overall toxicity profile, the Safety Lead-in will be 
expanded by at least an additional 16 up to a maximum of 21 patients to account for patients at 
various stages of screening at the time.  
Once the first 6 evaluable patients in this Safety Lead-in expansion have been treated for at least 
1 cycle, the DMC will again review all the available data. The overall safety profile of the 
evaluable 15 patients, including data from all cycles of treatment, will be considered in the 
evaluation.  
At the completion of the Safety Lead-in when all 25-30 patients (the initial 9 plus the additional 
16-21 patients in the expansion) have been followed for a minimum of 1 cycle, the DMC will 
again review all accumulated safety data to confirm that the doses are acceptable for use in the 
Triplet Arm (encorafenib + binimetinib + cetuximab) of the randomized Phase 3 portion of the 
study. Following their review of the cumulative data after the first 15 patients treated and / or at 
the end of the Safety Lead-in, the DMC will either confirm the tolerability of the current dose or 
may recommend de-escalation. 
In the event that the initial doses are not tolerated and Dose Level -1 is evaluated, it will be 
conducted as described above with the DMC reviewing the data after the first 9 patients, during 
the Safety Lead-in expansion (first 15 patients), and at the end of the Safety Lead-in 
(25-30 patients) (see Figure 6). Inclusion of the Triplet Arm in the Phase 3 portion of the trial 
will be reconsidered if it is determined that Dose Level -1 is not tolerable. 
Patients who require a dose interruption or reduction during the initial 28-day treatment period 
(Cycle 1) will remain evaluable for tolerability decisions if the reason for the reduction and/or 
interruption represents a DLT. Patients will be replaced if they have received less than 75% dose 
intensity [(administered dose in mg/planned dose in mg) x 100] of binimetinib, encorafenib or 


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BID/encorafenib 300 mg QD/cetuximab 
400 followed by 250 mg/m
2IV weekly
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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
84 
 
11 July 2019 
hospitalized for the first 2 weeks of treatment. If the treating physician determines the patient is 
tolerating therapy well, the patient may be treated as an outpatient for the remainder of the cycle. 
If multiple patients are ready to start treatment in the Japanese Safety Lead-in, then initiation of 
study therapy for each patient (i.e., Cycle 1 Day 1) must be separated by at least 24 hours. The 
tolerability assessment will be based upon occurrence of DLTs (see Section 4.2.1) in all patients. 
Enrollment will be put on hold if 2 patients experience DLTs until a discussion with the DMC 
can occur. If it is determined that the MTD has been exceeded, dosing at the current dose will be 
suspended and the next 6 patients will be enrolled on a rolling basis in a separate cohort to test 
lower doses of binimetinib or encorafenib, in combination with the standard cetuximab dose. It is 
possible that doses of binimetinib, encorafenib, or both may be reduced depending on the 
observed pattern of toxicity and based on the known AE profiles of both drugs.   
If DLTs are observed in fewer than 2 of the 6 evaluable patients, the DMC will review data after 
the 6th patient has been followed for at least one 28-day cycle to confirm tolerability of the doses 
(the DMC review may also be conducted after the 5th patient has been followed for at least one 
28-day cycle if no DLTs have been observed). Patients who require a dose interruption or 
reduction during the initial 28-day treatment period (Cycle 1) will remain evaluable for 
tolerability decisions if the reason for the reduction and/or interruption represents a DLT. 
Patients will be replaced if they have received less than 75% dose intensity [(administered dose 
in mg/planned dose in mg) × 100] of binimetinib, encorafenib or cetuximab for any reason other 
than an AE or abnormal laboratory value that is not related to disease, disease progression, 
intercurrent illness or concomitant medications/therapies before completing Cycle 1.  
As the initial 6 patients will be enrolled over time, the DMC will have available information 
beyond the first 28 days of treatment on several patients, and this information will also be 
reviewed and incorporated into decisions regarding tolerability of the regimen. If the DMC 
determines the doses to be tolerable in the first 6 evaluable patients based on observing DLTs in 
< 33% of patients and evaluation of the overall toxicity profile in Japanese patients, the Japanese 
Safety Lead-in will be considered complete. 
4.3 
Randomized Phase 3 
A total of 615 eligible patients with BRAFV600E mutant mCRC who have progressed on 1 or 2 
prior metastatic regimens will be randomized 1:1:1 to the 3 treatment arms (Triplet, Doublet or 
Control). The number of 3rd-line patients (those having received 2 prior regimens) will be limited 
to 215 after which only patients with 1 prior regimen will be 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. Patients 
randomized to the Control Arm may be treated with irinotecan + cetuximab or FOLFIRI + 
cetuximab as per Investigator’s choice. The choice of irinotecan or FOLFIRI must be declared 
prior to randomization.    


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Randomization will be stratified by baseline ECOG PS (0 vs. 1), prior use of irinotecan (yes vs. 
no) and cetuximab source (US-licensed vs. EU-approved). The DMC will review all available 
safety information after the first 30 patients in the randomized Phase 3 portion of the study (i.e., 
approximately 10 patients in each arm) have had the opportunity to complete at least 1 cycle of 
treatment to confirm tolerability. During the remainder of the study, the DMC will review safety 
data at regular intervals. 
An initial analysis of the study will be performed when all three of the following criteria have 
been met: 
• approximately 9 months after randomization of the 330th patient (i.e., approximately 
110 patients per arm), to allow a majority of responders among the 330 Phase 3 patients 
to have the opportunity to be followed for approximately 6 months or longer after their 
first response 
• at least 188 OS events have occurred in the Triplet and Control arms combined 
(i.e., approximately 70% information) 
• at least 169 OS events have occurred in the Doublet and Control arms combined 
(i.e., approximately 50% information) 
The primary analysis of Triplet vs. Control ORR by BICR will occur at this time and will be 
based on the first 330 randomized patients. An interim analysis for superiority or (non-binding) 
futility of the Triplet vs Control OS endpoint will also be performed at the time of the primary 
ORR analysis based on all available data (Section 11.3.9). The DMC will perform the analyses 
for both of the comparisons at this time point. If the interim analysis for OS of Triplet vs. Control 
exceeds the superiority boundary, patients in the Triplet and Doublet arms may continue to be 
followed for a more mature comparison. 
If the OS interim analysis results do not cross the superiority boundary, the OS final analysis will 
occur once at least 268 events are observed in the Triplet Arm + Control Arm and at least 338 
events are observed in the Doublet Arm + Control Arm.  
4.4 
Measures to Minimize Bias 
This is an open-label study, so the following steps will be taken during the randomized Phase 3 
portion of the study to minimize any possible bias:  
• The randomization schedule will be created and managed by a third-party vendor, and 
treatments will be assigned according to a computerized central randomization list using 
an interactive web response system (IWRS) (see Section 6.2). 
• The Sponsor (and their designee trial team) will be blinded to treatment group 
assignments presented in aggregate data summaries. 


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• A limited number of study team members will be unblinded to individual treatment 
assignments for purposes of study conduct (e.g., site monitoring, data management, 
patient emergencies or for regulatory reporting purposes). The names and roles of these 
team members will be documented by the Sponsor, and they will not have access to 
unblinded aggregate summaries. 
• Patients with BRAFwt tumors as determined by a local laboratory test are not excluded 
from molecular prescreening or screening. Screening using the central laboratory test is 
encouraged particularly where clinicopathological features are consistent with BRAFV600E 
mutation. 
These steps will remain in place until a database lock supporting a clinical study report occurs. 
The Sponsor will remain blinded to aggregate OS results until the Triplet vs Control OS endpoint 
exceeds the superiority boundary or the study stops for futility.   
4.5 
Duration of Treatment 
Patients may continue receiving study drug as long as none of the treatment discontinuation 
criteria are met (see Section 9.2). Continuing study treatment beyond disease progression for any 
patient is only to be considered under special circumstances when it is believed that the patient 
may clinically benefit from continued treatment beyond progression. If it is judged by the 
Investigator in consultation with the Sponsor, to be in the best interest of the patient, the patient 
may remain on study treatment as long the patient continues to benefit from the study treatment 
per Investigator assessment. Special circumstances can be defined by e.g., mixed responses and 
appearance of new brain metastases (only) which is treatable with stereotactic radiotherapy 
or surgery but does not require whole brain radiotherapy. 
Dosing beyond progression is not allowed in the following cases: 
• Patients with clear evidence of disease progression at multiple sites or clear evidence of 
new lesions outside the central nervous system (CNS) 
• Patients with rapid progression of disease at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention cannot be dosed beyond 
progression 
• Patients who have clinically relevant worsening of laboratory values 
• Patients who have a clinically significant decline in performance status at time of 
progression. 
After patients have discontinued treatment for any reason, they will be followed every 3 months, 
or more frequently as needed, until withdrawal of consent, the patient is lost to follow-up, death 
or defined end of study (Section 4.6). If patients withdraw consent, they will be asked if they are 


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willing to be contacted via telephone for survival status. If the patient refuses to be contacted 
(or, for patients in the Safety Lead-in, where informed consent cannot be obtained due to the 
patient being lost to follow-up or previous withdrawal of consent), attempts to determine survival 
status should be made via access to public records where permitted by local laws. 
4.6 
End of Study 
End of study will be defined as the point when all patients have the opportunity to be followed 
for at least 1 year after the randomization date of the last patient enrolled and at least 80% of 
patients have an OS event (or are lost to follow-up). Any patients still receiving study drugs at 
the end of the study will be allowed to continue at the discretion of the Investigator and as long 
as none of the treatment discontinuation criteria are met (see Section 9.2). The Sponsor will 
notify all applicable regulatory agencies in accordance with local requirements when the study 
has ended. After the end of the study, access to study drugs will be provided only in accordance 
with local regulations and requirements. 
4.7 
Data Review Committees 
4.7.1 Data Monitoring Committee 
The DMC will be responsible for reviewing safety data in the non-Japanese and Japanese Safety 
Lead-in portions of the study in order to evaluate the safety and tolerability of the combination of 
encorafenib + binimetinib + cetuximab. Once the Phase 3 portion has been initiated, the DMC 
will confirm the safety and tolerability of the triple combination after the first 30 patients have 
been randomized and then will be responsible for reviewing safety data at regular intervals as 
well as performing the efficacy analyses for Triplet vs Control OS (interim analysis for 
superiority and [non-binding] futility) and Triplet vs Control ORR (primary analysis) 
(Section 11.3.9). A DMC Charter that outlines DMC membership, precisely the data that will be 
reviewed and the timing and frequency of the reviews will be established. DMC 
recommendations will be provided to the Sponsor in compliance with the DMC Charter. 
4.7.2 Steering Committee 
The Steering Committee (SC) will be appointed by the Sponsor prior to the initiation of the 
study. The SC will include Investigators participating in the study, leading experts in colorectal 
cancer and Sponsor representatives. The SC will be involved in the oversight of the study and 
will ensure transparent management of the study according to the protocol. Details on the role of 
the SC and working procedures will be defined in the SC Charter. 


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5.0 
PATIENT POPULATION 
5.1 
Number of Patients 
Approximately 646 to 651 patients at approximately 300 study centers are planned (includes 
31 to 36 patients for the non-Japanese and Japanese Safety Lead-in study portions; additional 
patients may be included if lower dose levels are evaluated during the Safety Lead-in). 
5.2 
Selection of Patients 
The eligibility criteria described in this study protocol are designed to identify patients for whom 
study treatment is considered appropriate. All relevant medical conditions should be considered 
when deciding whether a patient is suitable for enrollment in the study. 
Eligibility will be determined separately for molecular tumor testing during a Prescreening Phase 
and for enrollment/randomization in the study during a Screening Phase. Questions regarding 
patient eligibility should be addressed to the Sponsor or delegate prior to 
enrollment/randomization. Patients will be considered enrolled in the study once they have 
signed the Screening ICF.   
5.2.1 Eligibility Criteria for Molecular Prescreening 
Patients may undergo molecular tumor prescreening with the central laboratory BRAF mutation 
assay at any time prior to Screening as long as they meet all the Molecular Prescreening 
inclusion/exclusion criteria. Note that tumor samples previously determined to be BRAFwt by 
local assessment may be submitted to the central laboratory. In particular, tumors with 
clinicopathological features of BRAF mutations such as right colon tumors, poorly differentiated, 
mucinous, or signet-ring carcinomas, or tumors metastasized to the peritoneum (Yokota et al. 
2011), may be considered for testing by central laboratory regardless of the results of  prior local 
BRAF mutation testing (see Section 7.1.1). 
5.2.1.1 Inclusion Criteria for Molecular Prescreening 
All the following inclusion criteria at Prescreening must be met for a patient to be eligible to 
undergo molecular tumor prescreen: 
1. Provide a signed and dated Prescreening informed consent document 
2. Age ≥ 18 years at time of informed consent 
3. Histologically- or cytologically-confirmed CRC that is metastatic 
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5. Able to provide a sufficient amount of representative tumor specimen (primary or 
metastatic, archival or newly obtained) for central laboratory testing of BRAF and KRAS 
mutation status (minimum of 6 slides; optimally up to 15 slides). 
5.2.1.2 Exclusion Criteria for Molecular Prescreening 
Patients meeting any of the following criteria at Prescreening are not eligible to undergo 
molecular tumor prescreen: 
1. Leptomeningeal disease 
2. 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) 
3. Known history of acute or chronic pancreatitis 
4. History of chronic inflammatory bowel disease or Crohn’s disease requiring medical 
intervention (immunomodulatory or immunosuppressive medications or surgery) 
≤ 12 months prior to randomization 
5. Concurrent neuromuscular disorder that is associated with the potential of elevated CK 
(e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy) 
6. Known history of human immunodeficiency virus (HIV) infection 
7. 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 
8. Known contraindication to receive cetuximab or irinotecan at the planned doses; refer to 
the most recent cetuximab and irinotecan summary of product characteristics (SPC) or 
local label as applicable 
9. Prior anti-EGFR treatment 
10. More than 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. 


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5.2.2 Patient Eligibility  
Patients must fulfill all of the following inclusion criteria and none of the exclusion criteria to be 
included in this study. 
5.2.2.1 Inclusion Criteria  
All the following inclusion criteria must be met for a patient to be eligible to be included in this 
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 as previously determined by a local assay at 
any time prior to Screening or by the central laboratory (see Section 7.1.1) 
Notes:  
a. Only PCR and NGS-based local assays results will be acceptable 
b. If at any time in the Phase 3 portion of the study there is lack of BRAFV600E 
confirmation by the central laboratory (for any reason including discordance and 
inadequate available tissue) in 37 total patients or discordance (a valid result of “no 
BRAFV600E mutation” as determined by the central laboratory) between the local assay 
and the central laboratory in 18 patients, all subsequent patients will be required to 
have BRAFV600E determined by the central laboratory prior to enrollment 
(see Section 7.1.1). 
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 is 
inadequate for testing, additional samples may be submitted.   
e. Results from local laboratories with more than 1 discordant result leading to patient 
enrollment will not be accepted for further patient enrollment.    
f. Sites with more than 2 randomized patients having indeterminate results after 
initiation of protocol version 6 will be required to enroll all subsequent patients based 
only on central laboratory assay results. 


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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 6 slides; optimally up to 15 slides) 
Note:  For patients enrolled on the basis of a local BRAF mutation assay, 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. If the central 
laboratory determines that the sample is inadequate for analysis, a second sample may be 
submitted (see Section 7.1.1). 
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. Patients who have received 2 prior regimens (i.e., those entering the study in the 
3rd line setting), must have received or have been offered and refused prior 
oxaliplatin unless it was contraindicated due to underlying conditions. 
c. Maintenance therapy given in the metastatic setting will not be considered a 
separate regimen. 
d. 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. 


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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 electrolytes at Baseline, defined as serum potassium and magnesium levels 
within institutional normal limits (Note: replacement treatment to achieve adequate 
electrolytes will be allowed). 
13. 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 
14. 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 
15. Able to take oral medications 
16. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and 
other study procedures 
17. 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 contraceptive methods listed in Section 5.3.1 should be communicated to 
the patients and their understanding confirmed. For all females, the pregnancy test result 
must be negative at screening. 
18. Males must agree to take appropriate precautions to avoid fathering a child from 
screening through 90 days following end of therapy.   
Note: Permitted contraceptive methods listed in Section 5.3.1 should be communicated to 
the patients and their understanding confirmed. 
19. Patients under guardianship or partial guardianship will be eligible unless prohibited by 
local laws or by local/central ethic committees (e.g., France, Germany). Where allowed, 
all procedures prescribed by law must be followed. 


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5.2.2.2 Exclusion Criteria  
Patients meeting any of the following criteria at screening 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. 


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10. Uncontrolled hypertension defined as persistent elevation of 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 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 


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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 cetuximab or irinotecan at the planned doses; refer to 
the most recent cetuximab and irinotecan SPC or local label as applicable 
22. 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. 
23. Concomitant use of St. John’s Wort (hypericum perforatum) 
24. 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 
25. Pregnant, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test 
result, or nursing (lactating) 
26. Prior enrollment into this clinical study. 
5.2.3 Eligibility Criteria for Treatment Crossover 
5.2.3.1 Inclusion Criteria for Treatment Crossover 
All of the following inclusion criteria must be met within 28 days prior to initiation of crossover 
treatment.  
1. Patient was randomized to the Control arm and: 
• Discontinued Control arm treatment for any reason on or after 13 June 2019 
(i.e., 4 weeks before the date of protocol version 8.0), 
• Received no systemic anticancer therapy after discontinuation of Control arm 
treatment, and  
• Remains in survival follow-up. 
2. Provide a signed and dated Crossover informed consent document. 
3. ECOG PS of 0 or 1. 
4. Adequate bone marrow function characterized by the following: 
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L; 
• Platelets ≥ 100 × 109/L; 
• Hemoglobin ≥ 9.0 g/dL 


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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 these criteria.  
5. 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. 
6. Adequate electrolytes defined as serum potassium and magnesium levels within 
institutional normal limits (Note: replacement treatment to achieve adequate electrolytes 
will be allowed). 
7. Adequate hepatic function characterized by the following: 
• 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 
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × 
ULN, or ≤ 5 × ULN in presence of liver metastases. 
8. Adequate cardiac function characterized by the following: 
• Mean triplicate QT interval corrected for heart rate using Fridericia's formula 
(QTcF) value ≤480 msec. 
9. Able to take oral medications. 
10. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and 
other study procedures. 
11. 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 through 
follow-up if of childbearing potential. 
Note: Permitted contraceptive methods listed in Section 5.3.1 should be communicated to 
the patients and their understanding confirmed. For all females, the pregnancy test result 
must be negative at crossover screening and at the time of crossover. 
12. Males must agree to take appropriate precautions to avoid fathering a child through 90 
days following end of therapy. 
Note: Permitted contraceptive methods listed in Section 5.3.1 should be communicated to 
the patients and their understanding confirmed. 
13. Patients under guardianship or partial guardianship will be eligible unless prohibited by 
local laws or by local/central ethic committees (e.g., France, Germany). Where allowed, 
all procedures prescribed by law must be followed. 
5.2.3.2 Exclusion Criteria for Treatment Crossover 
Patients randomized to the Control arm who meet any of the following criteria within 28 days 
prior to initiation of crossover treatment will not be eligible for crossover. 


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1. Patients for whom cetuximab was permanently discontinued due to cetuximab-related 
toxicity in the randomized Phase 3 portion of the study. 
2. 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., MRI or CT) demonstrating no current 
evidence of progressive brain metastases.  
3. Leptomeningeal disease. 
4. 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 crossover. 
5. Known history of acute pancreatitis. 
6. History of chronic inflammatory bowel disease or Crohn’s disease requiring medical 
intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 
months prior to crossover. 
7. Impaired cardiovascular function or clinically significant cardiovascular diseases, 
including any of the following: 
• History of acute myocardial infarction, acute coronary syndromes (including 
unstable angina, CABG, coronary angioplasty or stenting) ≤ 6 months prior to 
start of crossover; 
• 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 crossover, except atrial fibrillation and 
paroxysmal supraventricular tachycardia. 
8. Impaired hepatic function, defined as Child Pugh class B or C. 
9. 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). 
10. Treatment with irinotecan within 3 weeks prior to Day 1 of crossover treatment.  
11. Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the 
exception of Grade 2 alopecia or Grade 2 neuropathy.  
12. Concomitant use of St. John’s Wort (hypericum perforatum). 
13. 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 crossover treatment. 


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14. Pregnant, confirmed by a positive hCG laboratory test result, or nursing (lactating) at 
time of crossover. 
15. Left ventricular ejection fraction (LVEF) < 50% as determined by a MUGA scan or 
ECHO. 
16. Current evidence or history of RVO or current risk factors for RVO (e.g., uncontrolled 
glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability 
syndromes). 
17. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or 
diastolic blood pressure ≥ 100 mmHg despite current therapy. 
18. History of thromboembolic or cerebrovascular events ≤ 6 months prior to crossover, 
including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or 
pulmonary emboli. 
19. Concurrent neuromuscular disorder that is associated with the potential of elevated CK 
(e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy) 
5.3 
Lifestyle Guidelines 
5.3.1 Contraception 
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 in any treatment arm if of childbearing potential. Males must agree to take 
appropriate precautions to avoid fathering a child from screening through 90 days following end 
of therapy.   
Patients should also be referred to the locally approved prescribing information for cetuximab, 
irinotecan, fluorouracil and folinic acid for additional guidance (as applicable). The following 
methods have been determined to be effective and acceptable and are permitted under this 
protocol for use by the patient and his/her partner (Clinical Trials Facilitation Group Guidelines 
2014): 
• Complete abstinence from sexual intercourse when this is in line with the preferred and 
usual lifestyle of the patient 
• Double barrier method (condom with spermicide in conjunction with use of an 
intrauterine device) 
• Due to the potential of encorafenib to induce CYP3A4, hormonal agents (including but 
not limited to birth control patch, vaginal ring, oral, injectable, or implanted 
contraceptives) are permissible only when combined with other highly effective or 
acceptable methods 


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• Surgical sterilization (bilateral oophorectomy with or without hysterectomy, tubal 
ligation or vasectomy) at least 6 weeks prior to taking study treatment. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up levels of luteinizing hormone (LH), follicle-stimulating hormone 
(FSH), and/or estradiol. 
• It is recommended that patients experiencing vomiting or diarrhea should be counseled to 
use non-oral methods of contraception. 
5.3.2 Photosensitivity 
Patients treated with encorafenib, cetuximab and/or 5-FU should avoid extended exposure to 
ultraviolet light and when outdoors, should wear occlusive clothing, sunscreen and sunglasses 
while receiving study drugs and for 2 months following the last dose of encorafenib, cetuximab 
and/or 5-FU. 


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6.0 
STUDY TREATMENT AND CONCOMITANT MEDICATIONS/THERAPIES 
The term “study drug” is used to refer to encorafenib, binimetinib, cetuximab, irinotecan, and 
5-FU and FA, collectively. In addition to the information provided in this protocol, refer to the 
SPC for cetuximab, irinotecan, fluorouracil, and folinic acid for the management of patients, 
concerning contraindications, duration of contraception, special warnings and precautions, and 
medications that are contraindicated or that must be used with caution. Patients with known 
contraindications to either 5-FU or FA may be included in the study, and if randomized to the 
control arm, will be treated with irinotecan and cetuximab. 
6.1 
Patient Numbering 
Patients who sign informed consent to participate in Molecular Prescreening will be assigned a 
unique number by IWRS. This number will identify the patient if they decide to participate in 
screening and if they are eventually enrolled into the study. Once a patient is in screening or is 
enrolled in the study, that patient will be identified only by the assigned patient number. Once 
assigned, the patient number must not be reused for any other patient.  
Patients who sign informed consent to enter Screening based on molecular characterization of 
their tumor based on a prior test will be assigned a unique number by IWRS which will identify 
the patient if they are eventually enrolled into the study. Once assigned, the patient number must 
not be reused for any other patient.  
6.2 
Allocation to Treatment 
In Phase 3, patients will be randomized in a 1:1:1 ratio to receive encorafenib + binimetinib + 
cetuximab (Triplet Arm), encorafenib + cetuximab (Doublet Arm) or to the Control Arm 
(irinotecan/cetuximab or FOLFIRI/cetuximab, per Investigator’s choice).  
The number of patients with 2 prior regimens will be limited to 215 after which only patients 
with 1 prior regimen will be 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. 
Randomization will be stratified by ECOG PS (0 or 1), prior use of irinotecan (yes or no), and 
cetuximab source (US-licensed vs. EU-approved). The randomization schedule will be created 
and managed by an independent statistician not assigned to support the study and treatments will 
be assigned according to a computerized central randomization list using an IWRS. 
6.2.1 Treatment Crossover 
Upon implementation of protocol version 8, patients randomized to the Control Arm who meet 
crossover eligibility criteria (Section 5.2.3) may cross over to receive the triplet regimen.  


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6.3 
Doses and Schedule of Administration 
The investigational products in this study are encorafenib and binimetinib, which will be 
administered PO in combination with cetuximab (i.e., encorafenib + binimetinib + cetuximab 
[Safety Lead-in and Triplet Arm] and encorafenib + cetuximab [Doublet Arm]). The comparator 
combination treatment will be the Investigator’s choice of either irinotecan/cetuximab or 
FOLFIRI/cetuximab administered IV (Control Arm) (Table 9).  
Table 9: 
Starting Dose and Treatment Schedule 
Study Treatments 
Pharmaceutical Form and  
Route of Administration 
Dose 
Frequency 
Safety Lead-in and 
Triplet Arm 
 
 
 
Encorafenib 
4 × 75 mg oral capsule  
300 mg 
QD 
Binimetinib 
3 × 15 mg oral film-coated tablet 
45 mg 
BID 
Cetuximab 
IV infusion 
400 mg/m2 initial dose (120-minute infusion), 
then 250 mg/m2 (60-minute infusion) thereafter 
once weekly 
Doublet Arm 
 
 
 
Encorafenib 
4 × 75 mg oral capsule 
300 mg 
QD 
Cetuximab 
IV infusion 
400 mg/m2 initial dose (120-minute infusion), 
then 250 mg/m2 (60-minute infusion) thereafter 
once weekly 
Control Arm 
 
 
 
Irinotecan/Cetuximab 
 
 
Irinotecan 
IV infusion 
180 mg/m2  (90-minute infusion or as per 
institutional standards) 
every 2 weeks 
Cetuximab 
IV infusion 
400 mg/m2 initial dose (120-minute infusion), 
then 250 mg/m2 (60-minute infusion) thereafter 
once weekly 
FOLFIRI/Cetuximab 
 
 
 
Irinotecan 
IV infusion 
180 mg/m2 (90-minute infusion or as per 
institutional standards) 
every 2 weeks 
Folinic acida  
IV infusion 
400 mg/m2 (120-minute infusion or as per 
institutional standards) or maximal dose 
tolerated in a prior regimen 
every 2 weeks 
5-FUa 
IV bolus/IV infusion 
400 mg/m2 initial dose bolus (not to exceed 
15 minutes), then 1200 mg/m2/day x 2 days 
(total 2400 mg/m2 over 46-48 hours) continuous 
infusion or maximal dose tolerated in a prior 
regimen 
every 2 weeks 
Cetuximab 
IV infusion 
400 mg/m2 initial dose (120-minute infusion), 
then 250 mg/m2 (60-minute infusion) thereafter 
once weekly 
Crossover Triplet Regimen 
 
 
 
Encorafenib 
4 × 75 mg oral capsule  
300 mg 
QD 
Binimetinib 
3 × 15 mg oral film-coated tablet 
45 mg 
BID 
Cetuximab 
IV infusion 
250 mg/m2 (60-minute infusion) or the dose 
level the patient was receiving in the Control 
arm prior to crossover 
once weekly 
Patients who experienced unacceptable toxicities requiring 5-FU and FA dose reductions in prior regimens (e.g. as part of 
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6.3.1 Administration of Encorafenib or Encorafenib + Binimetinib 
Encorafenib will be administered on a QD schedule and binimetinib will be administered on a 
BID schedule, both PO as a flat-fixed dose, and not by body weight or body surface area (BSA) 
(Table 9). Binimetinib and encorafenib should be taken without regard to food.  Patients should 
be instructed to swallow the capsules/tablets whole and not to chew or crush them. 
• QD Dosing: Patients should be instructed to take encorafenib capsules daily with a large 
glass of water (~250 mL) in the morning at approximately the same time every day. 
Doses of encorafenib that are omitted for AEs or any other reason can be taken up to 
12 hours prior to the next dose. 
• BID Dosing: Patients should be instructed to take binimetinib tablets 12 ± 2 hours apart 
with a large glass of water (~250 mL) in the morning and in the evening at approximately 
the same times every day. Doses of binimetinib that are omitted for AEs or any other 
reason should not be made up later in the day, or at the end of the dosing period. 
In the Safety Lead-in and Triplet Arm and in Crossover patients, both oral study drugs 
(encorafenib + binimetinib) are to be instructed to be taken together in the morning and only the 
BID administered drug (binimetinib) is to be taken in the evening without regard to food.  
On days when a blood collection is scheduled at the investigational site, patients will take the 
morning dose of encorafenib and binimetinib (as applicable) at the site, after the collection, 
under the supervision of the Investigator or designee. On the evening of the visit day, patients 
will take binimetinib (as applicable) at home. On all other days, patients will take encorafenib 
and binimetinib (as applicable) at home. Predose PK samples for encorafenib and binimetinib 
analysis should be collected just prior to intake of encorafenib and binimetinib (as applicable). 
If a patient vomits at any time after dosing, the dose of study drug should not be re-administered. 
Patients must avoid consumption of grapefruit, pomegranates, star fruits, Seville oranges or 
products containing the juice of each during the entire study and preferably 7 days before the 
first dose of study drugs, due to potential CYP3A4 interaction with the study drugs. Orange juice 
is allowed.  
Encorafenib and binimetinib (if applicable) will be administered at least 30 minutes prior to 
cetuximab.  
The pharmacist or study nurse will ensure that the appropriate dose is dispensed and will provide 
the patient with at least the appropriate number of encorafenib capsules and binimetinib tablets 
(if applicable) for the number of doses to be taken prior to the next scheduled visit. The site 
personnel will train the patient and/or the patient’s caregiver on dosing procedures for the study 
drug. 


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Patients will receive a diary to document self-administered dosing of encorafenib and 
binimetinib (if applicable) in each cycle to include the dose of study drug taken, the date of 
dosing (and times if applicable), and if any doses were missed and the reason for the missed 
dose. One diary will be provided per cycle. Patients will be instructed to return unused 
encorafenib and binimetinib and the patient diary to the site at the end of each cycle. Drug 
accountability must be performed on a regular basis. 
The Investigator or responsible site personnel should instruct the patient to take encorafenib and 
binimetinib (if applicable) as per protocol (promote compliance). The dosage prescribed and 
dispensed to the patient and all dose changes and all missed doses during the study must be 
recorded in the electronic case report form (eCRF).  
6.3.2 Administration of Cetuximab 
Cetuximab will be administered IV weekly on Days 1, 8, 15 and 22 (±3 days) of every 28-day 
cycle at the study site (Table 9) according to institutional standards. The initial cetuximab dose 
(Cycle 1 Day 1) is 400 mg/m2 administered as a 120-minute IV infusion followed thereafter by a 
250 mg/m2 dose administered as a 60-minute IV infusion. The infusion rate should be consistant 
with the local label but should not exceed 10 mg/min. Close monitoring is required during the 
infusion and for at least 1 hour after the end of the infusion. If an infusion reaction occurs while 
cetuximab is being administered, the infusion should be stopped immediately, and the patients 
should be closely monitored and treated in line with institutional standards. Any rechallenge with 
cetuximab following an infusion reaction should be first discussed with the Sponsor. Cetuximab 
administration should be completed 1 hour prior to the start of FOLFIRI or irinotecan infusion 
for Control Arm patients. For patients who cross over from the Control arm, the first dose after 
crossover will be 250 mg/m2 or the dose level the patient was receiving prior to crossover. 
Premedications for routine cetuximab infusions may be used in accordance with the label and 
with the national and/or institutional standards, but preferably be based on a combination of an 
H1 antagonist (e.g., diphenhydramine) and dexamethasone (10 mg IV). Premedications should 
be administered approximately 30 minutes prior to cetuximab infusion. Following cetuximab 
label instructions, medications such as corticosteroids and antihistamines may be administered at 
the discretion of the Investigator to treat an existing infusion reaction, or as premedication for a 
patient who has previously experienced an infusion reaction. Predose PK samples for cetuximab 
analysis should be collected just prior to the beginning of the infusion of cetuximab. 
Doses of cetuximab that are omitted for AEs or any other reason should not be made up. If 
cetuximab is discontinued, the frequency of study visits may be decreased after discussion with 
Sponsor.  


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6.3.3 Administration of Irinotecan 
Irinotecan will be administered IV biweekly on Days 1 and 15 (±3 days) of every 28-day cycle at 
the study site (Table 9) according to institutional standards. The initial irinotecan dose (Cycle 1 
Day 1) is 180 mg/m2 administered as a 90-minute IV infusion or as per institutional standards.  
Doses of irinotecan that are omitted for AEs or any other reason should not be made up.  
6.3.4 
Administration of FOLFIRI 
The starting doses of 5-FU, FA and irinotecan are provided in Table 9. Patients who required 
5-FU and FA dose reductions in prior regimens (e.g., as part of FOLFOX or FOLFOXIRI 
regimens) should be initiated at the doses listed in Table 9 which most closely approximate, 
without exceeding, the previously tolerated dose. In these circumstances, the starting irinotecan 
dose should not be reduced. See Section 6.3.3 for information on the administration of 
irinotecan. 
6.3.4.1 Folinic Acid 
Folinic acid will be administered IV biweekly on Days 1 and 15 (±3 days) of every 28-day cycle 
at the study site (Table 9) according to institutional standards. The initial FA dose is 400 mg/m2 
administered as a 120-minute IV infusion or as per institutional standards. Alternatively FA may 
be administered (via separate infusion lines) concurrently with irinotecan.  
Doses of FA that are omitted for AEs or any other reason should not be made up. 
6.3.4.2 5-Fluorouracil 
5-Fluorouracil will be administered IV biweekly on Days 1 and 15 (±3 days) of every 28-day 
cycle at the study site (Table 9) immediately following completion of the FA infusion according 
to institutional standards. The initial 5-FU dose is 400 mg/m2 bolus (not to exceed 15 minutes) 
administered IV on Days 1 and 15, followed by 1200 mg/m2/day x 2 days (total 2400 mg/m2 
over 46-48 hours) continuous IV infusion or as per institutional standards.  
Doses of 5-FU that are omitted for AEs or any other reason should not be made up. 
6.4 
Dose Modifications 
Patients will be monitored for AEs on an ongoing basis. The severity of AEs will be evaluated 
using the NCI CTCAE, v.4.03. If a patient develops a toxicity, the dose may be modified as 
outlined in Table 16, Table 17, Table 18 and Table 19, which include criteria for interruption and 
reduction of encorafenib and/or binimetinib, cetuximab, FOLFIRI and irinotecan when given 
without 5-FU and FA, respectively. All dose modifications should be based on the worst 
preceding toxicity. All dosing interruptions and modifications must be recorded in the eCRF. 


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In the Safety Lead-in and Triplet Arms and in Crossover patients, if a patient permanently 
discontinues binimetinib due to an AE or clinically significant laboratory value, they may 
continue to receive encorafenib in combination with cetuximab. Due to the lack of efficacy of 
binimetinib, encorafenib, or cetuximab when used as single agents in patients with BRAF-mutant 
mCRC, patients who cannot tolerate these agents in combination with at least one other agent, 
should discontinue study treatment altogether, complete the end of treatment visit and continue 
to be followed for survival (and disease progression, if applicable). 
Cetuximab may be reduced 2 dose levels to a minimum of 150 mg/m2 for AEs or laboratory 
abnormalities (Table 10). When a dose reduction is required because of an AE, no subsequent 
dose re-escalation of cetuximab will be permitted for that patient for the duration of study 
treatment. If after resolution of an AE, treatment is resumed at the same dose, and the same 
toxicity reoccurs with the same severity, any re-initiation of treatment must be at the next lower 
dose level irrespective of duration, with some exceptions for skin toxicity. In addition, a patient 
must discontinue study treatment if, after treatment is resumed at a lower dose of cetuximab, the 
same toxicity reoccurs with the same or worse severity.  
In the Control Arm, irinotecan may be reduced up to 3 dose levels to a minimum dose of 
100 mg/m2 (Table 10). When a dose reduction is required because of an AE, no subsequent dose 
re-escalation will be permitted for the duration of study treatment. If after resolution of an AE, 
treatment is resumed at the same dose and the same toxicity reoccurs with the same severity, any 
re-initiation of treatment must be at the next lower dose level irrespective of duration, with some 
exceptions for skin toxicity. In addition, a patient must discontinue study treatment if, after 
treatment is resumed at a lower dose of irinotecan, the same toxicity reoccurs with the same or 
worse severity. Due to the lack of efficacy of single-agent cetuximab or 5-FU/FA in patients with 
previously treated BRAF-mutant mCRC, patients who cannot tolerate irinotecan either alone or 
as a component of FOLFIRI should discontinue study treatment altogether, complete the end of 
treatment visit and continue to be followed for survival (and disease progression, if applicable). 
For patients in the control arm receiving FOLFIRI an individual patient may have their doses of 
5-FU reduced to the dose levels specified in Table 10. For FOLFIRI dose modification, dose 
modifications of irinotecan, 5-FU bolus or 5-FU infusion are to be made independently, based on 
the specific types of toxicity observed. In general, if a dose is reduced because of toxicity, it is 
not to be re-escalated to the starting level. However, patients who require multiple dose 
reductions during a cycle for a Grade 2 toxicity could, at the investigator’s discretion, begin the 
following cycle at 1 dose level higher than the final dose level during that cycle.  


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Table 10: 
Dose Levels for Dose Modification 
 
Encorafenib 
(mg QD) 
Binimetinib 
(mg BID) 
Cetuximab 
(mg/m2 once 
weekly) 
Irinotecan 
(mg/m2 
every 
2 weeks) 
5-FU 
5-FU Bolus 
(mg/m2 every 
2 weeks) 
5-FU Infusion 
(mg/m2 over  
46-48 hours 
every 2 weeks) 
Starting Dose 
300 
45 
400 initial 
dose then 250 
thereaftera 
180 
400  
2400  
Dose level -1 
225 
30 
200 
150 
200  
2000  
Dose level -2 
150 
15 
150 
120 
0 
1600  
Dose level -3 
 
 
 
100 
0 
1200  
Abbreviations: BID = twice daily; 5-FU = 5-fluorouracil; QD = once daily.  
a 400 mg/m2 initial dose (120-minute infusion), then 250 mg/m2 (60-minute infusion) thereafter. For patients who 
cross over from the Control arm, the first dose after crossover will be 250 mg/m2 or the dose level the patient was 
receiving prior to crossover.  
 
 
If a patient misses > 28 consecutive days of encorafenib, or binimetinib, > 4 consecutive 
cetuximab doses, or 2 consecutive irinotecan, 5-FU or FA doses, as the result of an AE or 
clinically significant laboratory abnormality, then the respective agent should be discontinued. 
As previously noted, due to the lack of efficacy in patients with BRAF-mutant mCRC, patients 
will not be permitted to continue on single agent binimetinib, encorafenib or cetuximab and will 
be discontinued from study treatment altogether, and following completion of the end of 
treatment visit, will continue to be followed for survival (and disease progression, if applicable). 
Patients receiving FOLFIRI may only continue in the study if they are able to continue with 
irinotecan.  
Patients who discontinue study treatment for a study-related AE or an abnormal laboratory value 
must be followed as described in Section 8.6. 
Under special circumstances, when according to the assessment of the Investigator, a patient 
with progression of disease may benefit from continuation of study treatment, treatment beyond 
progression can be considered following discussion with the Sponsor (see Section 4.5).  
6.4.1 Dose Modifications for Encorafenib and/or Binimetinib 
Doses of encorafenib and/or binimetinib should be adjusted for AEs throughout the study 
(Table 16). In general, doses should not be reduced or interrupted for Grade 1 AEs unless the AE 
is a specific ocular AE referred to in Table 16 but treatment to control symptoms should be 
provided as appropriate, if applicable.  


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An individual patient may have their dose of encorafenib and/or binimetinib reduced to the dose 
levels specified in Table 10. The lowest recommended dose level of encorafenib is 150 mg QD 
and the lowest recommended dose level of binimetinib is 15 mg BID. When the AE that resulted 
in a dose reduction improves to and remains stable at the patient’s Baseline for a minimum of 
14 days, the dose can be re-escalated to the next dose level at the discretion of the Investigator, 
provided there are no other concomitant toxicities that would prevent drug re-escalation. There is 
no limit to the number of times the patient can have their dose reduced or re-escalated (in 
increments specified in Table 10); however: 
• No dose re-escalation of encorafenib is allowed after a dose reduction due to prolonged 
QTcF ≥ 501 msec  
• No dose re-escalation of binimetinib is allowed after a dose reduction due to LVEF 
dysfunction or prolonged QTcF ≥ 501 msec 
• No dose re-escalation of binimetinib or encorafenib is allowed after a dose reduction due 
to retinal toxicity ≥ Grade 2. 
Please refer to Table 16 for recommended dose modifications for encorafenib and/or binimetinib, 
if applicable, based on the occurrence of encorafenib and/or binimetinib treatment-related AEs. 
Eye disorders that cannot be specifically graded according to NCI CTCAE, v.4.03 should be 
graded according to Table 11. Serous detachment of the retina should be graded according to 
Table 12. Uveitis should be graded according to NCI CTCAE, v.4.03 as described in Table 13. 
Hand-foot skin reaction should be graded according to NCI CTCAE, v.4.03 as described in 
Table 14. Diarrhea should be graded according to modified NCI CTCAE, v.4.03 as described in 
Table 15. Furthermore, please refer to the following appendices for additional supportive care 
recommended guidelines for the management of cetuximab-induced, encorafenib-induced and/or 
binimetinib-induced skin toxicity (Appendix 1), encorafenib-induced HFSR (Appendix 2), 
binimetinib-induced diarrhea (Appendix 3) and binimetinib-associated interstitial lung 
disease/pneumonitis (Appendix 8). 
Table 11: 
Modified NCI CTCAE, Version 4.03 Grading of Eye Disorders 
Grade 
Description 
1 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living 
3 
Severe or medically significant but not immediately sight threatening; hospitalization or 
prolongation of existing hospitalization indicated; disabling; limiting self-care activities of daily 
living 
4 
Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) in the 
affected eye 


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Table 12: 
NCI CTCAE, Version 4.03 Grading of Serous Detachment of the Retina 
Grade 
Description 
1 
Asymptomatic (but with findings in ocular coherence tomography, fundoscopy and/or slit lamp 
biomicroscopy) 
2 
Symptomatic with moderate decrease in visual acuity (20/40a or better); limiting instrumental 
activities of daily living 
3 
Symptomatic with marked decrease in visual acuity (worse than 20/40a); limiting self-care activities 
of daily living  
4 
Blindness (20/200a or worse) in the affected eye 
Note: For rhegmatogenous retinal detachment, grade according to NCI CTCAE v.4.03 Retinal Detachment. 
a Please refer to Appendix 4 for Snellen Equivalence (Visual Acuity Conversion Chart). 
 
Table 13: 
NCI CTCAE, Version 4.03 Grading of Uveitis 
Grade 
Description 
1 
Asymptomatic; clinical or diagnostic observations only 
2 
Anterior uveitis; medical intervention indicated 
3 
Posterior or pan-uveitis 
4 
Blindness (20/200a or worse) in the affected eye 
a Please refer to Appendix 4 for Snellen Equivalence (Visual Acuity Conversion Chart). 
 
Table 14: 
NCI CTCAE, Version 4.03 Grading of Hand-foot Skin Reaction (HFSR)a 
Grade 
Descriptionb 
1 
Minimal skin changes or dermatitis (e.g., erythema, edema, numbness, dysesthesia, paresthesia, 
tingling or hyperkeratosis) without pain 
2 
Skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting 
instrumental ADL 
3 
Severe skin changes (e.g., peeling, ulceration, blisters, bleeding, edema, or hyperkeratosis) with 
pain; limiting self-care ADL 
Abbreviations: ADL=activities of daily living. 
a HFSR or palmar-plantar erythrodysesthesia syndrome, a disorder characterized by redness, marked discomfort, 
swelling, and tingling in the palms of the hands or the soles of the feet; 
b More specifics examples to Grade 1 and Grade 3 are added to facilitate proper grading [from the sorafenib 
package insert (West Haven, CT: Bayer Pharmaceuticals Corporation; 2007). 
 
Table 15: 
Modified NCI CTCAE, Version 4.03 Grading of Diarrhea 
Grade 
Description 
1 
Increase of < 4 stools per day over Baseline; mild increase in ostomy output compared to Baseline 
2 
Increase of 4-6 stools per day over Baseline; moderate increase in ostomy output compared to 
Baseline 


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Grade 
Description 
1/2 
Complicated  
Definition as above (Grade 1/2) with the following complicating signs/symptoms: 
• 
Moderate to severe cramping 
• 
Grade ≥ 2 nausea/vomiting 
• 
Decreased performance status 
• 
Fever 
• 
Sepsis 
• 
Neutropenia 
• 
Frank bleeding 
• 
Dehydration 
• 
Unresolved diarrhea after 48 hours of treatment with loperamide (including high-dose 
administration) and initiation of second-line treatment 
3 
Increase of ≥ 7 stools per day over Baseline; incontinence; hospitalization indicated; severe increase 
in ostomy output compared to Baseline; limiting self-care activities of daily living 
4 
Life threatening consequences; urgent intervention indicated 
 
 


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Table 16: 
Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 
Worst toxicity 
CTCAE, v.4.03 
Grade  
(unless otherwise 
specifieda) 
Dose Modification for Encorafenib (Doublet Arm, Triplet Arm and Crossover 
Patients) 
and for Binimetinib (Triplet Arm and Crossover Patients) 
Eye Disorders - Retinal Events (including serous detachment of the retina), Posterior Uveitisc 
Note: Results and images of ocular coherence tomography (OCT) must be made available upon request. 
Any visual acuity impairment at screening should be documented and should be considered as baseline. 
Grade 1 
Maintain dose levels of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days 
• 
If patient remains asymptomatic (Grade 1), maintain dose level of encorafenib and 
binimetinib and continue the schedule of visual assessments established per 
protocol 
• 
If patient becomes symptomatic (blurred vision, photophobia, etc.) or visual acuity 
assessment shows Grade 2, follow Grade 2 dose guidelines below 
Grade 2 
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days 
• 
If resolved to baseline or Grade ≤ 1, resume treatment at current dose level of 
encorafenib and binimetinib and continue the schedule of visual assessments 
established per protocol 
• 
If not resolved to baseline or Grade ≤ 1, resume treatment at 1 reduced dose levelb 
of encorafenib and binimetinib and continue the schedule of visual assessments 
established per protocol 
• 
If posterior uveitis lasts > 6 weeks, permanently discontinue binimetinib and 
encorafenib. 
Grade 3 
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days: 
• 
If posterior uveitis resolves to Baseline or Grade ≤ 1 in < 6 weeks, resume 
treatment at 1 reduced dose levelb of encorafenib and binimetinib and continue the 
schedule of visual assessments established per protocol  
• 
If posterior uveitis does not resolve to Baseline or Grade ≤ 1 in < 6 weeks, 
permanently discontinue binimetinib and encorafenib 
• 
If resolved to baseline or Grade ≤ 2, resume treatment at 1 reduced dose levelb of 
encorafenib and binimetinib and continue the schedule of visual assessments 
established per protocol  
• 
If not resolved to baseline or Grade ≤ 2, continue the interruption and repeat the 
ophthalmic assessment in 10 days. 
o 
If resolved to baseline or Grade ≤ 2, resume treatment at 1 reduced dose 
levelb of encorafenib and binimetinib and continue the schedule of visual 
assessments established per protocol 
o 
If remains Grade 3, permanently discontinue encorafenib and binimetinib 
Grade 4 
Permanently discontinue encorafenib and binimetinib and immediate follow-up with 
ophthalmic monitoringc 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
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Worst toxicity 
CTCAE, v.4.03 
Grade  
(unless otherwise 
specifieda) 
Dose Modification for Encorafenib (Doublet Arm, Triplet Arm and Crossover 
Patients) 
and for Binimetinib (Triplet Arm and Crossover Patients) 
Eye Disorder - RVOc 
Note: Results and images of ophthalmic examinations should be made available upon request. This includes 
scans/images of fluorescein angiography should a patient be assessed using this technique. 
RVO of any grade 
Permanently discontinue encorafenib and binimetinib and immediately follow-up with 
ophthalmic monitoringc 
Other Eye Disorders (i.e., Non-retinal Events) 
Grade 1 – 2 
Maintain dose level of encorafenib and binimetinib and increase frequency of ophthalmic 
monitoring to at least every 14 days until stabilization or resolution 
Grade 3 
Interrupt dosing of encorafenib and binimetinib and refer patient to ophthalmologist within 
7 daysc: 
• 
If resolved to Grade ≤ 1 in ≤ 21 days, resume treatment at 1 reduced dose levelb of 
encorafenib and binimetinib 
• 
If not resolved to Grade ≤ 1 in ≤ 21 days, permanently discontinue encorafenib 
and binimetinib and close follow-up with ophthalmic monitoring until stabilization 
or resolutionc 
Grade 4 
Permanently discontinue encorafenib and binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolutionc 
Liver-related Adverse Events 
Grade 1  
AST or ALT  
> ULN to 3 × ULN 
Maintain dose level of encorafenib and binimetinib  
Grade 2 
AST or ALT  
> 3 to 5.0 × ULN or  
3 × baseline valued 
AND  
blood bilirubing  
≤ 2.0 × ULN 
 
 
 
 
 
Maintain dose level of encorafenib and interrupt dosing of binimetinib until resolved to 
Grade ≤ 1 (or Grade ≤ 2 in case of liver metastasis), then: 
• 
If resolved in ≤ 14 days, maintain dose level of encorafenib and binimetinib 
• 
If not resolved in ≤ 14 days, interrupt dose of encorafenib (in addition to prior 
binimetinib) until resolved to Grade ≤ 1 (or Grade ≤ 2 in case of liver metastasis), 
then resume treatment at current dose level of encorafenib and 1 reduced dose 
levelb of binimetinib 
If additional occurrence:  
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 (or 
Grade ≤ 2 in case of liver metastasis), then resume treatment at 1 reduced dose 
levelb of encorafenib and binimetinib 
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
Investigator’s discretion, with encorafenib being resumed alone for one week before 
resuming binimetinib treatment 
AST or ALT  
> 3.0 to 5.0 × ULN 
AND  
blood bilirubing 
 > 2.0 × ULN 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1, then: 
• 
If resolved in ≤ 7 days, resume treatment at 1 reduced dose levelb of encorafenib 
and binimetinib 
• 
If not resolved in ≤ 7 days, permanently discontinue encorafenib and binimetinib 
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
investigator’s discretion, with encorafenib being resumed alone for one week before 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
112 
 
11 July 2019 
Worst toxicity 
CTCAE, v.4.03 
Grade  
(unless otherwise 
specifieda) 
Dose Modification for Encorafenib (Doublet Arm, Triplet Arm and Crossover 
Patients) 
and for Binimetinib (Triplet Arm and Crossover Patients) 
resuming binimetinib treatment 
Grade 3 
AST or ALT  
> 5.0 to 8.0 × ULN)  
AND  
blood bilirubing  
≤ 2.0 × ULN 
 
 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 (or Grade ≤ 2 in 
case of liver metastasis), then: 
• 
If resolved in ≤ 14 days, resume treatment at current dose level of encorafenib and 
binimetinib 
• 
If not resolved in ≤ 14 days, resume treatment at 1 reduced dose levelb of 
encorafenib and binimetinib 
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
investigator’s discretion, with encorafenib being resumed alone for one week before 
resuming binimetinib treatment 
 
If additional occurrence: 
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 (or 
Grade ≤ 2 in case of liver metastasis), then resume treatment at 1 reduced dose 
levelb of encorafenib and binimetinib 
AST or ALT  
>8 × ULN  
AND blood 
bilirubing  
≤ 2.0 × ULN 
Permanently discontinue encorafenib and binimetinib 
AST or ALT  
> 5.0 × ULN 
AND  
blood bilirubing  
> 2.0 × ULN 
Permanently discontinue encorafenib and binimetinib 
Grade 4  
AST or ALT  
> 20.0 × ULN 
Permanently discontinue encorafenib and binimetinib 
Cardiac Disorders - Left Ventricular Systolic Dysfunctiona (Dose Adjustment for Binimetinib ONLY) 
Asymptomatic 
absolute decrease 
of > 10% in LVEF 
compared to baseline 
and the LVEF is 
below the 
institution’s LLN 
(e.g., a decrease of 
60% to 48% is an 
absolute decrease of 
12%) 
Interrupt dosing of binimetinib and repeat evaluation of LVEF within 2 weeks 
• 
If the LVEF recovers (defined as LVEF ≥ 50% or ≥ LLN and absolute decrease  
≤ 10% compared to baseline) ≤ 21 days, resume treatment at 1 reduced dose levelb 
of binimetinib after approval of the Sponsor Medical Monitor. Monitor LVEF 2 
weeks after resuming binimetinib, every 4 weeks for 12 weeks and subsequently 
as per protocol 
• 
If the LVEF does not recover in ≤ 21 days, permanently discontinue binimetinib. 
Closely monitor LVEF until resolution or for up to 16 weeks 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
113 
 
11 July 2019 
Worst toxicity 
CTCAE, v.4.03 
Grade  
(unless otherwise 
specifieda) 
Dose Modification for Encorafenib (Doublet Arm, Triplet Arm and Crossover 
Patients) 
and for Binimetinib (Triplet Arm and Crossover Patients) 
Grade 3 – 4 
Permanently discontinue binimetinib. Closely monitor LVEF until resolution or up to 
16 weeks 
Note: Copies of ECHO and/or MUGA scans could be requested for patients to be available 
to the Sponsor for patients with absolute decrease of >10% in LVEF compared to baseline 
and LVEF < 50% or LLN 
CK Elevation  
Grade 1-2 
Maintain dose of encorafenib and binimetinib. Ensure patient is adequately hydrated. 
Closely monitor CK and serum creatinine 
• 
If total CK ≥ 3 × ULN, measure CK isoenzymes and myoglobin in blood or urine 
Grade 3 
> 5.0 - 10.0 x ULN 
without  
renal impairment 
(i.e., serum creatinine 
< 1.5 × ULN or  
1.5 × baseline) 
If asymptomatic, maintain dosing of encorafenib and binimetinib. Ensure patient is 
adequately hydrated. Monitor and measure isoenzymes and myoglobin in blood or urine 
and serum creatinine 
 
If symptomatic (muscle pain/spasms/muscle weakness), maintain dosing of encorafenib 
and interrupt dosing of binimetinib until resolved to CTCAE Grade ≤ 1 and monitor 
closely, then: 
• 
If resolved in ≤ 21 days, maintain dose of encorafenib and resume treatment at 
1 reduced dose levelb of binimetinib 
• 
If not resolved in ≤ 21 days, maintain dose of encorafenib and permanently 
discontinue binimetinib 
Grade 4  
without  
renal impairment 
(i.e., serum creatinine 
< 1.5 × ULN or  
1.5 × baseline) 
If asymptomatic, maintain dose of encorafenib and interrupt dosing of binimetinib. Ensure 
patient is adequately hydrated. Monitor and measure isoenzymes and myoglobin in blood 
or urine and serum creatinine 
• 
If resolved in ≤ 21 days, maintain dose of encorafenib and resume treatment at 
1 reduced dose levelb of binimetinib 
• 
If not resolved in ≤ 21 days, maintain dose of encorafenib and permanently 
discontinue binimetinib 
If symptomatic (muscle pain/spasms/muscle weakness), maintain dose of encorafenib and 
permanently discontinue binimetinib 
Grade 3 or 4  
with  
renal impairment 
(i.e., serum creatinine 
≥ 1.5 × ULN or  
1.5 × baseline) 
Interrupt dosing of encorafenib and binimetinib until resolved to CTCAE Grade < 1 or 
baseline level. Ensure patient is adequately hydrated. Monitor closely and measure 
isoenzymes and myoglobin in blood or urine and serum creatinine, then: 
• 
If resolved in ≤ 21 days, consider resuming treatment at 1 reduced dose levelb of 
encorafenib and binimetinib 
• 
If not resolved in ≤ 21 days, permanently discontinue encorafenib and binimetinib 
2nd occurrence: 
• 
Permanently discontinue encorafenib and binimetinib 
Cardiac Investigation – Prolongation of the QT interval QTcF value 
QTcF > 500 ms 
during treatment and 
change from pre-
treatment value 
remains ≤ 60 ms 
Patients should have regular ECG monitoring (continuous where appropriate) until an 
adequately trained physician (such as a cardiologist or internist) has reviewed the data.  
Electrolyte abnormalities including magnesium should be corrected and cardiac risk factors 
for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. 
1st occurrence:  


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
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11 July 2019 
Worst toxicity 
CTCAE, v.4.03 
Grade  
(unless otherwise 
specifieda) 
Dose Modification for Encorafenib (Doublet Arm, Triplet Arm and Crossover 
Patients) 
and for Binimetinib (Triplet Arm and Crossover Patients) 
• 
Temporarily interrupt dosing of encorafenib and binimetinib until QTcF < 500 ms. 
Then resume treatment at 1 reduced dose levelb of encorafenib and binimetinib 
2nd occurrence: 
• 
Temporarily interrupt dosing of encorafenib and binimetinib treatment until QTcF 
< 500 ms. Then resume treatment at 1 reduced dose levelb of encorafenib and 
binimetinib. If a patient restarts binimetinib and encorafenib following resolution 
of Grade 3 QTcF prolongation event, the patient should be evaluated with 
triplicate predose ECGs on Day 1 of the next cycle, followed by a single postdose 
ECG and a single predose ECG on Day 15, as well as triplicate predose ECGs and 
a single postdose ECG on Days 1 and 2 of the subsequent cycle (2nd cycle after 
the Grade 3 QT prolongation event). 
3rd occurrence:  
• 
Permanently discontinue encorafenib and binimetinib 
QTcF increase during 
treatment is both > 
500 ms and > 60 ms 
change from 
pre-treatment values  
Patients should have regular ECG monitoring (continuous where appropriate) until an 
adequately trained physician (such as a cardiologist or internist) has reviewed the data.  
Electrolyte abnormalities including magnesium should be corrected and cardiac risk factors 
for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. 
• 
Permanently discontinue encorafenib and binimetinib 
Rash [see cetuximab dose modifications (Table 17) and Appendix 1] 
Grade 1 
Maintain dose level of encorafenib and binimetinib 
Initiate Initial Rash Treatment Regimen if it was not already started and rash should be 
closely monitored 
Grade 2  
1st occurrence:  
• 
Maintain dose level of encorafenib and binimetinib 
• 
Initiate Initial Rash Treatment Regimen if it was not already started and rash 
should be closely monitored 
• 
Reassess within ≤ 14 days. If rash worsens or does not improve, interrupt dosing 
of encorafenib and binimetinib until resolved to Grade ≤ 1. Then resume treatment 
at current dose level of encorafenib and binimetinib. For dermatitis acneiform, 
treatment with encorafenib may be maintained if, in the judgment of the 
investigator, the rash is considered to be unrelated to encorafenib. If treatment 
with encorafenib was maintained and no improvement within 8 days, interrupt 
dosing of encorafenib 
 
2nd occurrence: 
• 
Reassess within ≤ 14 days. If rash worsens or does not improve, interrupt dosing 
of encorafenib and binimetinib until resolved to Grade ≤ 1. Then resume treatment 
at current dose level of encorafenib and 1 reduced dose levelb of binimetinib. For 
dermatitis acneiform rash, treatment with encorafenib may be maintained if, in the 
judgment of the investigator, the rash is considered to be unrelated to encorafenib. 
If treatment with encorafenib was maintained and no improvement within 8 days, 
interrupt dosing of encorafenib 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
115 
 
11 July 2019 
Worst toxicity 
CTCAE, v.4.03 
Grade  
(unless otherwise 
specifieda) 
Dose Modification for Encorafenib (Doublet Arm, Triplet Arm and Crossover 
Patients) 
and for Binimetinib (Triplet Arm and Crossover Patients) 
Grade 3 
1st occurrence:  
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. 
Reassess weekly. Then resume treatment at current dose level of encorafenib and 
binimetinib. 
• 
Consider referral to dermatologist and manage rash per dermatologist’s 
recommendation. 
2nd occurrence:  
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then 
resume treatment at 1 reduced dose levelb of encorafenib and binimetinib. 
Resume treatment with encorafenib at the same dose level if, in the judgment of 
the Investigator, the rash is considered to be unrelated to encorafenib 
• 
Consider referral to dermatologist and manage rash per dermatologist’s 
recommendation 
Grade 4 
Permanently discontinue encorafenib and binimetinibf 
Hand-foot Skin Reaction (HFSR)/Palmar-plantar Erythrodysesthesia Syndromee (Dose Adjustment for 
Encorafenib ONLY) (See Appendix 2) 
Grade 1 
Maintain dose of encorafenib. Promptly institute supportive measures, such as topical 
therapy, for symptomatic relief. Give instruction on life-style modifications.  
Grade 2  
1st occurrence:  
• 
Maintain dose of encorafenib and HFSR should be closely monitored. Promptly 
institute supportive measures, such as topical therapy, for symptomatic relief. Give 
instruction on life-style modifications. 
• 
If no improvement ≤ 14 days, interrupt dosing of encorafenib until resolved to 
Grade ≤ 1. Resume treatment with encorafenib at current dose level. Continue 
supportive measures, such as topical therapy, for symptomatic relief. Give 
instruction on life-style modifications. 
Additional occurrence:  
• 
Treatment with encorafenib may be maintained or interrupted based upon the 
Investigator’s discretion. Continue supportive measures, such as topical therapy, 
for symptomatic relief. Give instruction on life-style modifications. 
• 
If interrupted dosing of encorafenib per investigator’s judgment, interrupt until 
resolved to Grade ≤ 1. Resume treatment with encorafenib at the same dose level 
or 1 reduced dose levelb based upon the Investigator’s discretion. 
Grade 3 
1st or additional occurrence:  
• 
Interrupt dosing of encorafenib until resolved to Grade ≤ 1. Promptly initiate 
supportive measures, such as topical therapy, for symptomatic relief. Give 
instruction on life-style modifications. Reassess the patient weekly. 
Then resume treatment at one reduced dose levelb of encorafenib 
• 
Consider referral to dermatologist and manage HFSR per dermatologist’s 
recommendation 
> 3nd occurrence: 
• 
Interrupt dosing of encorafenib until resolved to Grade ≤ 1, decision to resume 
treatment with encorafenib at one reduced dose levelb or permanently discontinue 
encorafenib should be based upon the Investigator’s discretion. 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
116 
 
11 July 2019 
Worst toxicity 
CTCAE, v.4.03 
Grade  
(unless otherwise 
specifieda) 
Dose Modification for Encorafenib (Doublet Arm, Triplet Arm and Crossover 
Patients) 
and for Binimetinib (Triplet Arm and Crossover Patients) 
SCC, KA and any Other Suspicious Skin Lesion (Dose Adjustment for Encorafenib ONLY) 
Grade ≤ 3 
Maintain dose of encorafenib (dose interruptions or modifications are not required). 
Treatment of SCC, KA, and any other suspicious skin lesion (eg. new primary melanoma) 
should occur based upon institutional practice.  
Diarrhea (See Appendix 3) 
Uncomplicated  
Grade 1-2 
Maintain dose of encorafenib. Consider temporary interruption of binimetinib until 
resolved to Grade ≤ 1. Then resume treatment at current dose level of binimetinib 
Complicated 
Grade 1-2 
Consider temporary interruption of encorafenib until resolved to Grade ≤ 1. Then resume 
treatment at current dose level of encorafenib 
Interrupt dosing of binimetinib until resolved to Grade ≤ 1. Then resume treatment at 
1 reduced dose levelb of binimetinib 
Grade 3-4 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then resume 
treatment at current dose level of encorafenib if, in the judgment of the Investigator, the 
toxicity is considered to be unrelated to encorafenib, or at one reduced dose levelb. Resume 
treatment at 1 reduced dose levelb of binimetinib 
Nausea/Vomiting 
Grade 1-2 
Maintain dose level of encorafenib and binimetinib. Promptly institute antiemetic measure.  
Grade 3 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then resume 
treatment at 1 reduced dose levelb of encorafenib. Resume treatment with binimetinib at the 
current dose if, in the judgment of the Investigator, the toxicity is considered to be 
unrelated to binimetinib, or at 1 reduced dose levelb. 
Note: Interrupt dosing of encorafenib and binimetinib for ≥ Grade 3 vomiting or Grade 3 
nausea only if the vomiting or nausea cannot be controlled with optimal antiemetics (as per 
local practice) 
Grade 4 
Permanently discontinue encorafenib and binimetinibf 
Interstitial lung disease/pneumonitis (See Appendix 8) 
Grade 1 
Maintain dose level of encorafenib and binimetinib. Monitor weekly. 
Grade 2 
Maintain dose of encorafenib. Withhold binimetinib for up to 3 weeks. 
If improved to Grade 0 or 1, resume treatment at 1 reduced dose level of binimetinib. 
If not resolved within 3 weeks, permanently discontinue binimetinib. 
Grade 3-4 
Permanently discontinue binimetinib. 
All Other Adverse Events (Suspected To Be Related To Encorafenib and/or Binimetinib) 
Grade 1-2 
If the event is a persistent Grade 2 AE not responsive to a specific therapy, consider 
interruption or reduction of encorafenib and binimetinib, as applicable 
Grade 3 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤1 or to 
pretreatment/baseline level. If the event resolves ≤ 21 days, then study drug may be 
resumed at 1 reduced dose levelb based upon the Investigator’s discretion. 
Grade 4 
Permanently discontinue encorafenib and binimetinibf 
a Not according to NCI CTCAE. 
b Dose reduction below 150 mg QD for encorafenib, and below 15 mg BID for binimetinib is not allowed. 
c Ophthalmic monitoring mandated for retinal events, posterior uveitis, RVO: further evaluation with specialized 
retinal imaging (e.g. ocular coherence tomography, fluorescein angiography). Any diagnosis of retinal events must 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
117 
 
11 July 2019 
Worst toxicity 
CTCAE, v.4.03 
Grade  
(unless otherwise 
specifieda) 
Dose Modification for Encorafenib (Doublet Arm, Triplet Arm and Crossover 
Patients) 
and for Binimetinib (Triplet Arm and Crossover Patients) 
be supported by presence or absence of symptoms, visual acuity assessment and findings in OCT. 
d For patients enrolled with liver metastases and baseline LFT elevations. 
e Disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands 
or the soles of the feet. 
f A patient with a Grade 4 AE may resume treatment at the lower dose level if the AE recovers to Grade ≤ 1 within 
28 days of discontinuing drug and, if in the opinion of the Investigator and Sponsor Medical Monitor, the event is 
not life-threatening and the patient can be managed and monitored for recurrence of AE. Any patients requiring a 
treatment interruption of duration > 28 days must discontinue study drug permanently. 
g Refers to total bilirubin. 
 
6.4.2 Dose Modifications for Cetuximab 
Recommended dose modifications for cetuximab based on the occurrence of cetuximab 
treatment-related AEs are summarized in Table 17. Appendix 1 contains recommended 
guidelines for prophylactic and symptomatic treatment of cetuximab-induced rash.   
Table 17: 
Recommended Dose Modifications for Cetuximab-related Adverse Events 
Worst toxicity 
CTCAE, v.4.03 Grade 
Dose Modification for Cetuximab During a Cycle of Therapy 
Infusion Reaction 
If an infusion reaction occurs while cetuximab is being infused, the infusion should be 
stopped immediately and the patient should be evaluated. 
Grade 1 or 2 
 
Restart and complete the disrupted infusion at the discretion of the Investigator. The 
infusion must be restarted at a reduced rate. Additional pre-medications such as 
antihistamines or low-dose systemic corticosteroids may be administered when the 
infusion is restarted per instutional standards. 
All subsequent infusions must also be administered at the reduced rate. 
Grade 3 or 4 
Permanently discontinue cetuximab 
Rash [see encorafenib and/or binimetinib dose modifications (Table 16)] 
Grade 1 or 2 
Maintain dose level; consider initiating appropriate therapy (such as antihistamines, 
topical corticosteroids, and low-dose systemic corticosteroids) 
Grade 3, despite therapy 
Omit dose until resolved to ≤ Grade 2, then: 
• 
If resolved in ≤ 7 days (or ≤ 14 days for acneiform rash), then maintain dose 
level 
• 
If not resolved in ≤ 7 days despite appropriate skin toxicity therapy (or 
≤ 14 days for acneiform rash), then permanently discontinue cetuximab 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
118 
 
11 July 2019 
Worst toxicity 
CTCAE, v.4.03 Grade 
Dose Modification for Cetuximab During a Cycle of Therapy 
Grade 3 recurrent 
Omit dose until resolved to ≤ Grade 2, then: 
• 
If resolved in ≤ 7 days (or ≤ 14 days for acneiform rash), then decrease 1 dose 
level 
• 
If not resolved in ≤ 7 days despite appropriate skin toxicity therapy (or 
≤ 14  days for acneiform rash), then permanently discontinue cetuximab 
• 
Permanently discontinue cetuximab after 3rd recurrence (upon 4th 
occurrence) 
Grade 4, despite skin 
toxicity therapy 
Permanently discontinue cetuximab 
 
6.4.3 Dose Modifications for FOLFIRI Treatment 
Recommended dose modifications for 5-FU and irinotecan based on the occurrence of FOLFIRI 
treatment-related AEs are summarized in Table 18. No dose modifications are implemented for 
FA. If 5-FU is held or omitted, then FA should also be held or omitted, accordingly.  
Table 18: 
Recommended Dose Modifications for 5-FU and Irinotecan 
Treatment-related Adverse Events During FOLFIRI Treatment 
Worst toxicity 
CTCAE, v.4.03 Grade (value) 
Dose Modification for 5-FU and 
Irinotecan During a Cycle of 
FOLFIRI Therapy 
At Start of Next Cycles of FOLFIRI 
Therapy (After Adequate 
Recovery), Compared with Starting 
Dose in Previous Cycle 
Dose modifications below are for both 5-FU and irinotecan unless otherwise noted. 
Hematologic Toxicities 
A new cycle of therapy should not begin until the absolute neutrophil count (ANC) has recovered to ≥ 1500/mm3 
and the platelet count has recovered to ≥ 100,000/mm3. Treatment should be delayed 1-2 weeks to allow for 
recovery from treatment-related toxicities, unless otherwise noted. If the patient has not recovered after a 28-day 
delay, consideration should be given to discontinuing FOLFIRI. 
Neutropenia 
 
 
Grade 1 (1500 to 1999/mm3) 
Maintain dose level 
Maintain dose level 
Grade 2 (1000 to 1499/mm3) 
Decrease 1 dose level 
Maintain dose level 
Grade 3 (500 to 999/mm3) 
Omit dose until resolved to ≤ Grade 
1a, then decrease 1 dose level 
Decrease 1 dose level 
Grade 4 (< 500/mm3) 
Omit dose until resolved to ≤ Grade 
1a, then decrease 2 dose levels 
Decrease 2 dose levels 
Thrombocytopenia 
 
 
Grade 1 (< LLN to 75,000/mm3) 
Maintain dose level 
Maintain dose level 
Grade 2 (75,000 to 50,000/mm3) 
Decrease 1 dose level 
Maintain dose level 
Grade 3 (50,000 to 25,000/mm3) 
Omit dose until resolved to ≤ Grade 2, 
Decrease 1 dose level 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
119 
 
11 July 2019 
Worst toxicity 
CTCAE, v.4.03 Grade (value) 
Dose Modification for 5-FU and 
Irinotecan During a Cycle of 
FOLFIRI Therapy 
At Start of Next Cycles of FOLFIRI 
Therapy (After Adequate 
Recovery), Compared with Starting 
Dose in Previous Cycle 
then decrease 1 dose level 
Grade 4 (< 25,000/mm3) 
Omit dose until resolved to ≤ Grade 2, 
then decrease 2 dose levels 
Decrease 2 dose levels 
Neutropenic Fever 
Omit dose until resolved to ≤ Grade 1a 
ANC and platelet count (for a 
maximum time of two, 2-week 
treatments [approx 28 days]), then 
decrease 2 dose levels 
Decrease 2 dose levels 
 
Other Hematologic Toxicities 
Dose modifications for leukopenia and anemia during a cycle of therapy and at 
the start of subsequent cycles of therapy are also based on CTCAE toxicity 
criteria and are the same as those recommended for neutropenia as above. 
Diarrhea 
 
 
A new cycle of therapy should not begin until the treatment-related diarrhea has recovered to ≤ Grade 1 diarrhea. 
Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has 
not recovered after a 14-day delay, consideration should be given to discontinuing FOLFIRI. 
Grade 1 (2-3 stools/day > pretx) 
Maintain dose level 
Both - Maintain dose level 
Grade 2 (4-6 stools/day > pretx) 
Decrease 1 dose level 
5-FU - Decrease 1 dose 
Irinotecan - Maintain dose level 
Recurrent Grade 2 (4-6 stools 
/day > pretx) 
Decrease 1 dose level 
Both - Decrease 1 dose level 
Grade 3 (7-9 stools/day > pretx) 
Omit dose until resolved to ≤ Grade 1, 
then decrease 1 dose level 
Both - Decrease 1 dose level 
Grade 4 (≥ 10 stools/day > pretx) 
Omit dose until resolved to ≤ Grade 1 
(for a maximum time of two, 2-week 
treatments [approx 28 days]), then 
decrease 2 dose levels 
Both - Decrease 2 dose levels 
Mucositis (Dose Adjustment for 5-FU ONLY) 
 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
Decrease 1 dose level 
Decrease 1 dose level 
Recurrent Grade 2 
Decrease 1 dose level 
Decrease 2 dose levels  
Grade 3  
Omit dose until resolved to ≤ Grade 1, 
then decrease 1 dose level 
 
If unresolved to ≤ Grade 1, omit dose 
for maximum of 28 days, then 
decrease 2 dose levels  
Grade 4 
Omit dose until resolved to ≤ Grade 1 
(for a maximum time of two, 2-week 
treatments [approx 28 days]), then 
decrease 2 dose levels 
If unresolved to ≤ Grade 1, omit dose 
for maximum of 28 days, then 
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Worst toxicity 
CTCAE, v.4.03 Grade (value) 
Dose Modification for 5-FU and 
Irinotecan During a Cycle of 
FOLFIRI Therapy 
At Start of Next Cycles of FOLFIRI 
Therapy (After Adequate 
Recovery), Compared with Starting 
Dose in Previous Cycle 
Nausea/Vomiting (Dose reductions should occur only if symptoms persist despite 2 treatments with adequate 
[combination] antiemetic treatment.)  
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
Maintain dose level 
Maintain dose level 
Grade 3  
5-FU - Maintain dose level  
Irinotecan - Decrease 1 dose level 
5-FU - Maintain dose level  
Irinotecan - Decrease 1 dose level 
Grade 4 
5-FU - Decrease 1 dose level 
Irinotecan - Decrease 1 dose level 
5-FU - Decrease 1 dose level 
Irinotecan - Decrease 1 dose level 
Skin Toxicity (Including Palmar Plantar Erythrodysesthesia) (Dose Adjustment for 5-FU ONLY) 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
Maintain dose level 
Maintain dose level 
Grade 3  
Omit dose until resolved to ≤ Grade 1 
(for a maximum time of two, 2-week 
treatments [approx 28 days]), then 
decrease 1 dose level 
Decrease 1 dose level 
Grade 4 
Omit dose until resolved to ≤ Grade 1 
(for a maximum time of two, 2-week 
treatments [approx 28 days]), then 
decrease 2 dose levels 
Decrease 2 dose levels 
Cardiac Toxicity (Dose Adjustment for 5-FU ONLY) 
Grade ≥ 2 
Discontinue 5-FU 
Neurocerebellar Toxicity (Dose Adjustment for 5-FU ONLY) 
Any grade 
Discontinue 5-FU 
Other Nonhematologicb Toxicities 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
Maintain dose level 
Maintain dose level 
Grade 3  
Omit dose until resolved to ≤ Grade 1, 
then decrease 1 dose level 
Decrease 1 dose level 
Grade 4 
Omit dose until resolved to ≤ Grade 1, 
then decrease 1 dose level 
Decrease 1 dose level 
Abbreviations: approx = approximately, ANC = absolute neutrophil count, LLN = lower limit of normal, pretx = 
pretreatment. 
a If a dose delay is required due to any grade of neutropenia prophylactic use of granulocyte colony-stimulating 
factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) prior to the next administration 
of FOLFIRI is permitted at the Investigator’s discretion. (Smith et al. 2015 ASCO) 
b Excludes alopecia, anorexia, or asthenia. 
 


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6.4.4 Dose Modifications for Irinotecan When Given Without 5-FU and FA 
Recommended dose modifications for irinotecan when given without 5-FU or FA based on the 
occurrence of irinotecan treatment-related AEs are summarized in Table 19. 
Table 19: 
Recommended Dose Modifications for Irinotecan Treatment-related Adverse 
Events When Given Without 5-FU and FA 
Worst toxicity 
CTCAE, v.4.03 Grade (value) 
Dose Modification for Irinotecan  
During a Cycle of Therapy 
At Start of Next Cycles of 
Therapy (After Adequate 
Recovery) Compared with 
Starting Dose in Previous Cycle 
Hematologic Toxicities 
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥ 1500/mm3 and the platelet 
count has recovered to ≥ 100,000/mm3. Treatment should be delayed 1 to 2 weeks to allow for recovery from 
treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to 
discontinuing irinotecan. 
Neutropenia 
 
 
Grade 1 (1500 to 1999/mm3) 
Maintain dose level 
Maintain dose level 
Grade 2 (1000 to 1499/mm3) 
Decrease 1 dose level 
Maintain dose level 
Grade 3 (500 to 999/mm3) 
Omit dose until resolved to ≤ Grade 2a, 
then decrease 1 dose level 
Decrease 1 dose level 
Grade 4 (< 500/mm3) 
Omit dose until resolved to ≤ Grade 2a, 
then decrease 2 dose levels 
Decrease 2 dose levels 
Neutropenic Fever 
Omit dose until resolved, then decrease 2 
dose levels 
Decrease 2 dose levels 
Other Hematologic Toxicities 
Dose modifications for leukopenia, thrombocytopenia, and anemia during a 
cycle of therapy and at the start of subsequent cycles of therapy are also based 
on CTCAE toxicity criteria and are the same as those recommended for 
neutropenia as above. 
Diarrhea 
 
 
A new cycle of therapy should not begin until the treatment-related diarrhea has recovered to ≤ Grade 1 diarrhea. 
Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has 
not recovered after a 14-day delay, consideration should be given to discontinuing irinotecan. 
Grade 1 (2-3 stools/day > pretx) 
Maintain dose level 
Maintain dose level 
Grade 2 (4-6 stools/day > pretx) 
Decrease 1 dose level 
Maintain dose level 
Recurrent Grade 2 (4-6 stools /day 
> pretx) 
Decrease 1 dose level 
Decrease 1 dose level 
Grade 3 (7-9 stools/day > pretx) 
Omit dose until resolved to ≤ Grade 2, 
then decrease 1 dose level 
Decrease 1 dose level 
Grade 4 (≥ 10 stools/day > pretx) 
Omit dose until resolved to ≤ Grade 2 
then decrease 2 dose levels 
Decrease 2 dose levels 


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Worst toxicity 
CTCAE, v.4.03 Grade (value) 
Dose Modification for Irinotecan  
During a Cycle of Therapy 
At Start of Next Cycles of 
Therapy (After Adequate 
Recovery) Compared with 
Starting Dose in Previous Cycle 
Other Nonhematologicb Toxicities 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
Decrease 1 dose level 
Decrease 1 dose level 
Grade 3  
Omit dose until resolved to ≤ Grade 2, 
then decrease 1 dose level 
Decrease 1 dose level 
Grade 4 
Omit dose until resolved to ≤ Grade 2, 
then decrease 2 dose levels 
Decrease 2 dose levels 
Abbreviations: approx = approximately; pretx = pretreatment. 
a If a dose delay is required due to any grade of neutropenia prophylactic use of granulocyte colony-stimulating factor (G-CSF) 
and granulocyte-macrophage colony stimulating factor (GM-CSF) prior to the next administration of FOLFIRI is permitted at 
the Investigator’s discretion. (Smith et al. 2015 ASCO) 
b Excludes alopecia, anorexia, or asthenia. 
 
6.5 
Concomitant Medications/Therapies 
6.5.1 Permitted Concomitant Medications/Therapies 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient is permitted, unless otherwise specified. Additional information regarding concomitant 
medications/therapies is provided in the Investigator’s Brochures for encorafenib and binimetinib 
and the cetuximab and irinotecan locally approved labels. 
Patients receiving medications outlined below must be carefully monitored for potentiating of 
toxicity due to any individual concomitant medication and may require dose titration of the drug 
substance. Investigators should use caution when prescribing concomitant medications, as 
clinical experience with these compounds in patients with cancer is often limited. Investigators 
should contact the Sponsor when they are unsure whether a drug should be prescribed to a 
patient in the clinical study. All concomitant medications/therapies, transfusions, procedures and 
dietary supplements must be documented on the eCRF. Refer to Appendix 5 for a list of 
medications to be used with caution as mentioned above. 
6.5.1.1 Skin Toxicity Treatments 
Patients should be treated for cetuximab-induced, encorafenib-induced and/or binimetinib-
induced skin toxicity following the supportive care recommended guidelines for the management 
of these toxicities (Appendix 1). Prophylactic measures may be initiated as outlined in 
Appendix 1. 


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6.5.1.2 Hand-foot Skin Reaction Treatments 
Because HFSR has been reported for encorafenib, it is recommended that patients are educated 
prior to starting study treatment to avoid activities that can cause friction on hands and feet. In 
addition, supportive measures for prevention and/or management of HFSR should be instituted. 
Clinical judgment and experience of the treating physician should guide the management plan of 
each patient. Patients receiving encorafenib should be treated for encorafenib-induced HFSR 
following the supportive care recommended guidelines for the management of these toxicities 
(Appendix 2).  
6.5.1.3 Antidiarrheals 
Patients should be treated for diarrhea as per institutional guidelines, and/or as indicated in the 
locally approved prescribing information, or for patients receiving binimetinib, per the 
supportive care recommended guidelines for the management of binimetinib-induced diarrhea 
(Appendix 3). For patients in the Control Arm, lacrimation, rhinorrhea, miosis, diaphoresis, hot 
flashes, flushing, abdominal cramping, diarrhea, or other symptoms of early cholinergic 
syndrome may occur during or shortly after receiving irinotecan. Atropine, 0.25 to 1.0 mg IV or 
subcutaneously, may be used (unless clinically contraindicated to treat these symptoms at the 
discretion of the treating physician. Combination anticholinergic medications containing 
barbiturates or other agents should not be used because these may affect irinotecan metabolism.  
Anticholinergics should be used in caution in patients with potential contraindications (e.g., 
obstructive uropathy, glaucoma and tachycardia). Late diarrhea (e.g., developing more than 24 
hours after irinotecan) should be managed with loperamide.   
6.5.1.4 Antiemetics 
Prophylactic antiemetics should be started only once the patient experiences nausea or vomiting 
and at the discretion of the Investigator. It is recommended that patients use drugs that do not 
cause QT prolongation. Note that some antiemetics have a known risk for Torsade de Pointes 
(TdP) (Appendix 5). 
6.5.2 Permitted Concomitant Therapy Requiring Caution and/or Action 
6.5.2.1 CYP and UGT Substrates and Inhibitors 
Encorafenib is a reversible inhibitor of CYP2B6, CYP2C9, CYP3A4 and UGT1A1. It is also a 
time-dependent inhibitor of CYP3A4. Binimetinib is also a reversible inhibitor of CYP2B6. 
Permitted medications to be used with caution in this study include those that are sensitive 
substrates of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and UGT1A1 or those 
substrates that have a narrow therapeutic index (NTI). Substrates of CYP3A4 are allowed based 
on a lack of interaction with midazolam (Appendix 5). 


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There is a potential for encorafenib to induce CYP3A4, which may reduce the effectiveness of 
hormonal contraception methods. Therefore, the use of at least 1 form of non-hormonal 
contraception is required during participation in this study. See Section 5.3.1 for use of 
contraception methods required for this study. Caution should be used in patients receiving 
concomitant treatment with other drugs that are substrates of CYP3A4 as the efficacy of these 
drugs could be reduced when administered with encorafenib. 
Encorafenib has been identified to be metabolized by CYP3A4 and to a lesser extent by 
CYP2C19 in vitro. The use of strong inhibitors of CYP3A4 is prohibited (see Section 2.3.2). 
Moderate inhibitors of CYP3A4 and strong inhibitors of CYP2C19 should be used with caution 
when co-administered with encorafenib.  
Binimetinib has been identified to be primarily metabolized by glucuronidation. It is advised that 
strong inhibitors of UGT1A1 should be taken with caution when co-administered with 
binimetinib (Appendix 5).  
Patients should be closely monitored for the occurrence of AEs. 
6.5.2.2 Transporter Substrates and Inhibitors 
In vitro data showed that both encorafenib and binimetinib are substrates of the transporter P-
glycoprotein (P-gp). Binimetinib is also a substrate of BCRP. Thus, the use of drugs that are 
known to inhibit or induce P-gp or BCRP should be used with caution. Encorafenib is a BCRP 
inhibitor. Encorafenib is also a potent inhibitor of the renal transporters, OAT1, OAT3 and OCT 
2, and the hepatic transporter OATP1B1 and OATP1B3. The co-administration of drugs that are 
known to be sensitive or narrow therapeutic index (NTI) substrates of BCRP, P-gp, OAT1, 
OAT3, OCT 2, OATP1B1 and OATP1B3 should be used with caution (Appendix 5). 
6.5.2.3 Hematopoietic Growth Factors 
Hematopoietic growth factors (e.g., erythropoietin, granulocyte colony-stimulating factor 
[G-CSF] and granulocyte-macrophage colony stimulating factor [GM-CSF]) are not to be 
administered prior to first dose of study treatment. After irinotecan or FOLFIRI treatment, if a 
dose delay is required due to any grade of neutropenia, prophylactic use of G-CSF and GM-CSF 
prior to the next administration of FOLFIRI is permitted at the Investigator’s discretion. Use of 
these drugs should be reserved for patients requiring this therapy as per the labeling of these 
agents or as dictated by local practice (see also the ASCO guidelines; Smith et al. 2015).  
6.5.2.4 Drugs with a Conditional or Possible Risk to Prolong the QT Interval and/or 
Induce Torsade de Pointes 
Investigators should use caution when administering encorafenib or binimetinib with 
concomitant medications with a known, conditional or possible risk to prolong the QT interval 
and/or induce TdP (Appendix 5). Patients receiving such medications must be carefully 


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monitored for potentiating of toxicity due to any individual concomitant medication, and may 
require dose titration of the concomitant medication. 
6.5.3 Prohibited Concomitant Therapy 
6.5.3.1 Anticancer Therapy 
No additional anticancer agents such as cytotoxic chemotherapy, small-molecule targeted agents, 
biological agents, immune response modifiers or hormonal therapy are to be administered to 
patients while they are receiving study drug. 
6.5.3.2 Other Prohibited Therapies 
The following therapies are prohibited during the study (unless otherwise noted): 
• Investigational drugs and devices 
• Radiation therapy (not including palliative radiotherapy at focal sites that covers 
≤ 10% of the bone marrow reserve) 
• Herbal preparations/medications. Patients should stop using herbal medications 7 days 
prior to first dose of study treatment. 
• Concomitant strong systemic CYP3A4 inhibitors. These would likely significantly 
increase the exposure of encorafenib and thus should not be used during this study (see 
Appendix 5). 
6.6 
Study Drug Supply 
6.6.1 Manufacturing, Formulation, Packaging and Labeling 
Encorafenib is manufactured by Catalant Pharma Solutions and supplied by the Sponsor as 
capsules for PO administration in dosage strength of 75 mg and packaged into high-density 
polyethylene (HDPE) bottles with an induction seal, child-resistant cap and a desiccant. 
Encorafenib capsules consist of encorafenib drug substance and the following excipients: 
copovidone, poloxamer 188, succinic acid, microcrystalline cellulose, colloid silicon dioxide, 
crospovidone, and magnesium stearate of vegetable origin. The capsule shell is commercially 
available and contains gelatin and titanium dioxide as well as iron oxide red, yellow or black 
depending on the particular strength. 
Binimetinib is manufactured by Almac Pharma Services Limited and Novartis Pharma AG and 
supplied by the Sponsor as film-coated tablets for PO administration in a dosage strength of 
15 mg and packaged into HDPE bottles with an induction seal and child-resistant cap. 
Binimetinib film-coated tablets consist of binimetinib drug substance; colloidal silicon 
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stearate; microcrystalline cellulose/cellulose, microcrystalline; and a commercial film coating. 
The capsule-shaped tablets are yellow to dark yellow. 
For both encorafenib and binimetinib, each bottle will be labelled, at a minimum, with a unique 
identifier (medication number), the lot number, contents (number of tablets), dosage strength, 
storage conditions and the name and address of the Sponsor. Both encorafenib and binimetinib 
labels will be in the local language and comply with the legal requirements of each country. For 
patients randomized to the Triplet Arm or the Doublet Arm, responsible site personnel will 
identify the study treatment bottle(s) to dispense to the patient by using the IWRS which will 
provide the medication number(s) at each dispensing visit. Site personnel will add the patient 
number to the label. 
Cetuximab will be supplied either locally or by the Sponsor. A description of cetuximab for 
infusion is included in the locally approved prescribing information. Commercially available 
cetuximab vials are packaged in boxes and will be used in this study according to local 
regulations in each participating country. Cetuximab preparation must be in accordance with the 
label and with local institutional guidelines. 
Irinotecan will be supplied either locally or by the Sponsor. A description of irinotecan for 
infusion is included in the locally approved prescribing information. Commercially available 
irinotecan vials are packaged in boxes and will be used in this study according to local 
regulations in each participating country. Irinotecan preparation must be in accordance with the 
label and with local institutional guidelines. 
5-Fluoruracil and FA will be supplied either locally or by the Sponsor. A description of 5-FU 
and FA for IV administration is included in the locally approved prescribing information. 
Commercially available 5-FU and FA vials are packaged in boxes and will be used in this study 
according to local regulations in each participating country. 5-Fluoruracil and FA preparation 
must be in accordance with the label and with local institutional guidelines. 
6.6.2 Shipping, Storage and Handling 
Labeled, packaged encorafenib and binimetinib will be shipped to each site by the Sponsor or 
designee, as described in the Pharmacy Manual. The Investigator or an approved representative 
(e.g., registered pharmacist) will ensure that all encorafenib and binimetinib is stored as outlined 
in the Pharmacy Manual and in accordance with applicable regulatory requirements. The drug 
storage area at the site must be secure, with access limited to authorized personnel. 
Encorafenib capsules should not be stored above 25°C and should be protected from moisture. 
Binimetinib film-coated tablets should not be stored above 25°C and should be protected from 
light. Storage conditions will be described on the medication label.  


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Stability studies to support drug storage conditions have been conducted by the Manufacturer or 
an affiliate. The Manufacturer will continue to monitor the stability of encorafenib and 
binimetinib and the Sponsor will alert the site if a lot is nearing the end of its anticipated shelf 
life. 
Detailed instructions for storage and handling of encorafenib and binimetinib will be provided in 
the Pharmacy Manual. 
Irinotecan, cetuximab, 5-FU and FA should be stored according to the locally approved 
prescribing information. 
6.6.3 Accountability and Return of Study Drug Supply 
The Investigator or an approved representative (e.g., pharmacist) must maintain accurate records 
of dates and quantities of study drug received, to whom study drug is dispensed (patient-by-
patient accounting), and accounts of any study drug accidentally or deliberately destroyed. The 
Investigator must retain all unused or expired study drug supplies until the study monitor has 
confirmed the accountability records. If site policy prohibits holding study drug supplies for 
monitor review, then a copy of the standard operating procedure (SOP) for processing drug 
returns must be provided to the Sponsor. 
To ensure adequate records, all study drugs (encorafenib, binimetinib, cetuximab, irinotecan and 
FOLFIRI) will be accounted for on a drug accountability inventory form as instructed by the 
Sponsor. Refer to the Pharmacy Manual for details on how to process all unused or expired study 
supplies. 
6.7 
Treatment Compliance 
Patients receiving encorafenib and binimetinib, if applicable, should be instructed to bring their 
study drug supply and bottles, if applicable, to the site at each study visit. Compliance will be 
evaluated at each visit by review of patient diary entries, an accounting of returned study drug 
(i.e., encorafenib and binimetinib, if applicable) and patient interviews.  
Cetuximab, irinotecan and FOLFIRI will be administered per protocol in the clinic by study 
personnel. Information regarding individual study drug infusions is to be documented as 
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7.0 
STUDY PROCEDURES AND ASSESSMENTS 
The procedures and assessments that will be conducted during this study are described in this 
section in narrative form and are presented by study visit in Section 8.0 and summarized in 
Table 25 (Prescreening and Screening Phases), Table 26 (Safety Lead-in and Triplet Arm), 
Table 27 (Doublet Arm) and Table 28 (Control Arm).  
Patients in the Control arm who are determined to be eligible for treatment crossover 
(see Sections 5.2.3 and 8.2.1) will initiate study activities and assessments such that the first day 
of the crossover treatment regimen equates to Cycle 1 Day 1 on the Schedule of Events for the 
triplet regimen (Table 26). 
Written informed consent (Molecular Prescreening, Screening and Crossover informed consents) 
must be granted by each patient prior to the initiation of any study procedure or assessment 
(other than those considered standard of care). 
7.1 
Prescreening/Screening Assessments and Procedures 
7.1.1 BRAF Testing 
Patients will be eligible for the study based on identification of a BRAFV600E mutation in the 
tumor as determined by the central laboratory as part of Molecular Prescreening for the trial or 
by a local assay result obtained any time prior to Screening (see Figure 7). Only polymerase 
chain reaction (PCR) and next generation sequencing (NGS)-based local assays results will be 
acceptable. If the patient is enrolled based on local assay results, the BRAF mutation status must 
be confirmed by the central laboratory no later than 30 days from first dose of study treatment.  
In cases where there is discordance between the local assay and central laboratory results, or if 
the central laboratory is not able to confirm presence of a BRAFV600E due to inadequate or poor 
sample condition within 30 days of initiating study therapy, patients may only continue treatment 
if there is no clinical indication of deterioration or disease progression and the investigator 
determines that the patient is deriving benefit. In such instances, patients must be informed that 
the BRAF mutation status is unconfirmed and must sign a separate ICF that includes this 
information and describes alternative treatment options.  
Central laboratory BRAF mutation tests with a definitive result (positive or negative) cannot be 
repeated to resolve a discordant result. Patients whose sample is determined to be inadequate or 
who have an indeterminate result on central testing may have samples resubmitted for testing. 
Lack of BRAFV600E confirmation by the central laboratory may be due to discordance between 
the local assay and central laboratory results (potential false positive local assay results), or due 
to inadequate or poor sample condition for central testing (indeterminate results). If at any time 
in the study there is lack of BRAFV600E confirmation in a total of 37 patients (6% of the total 
planned enrollment of the randomized portion of the trial) or discordance between the local assay 


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and the central laboratory in 18 patients (3% of the total planned enrollment), all subsequent 
patients will be required to have BRAFV600E determined by the central laboratory for enrollment 
(i.e., local BRAF testing will no longer be accepted for trial eligibility). Information regarding 
sites and laboratories associated with discordant results will be maintained and results from 
laboratories with more than 1 prior discordant result will not be accepted for patient enrollment. 
Sites with more than 2 randomized patients having indeterminate results after initiation of 
protocol version 6 will be required to enroll all subsequent patients based only on central 
laboratory assay results. 
Tumor samples previously determined to be BRAFwt by local assessment may be submitted to the 
central laboratory. In particular, tumors with clinicopathological features of BRAF mutations 
such as right colon tumors, poorly differentiated, mucinous, or signet-ring carcinomas, or tumors 
metastasized to the peritoneum (Yokota et al. 2011), should be considered for testing by central 
laboratory regardless of the results of prior local BRAF mutation testing.  
Figure 7: 
BRAF Testing 
 
 
 
 
 
 
 
 
 
 
 
 
7.1.2 Molecular Prescreening 
The molecular prescreening can be performed at any time prior to Screening (see Section 5.2.1). 
An informed consent must be signed prior to any molecular prescreening procedure for 
BRAF
V600E by local assay 
Molecular Prescreening:  
submit sample to central laboratory 
Screening 
Randomization 
*Confirmation of BRAF
V600E by central laboratory 
required within 30 days of starting study therapy 
Molecular Prescreening:  
submit sample to central laboratory 
Screening 
BRAF
V600E by central laboratory  
Randomization* 
BRAF status unknown or 
BRAF
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confirmation of BRAFV600E status. If an archival tumor sample is not available, a fresh tumor 
biopsy must be obtained. In patients with documented BRAFV600E status determined by local 
assay prior to the study, when possible, the same tissue source should be submitted to the central 
laboratory in order to minimize the potential for discordance. Information regarding tissue 
specimen requirements, sample handling and shipment will be provided in the Laboratory 
Manual.  
Patients will be registered for the study using IWRS after the prescreening informed consent is 
obtained. Refer and comply with detailed guidelines in the IWRS manual.  
7.1.3 Screening 
Patients, with documented BRAFV600E status determined by the central laboratory during 
Molecular Prescreening or by local assay prior to this study, must sign a Screening ICF before 
additional screening procedures to determine eligibility for participation in the study are 
performed. A copy of the ICF will be given to the patient or their legal representative. The date 
that informed consent was obtained must be documented in source documents.  
Patient eligibility will be verified against the inclusion and exclusion criteria once all screening 
procedures are completed. The eligibility check will be embedded in the IWRS system.  
7.1.4 Information Collected for Screen Failures 
Patients who provide informed consent (i.e., via the Prescreening ICF or the Screening ICF) but 
are not enrolled/randomized for any reason will be considered screen failures.  
Date of informed consent and review of inclusion/exclusion criteria will be collected for screen 
failures as well as any AEs or SAEs possibly related to a study procedure during the screening 
period and any medications used to treat those AEs or SAEs (see Section 10.9 for SAE reporting 
details). For molecular prescreening failures, results of local BRAF assay available at 
Prescreening or Screening, AEs or SAEs possibly related to a study procedure will be reported. 
7.1.5 Patient Demographics and Other Baseline Characteristics 
Demographics, prior medications/therapies/procedures that were administered/conducted within 
28 days prior to Day 1, current medications, diagnosis and extent of tumor, baseline tumor 
mutation status including site of disease, and details of prior antineoplastic treatments including 
number of prior metastatic regimens and prior irinotecan will be recorded. Past and present 
medical history considered by the Investigator to be significant will also be recorded.  


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Array BioPharma Inc. 
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7.2 
Safety Assessments 
7.2.1 Adverse Events 
Adverse events will be assessed by direct observation and patient interviews on an ongoing 
basis. Patients should be questioned using non-leading questions. The severity of AEs will be 
evaluated using the NCI CTCAE, v.4.03. All AEs that occur from initiation of study drug 
through 30 days after the last dose of study drug must be recorded on the AE eCRF, regardless of 
causal assessment.  
Definitions and reporting of AEs are described in detail in Section 10.0. 
7.2.2 Clinical Laboratory Tests 
Laboratory parameters to be assessed are listed in Table 20. 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
133 
 
11 July 2019 
At Screening, laboratory results from the central laboratory should be used by the Investigator to 
determine the patient’s eligibility for the study. If a particular central laboratory result is not 
available, a local laboratory test result for that particular analyte may be utilized to determine a 
patient’s eligibility to participate in the study. Local laboratory test results may also be used 
when results are time-sensitive (e.g., for patient safety or adjustment of study drug dose or 
schedule). Part of the sample obtained for local laboratory analysis should be sent to the central 
laboratory for analysis. Local laboratory results obtained during the study will not be captured in 
the eCRF unless they are needed to clarify why a treatment decision was made or an AE was 
recorded. 
Additional clinical laboratory tests may be obtained at any time during the study at the 
Investigator’s discretion. 
7.2.2.1 Hematology, Coagulation and Clinical Chemistry 
Blood samples for the hematology, coagulation and chemistry laboratory tests listed in Table 20 
will be collected at the time points specified in Table 25 (Screening Phase), Table 26 (Safety 
Lead-in and Triplet Arm), Table 27 (Doublet Arm) and Table 28 (Control Arm). 
Blood sample collections occurring on dosing days must be performed prior to study drug 
administration. Laboratory test results required to make decisions regarding potential dose 
modifications (as specified in Section 6.4.1, Section 6.4.2, Section 6.4.3 and Section 6.4.4, 
respectively) should be reviewed prior to study treatment administration. 
7.2.2.2 Urinalysis 
Urine samples for the laboratory tests listed in Table 20 will be collected at the time points 
specified in Table 25 (Screening Phase), Table 26 (Safety Lead-in and Triplet Arm), Table 27 
(Doublet Arm) and Table 28 (Control Arm). 
All urine collections occurring on dosing days must be performed prior to study treatment 
administration. 
7.2.2.3 Pregnancy and Assessments of Fertility 
All females of childbearing potential are required to undergo a serum pregnancy assessment at 
Screening and EOT and local urine pregnancy assessments at time points specified in Table 25 
(Screening Phase), Table 26 (Safety Lead-in and Triplet Arm), Table 27 (Doublet Arm) and 
Table 28 (Control Arm). Female patients of nonchildbearing potential (as defined in 
Section 5.3.1) do not require pregnancy tests. Any positive pregnancy test will result in 
immediate cessation of study treatment administration. The serum pregnancy assessments 
conducted at Screening and EOT should be submitted to the central laboratory. 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
134 
 
11 July 2019 
Female patients who have undergone female sterilization using oophorectomy alone will have a 
blood sample for measurement of LH, FSH, and/or estradiol as described in Section 5.3.1. 
All urine collections for pregnancy tests occurring on dosing days must be performed and 
assessed prior to study treatment administration. 
7.2.3 Vital Signs 
Vital signs (blood pressure, pulse and temperature, as appropriate) will be measured per 
institutional standards at the time points specified in Table 25 (Screening Phase), Table 26 
(Safety Lead-in and Triplet Arm), Table 27 (Doublet Arm) and Table 28 (Control Arm). 
All vital sign measurements occurring on dosing days must be performed prior to study treatment 
administration. Any treatment-emergent abnormal findings will be recorded as AEs. 
7.2.4 Physical Examination 
Physical examinations will be performed by trained medical personnel at the time points 
specified in Table 25 (Screening Phase), Table 26 (Safety Lead-in and Triplet Arm), Table 27 
(Doublet Arm) and Table 28 (Control Arm).  
At Screening, the physical examination should include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities, vascular and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast and pelvic examinations will be performed. 
For subsequent visits, the physical examinations should be targeted as clinically indicated. 
Body weight will be measured as part of the physical examination. Height will be measured only 
at Screening. All physical examinations occurring on dosing days must be performed prior to 
study treatment administration. Any treatment-emergent abnormal findings will be recorded as 
AEs. 
7.2.4.1 Body Surface Area 
For cetuximab, irinotecan and FOLFIRI dosing, patients’ BSA will be calculated at the start of 
each cycle. The most recent patient weight available should be used to calculate BSA in order to 
determine the appropriate dose for that cycle. If the patient’s weight at the beginning of each 
cycle varies by >10% from the previous cycle, the dose must be recalculated.  
In calculating the BSA, actual height and weight should be used. In patients with BSA > 2.2 m2, 
either actual BSA or 2.2 m2 may be used. As per ASCO guidelines, any of the established 
formulas may be used to calculate BSA (Griggs et al. 2012).  


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
135 
 
11 July 2019 
7.2.5 Ophthalmic Assessments 
7.2.5.1 Routine Testing 
Full ophthalmic examination, including best corrected visual acuity for distance testing, 
automated visual field testing, slit lamp examination, intraocular pressure and dilated fundoscopy 
with attention to retinal abnormalities, especially retinal pigment epithelial detachment (RPED), 
serous detachment of the retina and RVO, will be performed by an ophthalmologist at the time 
points specified in Table 25 (Screening Phase), Table 26 (Safety Lead-in and Triplet Arm) and 
Table 27 (Doublet Arm). Patients randomized to the Control Arm will not have routine 
ophthalmic examinations. For all patients, ophthalmic assessments may be performed more 
frequently per standard of care or if clinically indicated for evaluation of any visual signs or 
symptoms.  
7.2.5.2 Additional Testing 
Patients with clinical suspicion of retinal abnormalities (i.e., RPED, serous detachment of the 
retina, RVO, photopsia, metamorphopsia, impairment of visual acuity, etc.), must complete at 
least one of the following additional assessments: 
• For non-vascular abnormalities: OCT of the macula (spectral domain OCT 
recommended) 
• For vascular abnormalities: fluorescein angiography of the central 30 degrees.  
Images/results of the ophthalmic examinations (at a minimum, OCT and/or fluorescein 
angiography) should be sent to the study site and be maintained in the patient’s source document 
file. These images/results may be requested to be sent to the Sponsor or designee. 
7.2.6 Dermatologic Evaluations 
For patients receiving encorafenib or encorafenib + binimetinib, dermatologic evaluations will be 
performed at the site by the Investigator to monitor for the possible development of 
keratoacanthoma (KA) and/or squamous cell carcinoma (SCC), as these have been reported to 
occur with selective BRAF inhibitor treatment (Flaherty et al. 2010, Kefford et al. 2010, 
Robert et al. 2011). This assessment can be done predose or postdose and will be performed at 
the time points specified in Table 25 (Screening Phase), Table 26 (Safety Lead-in and Triplet 
Arm) and Table 27 (Doublet Arm). 
In case of occurrence of KA or SCC, patients will undergo complete surgical excision of the skin 
lesion following institutional standards. Dermatologic evaluations should be performed by a 
dermatologist as clinically indicated. 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
136 
 
11 July 2019 
7.2.7 Electrocardiograms 
Standard single 12-lead ECGs will be performed at the time points specified in Table 25 
(Screening Phase), Table 26 (Safety Lead-in and Triplet Arm), Table 27 (Doublet Arm) and 
Table 28 (Control Arm). A triplicate ECG (3 serial ECGs conducted within approximately 5 to 
10 minutes total time) will only be performed predose on Cycle 1 Day 1. 
Prior to performing the 12-lead ECG, patients should rest in the supine position for at least 
5 minutes. The ECG measurement performed at the Screening Visit will be used to determine 
eligibility. The mean of the triplicate ECG measurements recorded pre-morning dose on Cycle 1 
Day 1 will serve as the patient’s Baseline value for all postdose comparisons. The ECG 
measurement at any time point should be used for AE grading and recommended dose 
modifications. 
When an ECG is to be performed at the same time point as a blood collection, the ECG is to be 
performed first.  
Interpretation of the tracing should be made by a qualified physician and documented in the 
eCRF. Clinically significant abnormalities present when the patient signed the Screening 
informed consent should be reported in the eCRF. New or worsened clinically significant 
findings occurring after the Screening informed consent must be recorded in the eCRF. 
7.2.8 Echocardiogram/Multi-gated Acquisition Scans 
Cardiac ejection fraction will be assessed by transthoracic ECHO or MUGA scans at the time 
points specified in Table 25 (Screening Phase) and Table 26 (Safety Lead-in and Triplet Arm). 
The same method should be used throughout the study. Patients who develop signs/symptoms of 
congestive heart failure at any point during the study are required to have an evaluation of LVEF 
measurement by ECHO or MUGA. 
7.2.9 ECOG Performance Status 
Assessment of ECOG PS (Table 21) will be performed at the time points specified in Table 25 
(Screening Phase), Table 26 (Safety Lead-in and Triplet Arm), Table 27 (Doublet Arm) and 
Table 28 (Control Arm). 
ECOG PS should be obtained on the scheduled day, even if study treatment is being held. 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
137 
 
11 July 2019 
Table 21: 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
 
 
7.3 
Pharmacokinetic and Biomarker Blood Sampling Assessments 
During the course of the study, blood sampling for safety monitoring will be consistent with 
standard-of-care. Additional blood samples that will be collected over the course of the study for 
PK and biomarker analyses are shown in Table 22. If a patient receiving any of the treatments 
defined in this protocol experiences an AE that results in an unscheduled visit or meets the 
criteria for an SAE (Section 10.0), a blood sample for measurement of plasma concentrations of 
drug-related analytes should be collected, if feasible, if less than 24 hours have elapsed since the 
last dose of study drug. 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
140 
 
11 July 2019 
Table 24: 
Pharmacokinetic Sampling Times for the Randomized Phase 3 Portion of 
Study ARRAY-818-302 for a Subset of the Triplet, Doublet, and Control 
Arms 
 
Cycle 1 Day 1 
Cycle 2 Day 1 
Time after dosing on designated 
dosing days (h) 
2 
6 
0 
(predose) 
2 
PK Sample 
Triplet Arma 
Doublet Armb 
Control Armc 
X 
X 
X 
X 
Abbreviations: h = hours; PK = pharmacokinetic. 
a Triplet Arm: PK samples will be collected for the first ~50 patients enrolled in the Triplet Arm on Cycle 1 Day 1 
postdose (encorafenib/binimetinib) and post-infusion (cetuximab) at 2 h (± 10 min) and 6 h (± 30 min). PK 
samples will be collected on Cycle 2 Day 1 predose (just prior to encorafenib/binimetinib dose) and pre-infusion 
(just prior to infusion of cetuximab) and postdose/post-infusion at 2 h (± 10 min). Blood samples for 
encorafenib/binimetinib PK will be processed to plasma. 
Blood samples for cetuximab PK will be processed to serum. 
b Doublet Arm: PK samples will be collected from the first ~50 patients enrolled in the Doublet Arm on Cycle 1 
Day 1 postdose of encorafenib and post-infusion of cetuximab at 2 h (± 10 min) and 6 h (± 30 min). PK samples 
will be collected on Cycle 2 Day 1 predose of encorafenib and pre-infusion of cetuximab, and postdose/post-
infusion at 2 h (± 10 min). Blood samples for encorafenib PK will be processed to plasma.Blood samples for 
cetuximab PK will be processed to serum.   
c Control Arm: Cetuximab PK samples will be collected from the first ~100 patients enrolled in the Control Arm on 
Cycle 1 Day 1 post-infusion at 2 h (± 10 min) and 6 h (± 30 min). PK samples will be collected on Cycle 2 Day 1 
just prior to infusion and post-infusion at 2 h (± 10 min). Blood samples for cetuximab PK will be processed to 
serum. 
 
7.4 
Pharmacokinetics Assessment 
Blood samples (~4 mL each) for plasma PK analysis of encorafenib, binimetinib and/or the 
active metabolite of binimetinib (AR00426032), as appropriate, will be collected from all 
patients in the Safety Lead-in and from a subset of approximately 50 patients who are first to 
enroll in any site in the Triplet and Doublet Arms of the Phase 3 portion of the study, as specified 
in Table 26 (Safety Lead-in and Triplet Arm) and Table 27 (Doublet Arm).   
A second blood sample (~4 mL) will be collected from these patients for serum PK analysis of 
cetuximab from the Safety Lead-in, Triplet Arm and Doublet Arm and from approximately 
100 patients who are first to enroll in the Control Arm, as specified in Table 26 (Safety Lead-in 
and Triplet Arm), Table 27 (Doublet Arm) and Table 28 (Control Arm).  
Study visits for PK sampling should be scheduled in the morning so that a proper predose and 
postdose PK blood samples can be collected. On the PK visit days, the morning doses of 
encorafenib and binimetinib, if applicable, should be taken at the study site, only after collecting 
the predose PK sample for plasma. Predose sample collection for serum concentration of 
cetuximab should occur before the beginning of cetuximab infusion. Predose sampling 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
145 
 
11 July 2019 
All post-screening assessments should be performed every 6 weeks (±7 days) from the date of 
randomization (or from first dose for Safety Lead-in) until disease progression for the first 
24 weeks of treatment, then every 12 weeks thereafter until disease progression, withdrawal of 
consent, initiation of subsequent anticancer therapy, patient is lost to follow-up, death or defined 
end of study (Section 4.6). The interval should remain unchanged from study start for patients 
who cross over from the Control arm to receive the triplet regimen.   
Regardless of whether study treatment is discontinued, the following should be performed: 
• Chest, abdomen, and pelvis CT (or MRI) scans  
• Brain MRI or CT scan, if metastases were documented at baseline 
• Skeletal lesions identified at baseline should continue to be imaged at subsequent 
scheduled visits using localized CT, MRI, or X-ray (using the same method used at 
baseline for all visits for any given lesion). After baseline, whole body bone scans need 
not be repeated, unless clinically indicated. 
• Additional imaging evaluations may be performed if there is symptomatic evidence 
suggesting the possibility of disease progression based on clinical symptoms or physical 
examination at any time. 
If off-schedule imaging evaluations are performed or if progression is suspected, every effort 
should be made to perform subsequent imaging evaluations in accordance with the original 
imaging schedule.  
If a patient has disease progression during the first 5 weeks of study treatment, that patient’s 
BOR is PD. The BOR in patients who have been participating in the study for at least 5 weeks 
and who have not experienced a CR or PR per RECIST will be SD.  
All CT scans should be performed with IV contrast. If a patient is known to have a medical 
contraindication to the contrast agent or develops a contraindication during the study, a CT scan 
without IV contrast of the chest and MRI with IV contrast, if possible, of the abdomen and pelvis 
may be performed. A CT scan of the brain, preferably with IV contrast, may be performed if 
MRI is contra-indicated. 
Chest X-ray or ultrasound should not be used for tumor response assessments in this study. 
Any lesions that have been subjected to loco-regional therapies (e.g., radiotherapy, ablation, etc.) 
should not be considered measurable, unless they have clearly progressed since the therapy. 
Previously treated lesions that have not progressed should be considered non-measurable and 
therefore, assessed as non-target lesions. 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
146 
 
11 July 2019 
While FDG-PET scans are not required for this study, sites may perform combined PET/CT 
scans per their local standard of care, provided the CT is of similar diagnostic quality as CT 
performed without PET, including the use of oral and IV contrast media. If acquired according to 
local standard of care, FDG-PET may be relied upon to document PD in accordance with 
RECIST.  
When possible, each center should have a designated radiologist responsible for the 
interpretation of scans and response evaluations for study patients. At a minimum, a single 
radiologist should perform all evaluations for an individual patient. 
For patients who cross over from the Control arm to receive the triplet regimen, the last tumor 
assessment prior to treatment crossover will be considered the baseline assessment for 
determination of disease progression. 
7.6.1 BICR Evaluation of Imaging Data 
All imaging data acquired for efficacy purposes (e.g., CT/MRI scans) will be transmitted to an 
imaging vendor for BICR review. Image transmission to the imaging vendor should be 
performed according to the imaging vendor manual. 
The images will be read by readers who are blinded to treatment assignment and to other clinical 
data as specified in the BICR charter. BICR review of imaging data will be performed 
retrospectively and will not be provided to Investigators for decisions regarding patient 
treatment. 
Once patients cross over from the Control Arm to the triplet regimen, images for those patients 
will no longer be submitted for BICR review. 
7.6.2 Patient-reported Outcome Assessments  
Patient-reported outcome (PRO) assessments will be collected using the QoL questionnaires 
EORTC QLQ-C30, FACT-C, EQ-5D-5L and PGIC (Appendix 7) at the time points specified in 
Table 25 (Screening Phase), Table 26 (Safety Lead-in and Triplet Arm), Table 27 (Doublet Arm) 
and Table 28 (Control Arm). These questionnaires will be used to explore patient-reported 
outcome measures of health-related quality-of-life, functioning, cancer symptoms, and treatment-
related side effects. The QLQ-C30, FACT-C, EQ-5D-5L and PGIC are recognized reliable and 
valid measures in the treatment of cancer patients (Aaronson et al, 1993, Rabin and de Charro 
2001, and Mesa et al. 2013).  
PRO assessments will not be collected in patients after treatment crossover. 
The questionnaires should be administered to patients in the patients’ local language at the 
beginning of the study visit prior to receiving any study treatment, prior to any other study 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
147 
 
11 July 2019 
assessment or consultation with the Investigator, and prior to being informed of their current 
disease status.  
Attempts should be made to collect all questionnaires for all patients, including those who 
discontinue prior to the End of Treatment visit. However, if the patient refuses to complete the 
questionnaires, this should be documented in study source records. Patient refusal to complete 
study questionnaires is not a protocol deviation. 
Patients should be given sufficient space and time to complete all study questionnaires, and all 
administered questionnaires should be reviewed for completeness. If missing responses are 
noted, patients should be encouraged to complete any missing responses. 
Completed questionnaires, including both responses to the questions and any unsolicited 
comments written by the patient, should be reviewed by the Investigator or designee to ensure 
every question has been answered and that there is only 1 response for each question. If 
omissions or double responses occur, they should be brought to the attention of the patient. 
Investigators must not encourage the patient to change responses reported in questionnaires.  
In addition, the completed questionnaires should be reviewed and assessed by the Investigator 
for responses which may indicate potential AEs or SAEs. This review should be documented in 
study source records.  


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
148 
 
11 July 2019 
8.0 
SCHEDULE OF PROCEDURES AND ASSESSMENTS 
The procedures and assessments that will be conducted during this study are described in this 
section by study visit, described in narrative form in Section 7.0, and presented in separate tables 
for:  Prescreening and Screening Phases (Table 25), Safety Lead-in and Triplet Arm (Table 26), 
Doublet Arm (Table 27) and Control Arm (Table 28).  
Patients in the Control arm who are determined to be eligible for treatment crossover 
(see Section 8.2.1) will initiate study activities and assessments such that the first day of the 
crossover treatment regimen equates to Cycle 1 Day 1 on the Schedule of Events for the triplet 
regimen (Table 26). 
For all visits, there is a general ±3-day window on assessments to take into account scheduling 
over public or religious holidays, if not explicitly specified otherwise. For PK sampling, the 
samples may be obtained ±1 day from the scheduled date (except for PK sampling on Cycle 1 
Day 1). For imaging assessments, a ±7-day window is allowed. The first post-baseline tumor 
assessment should be performed at 6 weeks (±7-day window permitted) from date of 
randomization (or from first dose for Safety Lead-in). 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
 
Protocol Version 8.0 
151 
 
11 July 2019 
Table 26: 
Schedule of Events for Safety Lead-in, Triplet Arm, and Crossover Patients (Encorafenib + Binimetinib + 
Cetuximab) 
Procedure/Assessment 
(± 3-day window for procedures/assessments) 
Treatment Phase 
Follow-up Phase 
Cycle 1 
Subsequent Cycles 
 
 
 
Day  
1 
Day  
8 
Day 
15 
Day 
22 
Day  
1 
Day  
8 
Day  
15 
Day  
22 
End of 
Treatment 
30-Day 
Follow-upm 
Survival 
Follow-up 
Verify inclusion/exclusion criteria 
Xb,n 
 
 
 
 
 
 
 
 
 
 
Medical history from screening to Day 1 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
Xc 
 
 
 
X 
 
 
 
X 
X 
 
BSA 
Xc 
 
 
 
X 
 
 
 
 
 
 
Vital signs 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination 
Xc 
 
 
 
X 
 
 
 
X 
X 
 
ECOG PS 
Xc,n 
 
 
 
X 
 
 
 
X 
X 
 
EORTC QLQ-C30, FACT-C, EQ-5D-5L, PGICa,o  
X 
 
 
 
X 
 
 
 
X 
X 
 
ECG 
Xd,n 
 
X 
 
Xd 
 
 
 
X 
X 
 
Ophthalmic examination 
Xn 
 
 
 
Xe 
 
 
 
X 
Xe 
 
Dermatologic examination 
Xn 
 
 
 
Xf 
 
 
 
X 
X 
 
ECHO/MUGA 
Xn 
 
 
 
Xg 
 
 
 
X 
 
 
Pregnancy testh 
Xc,n 
 
 
 
X 
 
 
 
Xh 
X 
 
Hematology 
Xc,n 
 
X 
X 
X 
 
 
 
X 
X 
 
Clinical chemistry 
Xc,n 
 
X 
 
X 
 
 
 
X 
X 
 
Coagulation 
Xc,n 
 
 
 
X 
 
 
 
X 
X 
 
Urinalysis 
Xc 
 
 
 
X 
 
 
 
X 
X 
 
Tumor evaluation (CT scan, MRI) 
Every 6 weeks (±7 days) from randomization date (or from first dose for Safety Lead-in)  
for the first 24 weeks, then every 12 weeksi (±7 days) 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
Protocol Version 8.0 
160 
 
11 July 2019 
8.1 
Molecular Prescreening  
Patient may undergo molecular prescreening at any time prior to randomization based on 
eligibility criteria described in Section 5.2.1.   
• Obtain written informed consent for molecular testing 
• Register the patient into the IWRS for screening and obtain a patient study number to be 
used throughout the study 
• If tumor has previously been determined to be BRAFV600E mutant by local assay, confirm 
that it was done using PCR or NGS 
• Obtain and send archival tumor specimen to the central laboratory, as soon as possible 
following the signing of the Molecular Prescreening informed consent for confirmation 
of histology and BRAFV600E (see Section 7.1.1). If an adequate archival tumor sample 
(minimum of 6 slides; optimally up to 15 slides) is not available, a tumor biopsy is 
required. The same tumor sample will be used for the companion diagnostic assay and 
MSI testing. If the central laboratory determines that the sample is inadequate for 
analysis, a second sample may be submitted. 
8.2 
Screening 
All screening procedures to determine eligibility for study participation must be performed 
within specific time windows before the first dose of study treatment. Eligibility is determined 
using results of screening assessments performed before the first dose of study treatment and up 
to and including Day 1. Patients may be re-screened once at the discretion of the Investigator 
and/or individual assessments may be repeated, as appropriate. If a particular assessment is 
repeated, the results obtained closest to the first dose of study treatment should be used to assess 
eligibility. 
At the site, the Investigator will maintain a log for all screened patients (including patients who 
fail screening after providing written informed consent) and all enrolled/randomized patients. If 
the patient has not been molecularly prescreened, obtain written informed consent for molecular 
testing. 
Screening:  Within 28 days prior to randomization (or from first dose for Safety Lead-in): 
• Obtain Screening informed consent (must be obtained prior to performance of any 
study-specific tests or evaluations that are not considered standard of care) 
• Record demographic information (age, race, ethnicity). 
• Administer QOL questionnaires (EORTC QLQ-C30, FACT-C, EQ-5D-5L, PGIC) 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
Protocol Version 8.0 
162 
 
11 July 2019 
• Randomize patient via IWRS (or enroll for Safety Lead-in).  
8.2.1 Screening for Treatment Crossover 
Within 28 days prior to initiation of crossover treatment:  
• Obtain crossover informed consent (must be obtained prior to performance of any 
study-specific tests or evaluations that are not considered standard of care) 
• Obtain full ophthalmic examination  
• Obtain full dermatologic examination  
• Assess vital signs (blood pressure, pulse and temperature)  
• Obtain single ECG  
• ECHO/MUGA 
• Collection of blood samples for the following: 
o Hematology, coagulation, chemistry  
o Serum pregnancy test (females of childbearing potential only)  
• Assess ECOG PS  
• Verify all Crossover inclusion/exclusion criteria 
• Enroll for Crossover treatment  
Note: Assessments performed during the treatment or follow-up period within 28 days prior to 
treatment crossover may serve as screening assessments and need not be repeated. 
8.3 
Cycle 1 
Following determination of eligibility and enrollment in treatment crossover, patients will initiate 
study activities and assessments such that the first day of the crossover treatment regimen 
equates to Cycle 1 Day 1 on the Schedule of Events for the triplet regimen (Table 26). 
8.3.1 Cycle 1 Day 1 
In the Phase 3 portion of the study, patients must receive the first dose of study drug within 
5 days of the randomization date.  


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
Protocol Version 8.0 
164 
 
11 July 2019 
 Phase 3 (first ~50 patients enrolled in the Doublet and Triplet Arms): 
obtain at 2 and 6 hours following administration of encorafenib and/or 
binimetinib 
o Serum PK samples: 
 Safety Lead-in: Predose and 1, 2, 4 and 6 hours after the beginning of the 
cetuximab infusion 
 Phase 3 (all Arms, first ~50 patients enrolled in the Doublet and Triplet 
Arms and the first ~100 patients enrolled in the Control Arm): obtain at 2 
and 6 hours following after the beginning of the cetuximab infusion 
• Safety Lead-in/Triplet Arm only: administer dose of encorafenib and binimetinib with 
water  
• Doublet Arm only: administer dose of encorafenib with water 
• All Arms: administer cetuximab premedication according to institutional standards  
• All Arms: administer cetuximab as an IV infusion  
• Control Arm only: administer irinotecan as an IV infusion either alone or in combination 
with 5-FU as an IV bolus and infusion and FA as an IV infusion 
• Safety Lead-in/Triplet Arm and Doublet Arm only: obtain a single ECG 2.0 (+0.5) hours 
following administration of encorafenib or encorafenib + binimetinib and before the start 
of the cetuximab infusion. Electrocardiograms should be performed prior to the 2-hour 
postdose PK blood collection. 
• Document concomitant medications/therapies 
• Assess AEs  
• Safety Lead-in/Triplet Arm only: dispense a 4-week supply of encorafenib and 
binimetinib along with a monthly diary. Review dosing instructions with patient.  
• Doublet Arm only: dispense a 4-week supply of encorafenib along with a monthly diary. 
Review dosing instructions with patient  
8.3.2 Cycle 1 Day 8 
• Assess vital signs (blood pressure, pulse and temperature)  
• All Arms: administer cetuximab premedication according to institutional standards  


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
Protocol Version 8.0 
165 
 
11 July 2019 
• All Arms: administer cetuximab as an IV infusion  
• Review concomitant medications/therapies 
• Assess AEs since previous visit  
8.3.3 Cycle 1 Day 15 
• Assess vital signs (blood pressure, pulse and temperature)  
• Obtain blood sample for hematology and chemistry  
• Obtain single ECG (predose)  
• Safety Lead-in/Triplet Arm only: administer dose of encorafenib and binimetinib with 
water  
• Doublet Arm only: administer dose of encorafenib with water  
• All Arms: administer cetuximab premedication according to institutional standards  
• All Arms: administer cetuximab as an IV infusion  
• Control Arm only: administer irinotecan as an IV infusion either alone or in combination 
with 5-FU as an IV bolus and infusion and FA as an IV infusion  
• Review concomitant medications/therapies 
• Assess AEs since previous visit  
8.3.4 Cycle 1 Day 22  
• Assess vital signs (blood pressure, pulse and temperature)  
• Obtain blood sample for hematology  
• Safety Lead-in/Triplet Arm only: administer dose of encorafenib and binimetinib with 
water  
• Doublet Arm only: administer dose of encorafenib with water 
• All Arms: administer cetuximab premedication according to institutional standards  
• All Arms: administer cetuximab as an IV infusion  
• Review concomitant medications/therapies 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
Protocol Version 8.0 
166 
 
11 July 2019 
• Assess AEs since previous visit  
8.4 
Subsequent Cycles 
Tumor assessments (i.e., appropriate radiological scans to document all suspected sites of 
disease) are to be performed (Section 7.6) every 6 weeks (±7 days) from the date of 
randomization (or from first dose for Safety Lead-in) for the first 24 weeks of treatment, then 
every 12 weeks thereafter until disease progression, withdrawal of consent, initiation of 
subsequent anticancer therapy, patient is lost to follow-up, or death, regardless of whether study 
treatment is discontinued. 
8.4.1 Subsequent Cycles Day 1 
• Administer QOL questionnaires (EORTC QLQ-C30, FACT-C, EQ-5D-5L, PGIC) 
• Complete physical examination including weight    
• Calculate BSA  
• Assess vital signs (blood pressure, pulse and temperature)  
• Assess ECOG PS 
• Safety Lead-in/Triplet Arm and Doublet Arm only: Cycle 2 only: obtain a single ECG 
predose and 2.0 hours (+0.5 hour) after administration of encorafenib or encorafenib + 
binimetinib and before the start of the cetuximab infusion 
• Control Arm: obtain single ECG 
• Safety Lead-in/Triplet Arm only: ophthalmic examination at Cycle 2 Day 1 and then 
every 8 weeks (Day 1 Cycles 4, 6, 8 …) 
• Doublet Arm only: ophthalmic examination only as needed while on study 
• Safety Lead-in/Triplet Arm and Doublet Arm only: dermatologic examination every 8 
weeks (i.e., Day 1 of Cycles 3, 5, 7 …)  
• Safety Lead-in/Triplet Arm only: ECHO/MUGA Cycle 2 Day 1 and Cycle 5 Day 1, then 
every 12 weeks  
• Collection of blood samples for the following:  


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
Protocol Version 8.0 
168 
 
11 July 2019 
8.4.2 Subsequent Cycles Day 8  
• Assess vital signs (blood pressure, pulse and temperature)  
• All Arms: administer dose of cetuximab premedication according to institutional 
standards  
• All Arms: administer cetuximab as an IV infusion 
• Review concomitant medications/therapies 
• Assess AEs since previous visit  
8.4.3 Subsequent Cycles Day 15 
• Assess vital signs (blood pressure, pulse and temperature)  
• Control Arm only: obtain blood sample for hematology 
• All Arms: administer cetuximab premedication according to institutional standards  
• All Arms: administer cetuximab as an IV infusion  
• Control Arm only: administer irinotecan as an IV infusion either alone or in combination 
with 5-FU as an IV bolus and infusion and FA as an IV infusion 
• Review concomitant medications/therapies 
• Assess AEs since previous visit 
8.4.4 Subsequent Cycles Day 22 
• Assess vital signs (blood pressure, pulse and temperature)  
• All Arms: administer cetuximab premedication according to institutional standards  
• All Arms: administer cetuximab as an IV infusion  
• Review concomitant medications/therapies 
• Assess AEs since previous visit  
8.5 
End of Treatment Visit 
At the time of study treatment discontinuation, the End of Treatment Visit should be completed 
for all patients as soon as possible after the last dose of study drug, and every effort should be 
made to perform the procedures listed below. This visit should take place as soon as possible and 


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Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
Protocol Version 8.0 
170 
 
11 July 2019 
• If patients withdraw consent, they should be asked if they are willing to be contacted via 
telephone for survival status. If patients refuse to be contacted by telephone (or, for 
patients in the Safety Lead-in, where informed consent cannot be obtained due to the 
patient being lost to follow-up or previous withdrawal of consent), attempts to determine 
survival status should be made via access to public records. 
Note: this visit is not required for Control patients prior to crossing over to the triplet 
regimen. 
8.6 
Follow-up Visits 
Tumor assessments (i.e., appropriate radiological scans to document all suspected sites of 
disease) are to be performed every 6 weeks (±7 days) from the date of randomization (or from 
first dose for Safety Lead-in) for the first 24 weeks of treatment, then every 12 weeks thereafter 
until disease progression, withdrawal of consent, initiation of subsequent anticancer therapy, 
patient is lost to follow-up, or death. 
8.6.1 30-Day Safety Follow-up Visit 
All patients will return for a 30-Day Safety Follow-up Visit approximately 30 days after the last 
dose of study drug, or prior to the initiation of subsequent anticancer therapy, whichever occurs 
first. Information related to AEs (including concomitant medication taken for ongoing AEs) and 
ongoing antineoplastic treatments will be collected for 30 days after the last dose of study drug. 
All AEs suspected to be related to study treatment should be followed up weekly, or as clinically 
indicated, until resolution or stabilization. 
• Administer QOL questionnaires (EORTC QLQ-C30, FACT-C, EQ-5D-5L, PGIC)  
• Assess vital signs (blood pressure, pulse and temperature)  
• Complete physical examination including measurement of body weight  
• Assess ECOG PS 
• Obtain a single ECG 
• Obtain blood samples for hematology, coagulation, clinical chemistry 
• Obtain urine sample for urinalysis and for pregnancy test for females of childbearing 
potential  
• Review concomitant medications/therapies 
• Assess AEs  


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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Protocol Version 8.0 
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• Safety Lead-in/Triplet Arm only: Full ophthalmic examination, only if clinically 
significant abnormality noted at EOT 
• Safety Lead-in/Triplet Arm and Doublet Arm only: Full dermatologic examination  
• Determine survival status 
• Document subsequent anticancer therapy 
Note: this visit is not required for Control patients prior to crossing over to the triplet 
regimen. 
8.6.2 Other Follow-up Visits 
8.6.2.1 Visits for Tumor Assessments 
Tumor assessments (i.e., appropriate radiological scans to document all suspected sites of 
disease) are to be performed (Section 7.6) every 6 weeks (±7 days) from the date of 
randomization (or from first dose for Safety Lead-in) for the first 24 weeks of treatment, then 
every 12 weeks thereafter until disease progression, withdrawal of consent, initiation of 
subsequent anticancer therapy, patient is lost to follow-up, or death, regardless of whether study 
treatment is discontinued. 
After the 30-day safety follow-up visit, only new SAEs that are considered related to study drug 
should also be assessed and recorded. 
8.6.2.2 Survival Follow-up (Safety Lead-in Patients) 
After the 30-day safety follow-up visit, patients who provide informed consent for survival 
follow-up will undergo the following assessments every 3 months, or more frequently as needed, 
until withdrawal of consent, patient is lost to follow-up, death or defined end of study 
(Section 4.6):  
• Record new SAEs that are considered related to study drug 
• Record all subsequent anticancer therapies 
• Determine survival status 
If informed consent cannot be obtained due to the patient being lost to follow-up or previous 
withdrawal of consent, attempts to determine survival status should be made via access to public 
records as permitted by local laws. 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
Protocol Version 8.0 
172 
 
11 July 2019 
8.6.2.3 Survival Follow-up (Randomized Phase 3 Patients) 
After the 30-day safety follow-up visit, the assessments listed below should be performed every 
3 months, or more frequently as needed, until withdrawal of consent, patient is lost to follow-up, 
death or defined end of study (Section 4.6):  
• Record new SAEs that are considered related to study drug 
• Record all subsequent anticancer therapies 
• Document the date of disease progression following the initiation of subsequent therapies 
• Determine survival status 
If patients withdraw consent, they should be asked if they are willing to be contacted via 
telephone for survival status. If patients refuse to be contacted by telephone, attempts to 
determine survival status should be made via access to public records as permitted by local laws. 
8.7 
Collection of Data for Ongoing Patients Following Database Lock 
If the primary objectives of the study have been met or the Sponsor decides to stop the study 
early, the database may be locked for the purpose of analyzing and reporting data. Patients may 
continue to receive study treatment per protocol beyond database lock if the Investigator and the 
Sponsor agree that patients’ best interests are served by continuing to receive study treatment.  
In such cases, appropriate safety information will continue to be captured per protocol and 
submitted to the Sponsor. The information to be collected may include treatment-related AEs and 
SAEs, laboratory results of special interest, study drug administration, patient status and date and 
reason(s) for study withdrawal. 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-818-302 
Protocol Version 8.0 
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9.0 
STUDY DISCONTINUATION 
9.1 
Termination of the Study by the Sponsor 
This study may be discontinued at any time due to safety concerns, failure to meet expected 
enrollment goals, administrative reasons or at the discretion of the Sponsor. Should the study be 
terminated prematurely, the Sponsor will provide written notification to all Investigators and 
regulatory authorities and will specify the reason(s) for early termination. The Investigator must 
inform the IRB promptly and provide the reason(s) for the termination. 
9.2 
Treatment Discontinuation for Individual Patients 
Patients may withdraw their consent to participate in the study at any time for any reason without 
prejudice to their future medical care by the physician or at the institution. However, patients 
should be asked if they are willing to be contacted by telephone for monitoring of survival. If a 
patient withdraws consent, the date, stated reason for and level of consent withdrawal should be 
documented. Patient data collected up to the date of consent withdrawal will be included in the 
analyses. Any blood or tissue samples collected up to the date of withdrawal of consent will be 
analyzed. 
Wherever possible, the tests and evaluations listed for the End of Treatment visit should be 
carried out and an effort should be made to continue follow-up. The Sponsor should be notified 
of all study withdrawals through the designated eCRFs in a timely manner. 
Patients meeting any of the following criteria must discontinue study drug treatment: 
• Withdrawal of consent (no further participation) - request patients to provide consent for 
further survival follow-up 
• Patient decision to discontinue study treatment (but request agreement to return for end of 
treatment assessments, safety follow-up assessments and/or survival follow-up) 
• Unacceptable AEs or failure to tolerate study drug 
• Dose interruption of > 28 consecutive days in administration of encorafenib or 
binimetinib, or noncompliance with study drug administration consisting of 2 missed 
consecutive doses of irinotecan, 5-FU, or FA or > 4 missed consecutive doses of 
cetuximab due to an AE or clinically significant laboratory abnormality, unless judged by 
the Investigator and Sponsor Medical Monitor or designee to be in the best interest of the 
patient to continue treatment 
• Changes in the patient’s condition or development of an intercurrent illness which 
renders the patient unacceptable for further treatment in the judgment of the Investigator 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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• Disease progression as defined by RECIST, v1.1 (continuation of treatment beyond 
progression permitted in special circumstances (defined in Section 4.5)  
• Receipt of non-protocol-specified anticancer therapy for study indication (chemotherapy, 
biological therapy or radiation therapy that includes > 30% of the bone marrow reserve) 
• Patient becomes pregnant or begins breastfeeding 
• Significant protocol deviation that, in the opinion of the Investigator and/or Sponsor, 
renders the patient unsuitable for further study drug administration 
• Lost to follow-up 
• Death 
• Termination of the study by the Sponsor (described in Section 9.1). 
Patients meeting any of the following criteria may be discontinued from study drug treatment if, 
during the course of the study: 
• Is found not to have met eligibility criteria; the patient would be discontinued if the 
investigator determines that the patient would not benefit from participation in the study 
due to eligibility deviation. 
• Is found to have a tumor that is BRAFwt by the central laboratory 
• Is noncompliant with study procedures or study drug administration in the opinion of the 
investigator (See Section 6.7). 
9.3 
Study Discontinuation for Individual Patients 
The patient may be considered discontinued from the study for the following reasons: 
• Withdrawal of consent for survival follow-up 
• Lost to follow-up 
• Death 
• Termination of the study by the Sponsor (described in Section 9.1). 
• Patients discontinuing treatment in Safety Lead-in  


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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9.4 
Replacement of Patients 
In the Safety Lead-in phase of the study, patients who terminate participation in the study for any 
reason other than an AE or abnormal laboratory value unrelated to disease, disease progression, 
intercurrent illness or concomitant medications/therapies before completing at least 75% dose 
intensity (administered dose in mg/planned dose in mg) of the binimetinib, encorafenib or 
cetuximab doses in Cycle 1 will be considered ineligible for the safety assessment required for 
tolerability and will be replaced. 
In the Phase 3 part of the study, randomized patients who discontinue prior to study completion 
will not be replaced. 
All patients receiving at least 1 dose of study drug will be evaluated for safety. 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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10.0 SAFETY MONITORING: DEFINITIONS AND REPORTING 
10.1 Adverse Event 
An AE is any untoward medical occurrence, including the exacerbation of a pre-existing 
condition, in a patient administered a pharmaceutical product regardless of causality. 
10.2 Events Related to Progression of Disease 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors) will be designated as progression 
of disease in the eCRF and should not be reported as a AEs or SAEs unless a causal relationship 
to study drug is suspected.   
10.3 Adverse Events Related to Subsequent Anticancer Therapy 
Adverse events specifically related to subsequent anticancer therapy are excluded from AE 
reporting, as are hospitalizations necessary for the administration of such therapy. 
10.4 Clinical Laboratory Abnormalities 
An abnormal laboratory value that is not associated with an already reported AE is to be 
recorded as an AE only if an action on the study drug is made as a result of the abnormality, if 
intervention for management of the abnormality is required, or at the discretion of the 
Investigator. 
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or baseline, or per Investigator discretion.  
10.5 Overdose 
An overdose of study drug (whether symptomatic or asymptomatic) will be reported as an AE. 
10.6 Assessment of Severity 
The severity rating of an AE refers to its intensity. The severity of each AE will be categorized 
using the NCI CTCAE, v4.03. For any term that is not specifically listed in the CTCAE scale, 
intensity should be assigned a Grade of 1 through 5 using the following CTCAE guidelines: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 


Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) 
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Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
10.7 Assessment of Causality 
Medical judgment should be used to determine the cause of the AE, considering all relevant 
factors such as (but not limited to) the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the study 
medication and de-challenge or re-challenge. 
Yes (possibly, probably or definitely related): there is a reasonable possibility that the study drug 
caused the event; one or more of the following criteria apply: 
• The event follows a reasonable temporal sequence from administration of study drug. 
• The event could not be reasonably attributed to the known characteristics of the patient’s 
clinical state, environmental or toxic factors or other modes of therapy administered to 
the patient. 
• The event follows a known pattern of response to study drug. 
• The event disappears or decreases on cessation or reduction in dose of the study drug. 
(It should be noted that in some situations an AE will not disappear or decrease in 
intensity upon discontinuation of study drug despite other clear indications of 
relatedness).  
• The event reappears or worsens when the study drug is re-administered. 
No (unlikely, probably not related or definitely not related): there is no reasonable possibility 
that the study drug caused the event; one or more of the following criteria apply: 
• The event does not follow a reasonable temporal sequence from administration of study 
drug. 
• The event could be reasonably attributed to the known characteristics of the patient’s 
clinical state, concurrent illness, environment or toxic factors or other modes of therapy 
administered to the patient. 
• The event does not follow a known pattern of response to study drug. 


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• The event does not disappear or decrease on cessation or reduction in dose of the study 
drug, and it does not reappear or worsen when the study drug is re-administered. 
10.8 Assessment of Seriousness 
An AE is considered “serious” if it results in any of the following outcomes: 
• Results in death. 
o Death is an outcome of an SAE and not an SAE in itself. Death should only be 
reported as an SAE term when no additional information is known about a fatal 
event. When death is an outcome, the event(s) resulting in death should be 
reported (e.g., “pulmonary embolism” with a fatal outcome) and assigned severity 
Grade 5. 
• Is immediately life-threatening (its occurrence places the patient at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
o Hospitalization includes any hospital admission, even if for less than 24 hours. 
The following do not meet hospitalization serious criteria: Preplanned or elective 
hospitalizations including social and/or convenience situations (e.g., respite care), 
emergency room visits or outpatient observation. 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Based upon appropriate medical judgment, represents an important medical event that 
may jeopardize the patient or may require intervention to prevent one of the outcomes 
described above. 
10.9 Reporting of Serious and Nonserious Adverse Events 
All AEs, serious and nonserious and regardless of causality to study drug (including the 
exacerbation of a pre-existing condition), will be fully recorded on the appropriate eCRF. For 
each AE, the Investigator must provide its duration (start and end dates or ongoing), severity 
(intensity), assessment of causality and whether specific action or therapy was required and 
whether action was taken with regard to study drug treatment. 
Any AE that occurs from the signing of the ICF until the first dose of study drug should be 
recorded on the AE eCRF page only if the event was related to a study procedure; all other 


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AEs/findings prior to the first dose of study drug should be recorded as medical history on the 
applicable eCRF page(s). All AEs occurring from the first dose of study drug until 30 days after 
the last dose of study drug must be recorded on the AE eCRF. 
All SAEs must additionally be reported to the Sponsor within 24 hours of the Investigator’s 
knowledge by faxing the completed SAE form to the Sponsor at the number provided on the 
SAE form or fax cover sheet.   
After the 30-day Safety Follow-up, only new SAEs that are considered related to study drug will 
be captured on the eCRF and reported to the Sponsor or designee using the SAE form. 
Investigators must follow patients with AEs/SAEs until the event has resolved, the condition has 
stabilized, withdrawal of consent, initiation of subsequent anticancer therapy, the patient is lost 
to follow-up or death OR until the 30-day Safety Follow-up, whichever occurs first. Ongoing 
treatment-related AEs/SAEs may be followed beyond the 30-day Safety Follow-up if clinically 
indicated.  
If a patient is lost to follow-up, this should be captured accordingly within the eCRF and on a 
follow-up SAE report. 
10.10 Reporting of Suspected Unexpected Serious Adverse Events (SUSAR) 
Suspected Unexpected Serious Adverse Events (SUSAR) will be collected and reported by the 
Sponsor and/or designee to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in participating 
countries. 
10.11 Pregnancy or Drug Exposure during Pregnancy 
If a patient becomes pregnant during the study, administration of study drug is to be discontinued 
immediately. 
Pregnancies (both those of female patients and female partners of male patients) must be 
reported to the Sponsor or designee within 24 hours of the Investigator’s knowledge using the 
Clinical Pregnancy Report. All pregnancies will be followed through to outcome and the 
outcome must be reported to the Sponsor or designee using the Clinical Pregnancy Outcome 
Report.  
Pregnancies themselves are not considered AEs or SAEs. However, any AEs or SAEs occurring 
during pregnancy are to be reported following AE and SAE reporting guidelines. 


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10.12 Review of Safety Data 
The Medical Monitor or designee, and the Sponsor’s Drug Safety Department will be responsible 
for the ongoing review and evaluation of safety data, including AEs, laboratory data, and any 
other safety evaluations, throughout the duration of the study.  
Additionally, an independent DMC with a defined charter will be used to determine if the study 
should be stopped or suspended at any time to allow additional review of safety data. 


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11.0 STATISTICAL METHODS 
The study contains a Safety Lead-in and a Japan Safety Lead-in Phase in which the safety and 
tolerability of encorafenib + binimetinib + cetuximab will be assessed. Once the safety profile 
has been assessed by the DMC, subsequent patients will be randomized to the Phase 3 portion of 
the study. The primary endpoints of the study are OS of Triplet Arm vs Control Arm and ORR 
(per BICR) of Triplet Arm vs Control Arm.  
An initial analysis conducted for the study will serve as the primary analysis for the ORR 
primary endpoint based on the first 330 patients randomized. At the same time, an interim 
analysis for superiority or (non-binding) futility of the OS primary endpoint will be performed. If 
the OS interim analysis results do not cross the superiority boundary, the OS primary endpoint 
will be analyzed again at the final analysis. If the interim analysis for OS of Triplet vs. Control 
exceeds the superiority boundary, patients in the Triplet and Doublet arms may continue to be 
followed for a more mature comparison. 
11.1 Determination of Sample Size 
The planned sample size is approximately 646-651 patients (includes 31-36 patients for the 
non-Japanese and Japanese Safety Lead-in study portions and approximately 615 in the 
randomized Phase 3 portion of the study). Additional patients may be included in Safety Lead-in 
if lower dose levels are evaluated. 
11.1.1 Safety Lead-in 
During the Safety Lead-In, the first 9 evaluable patients will be enrolled to the starting dose of 
the Triplet Arm. This Triplet dose will be presented to the DMC as tolerable if the observed 
Cycle 1 DLT rate is < 33% (i.e., < 3 patients with DLTs out of 9 patients). Table 29 provides a 
comparison of the operating characteristics for this dose-escalation rule with 9 patients and 
traditional 3+3 rules. The results illustrate the benefit of the additional patients as the probability 
of falsely declaring a dose to be toxic is lower with a 9-patient cohort when the true DLT rate is 
≤ 20%. Similarly the probability of correctly declaring a dose to be toxic is higher with the 
9-patient cohort when the true DLT rate is ≥40%. In addition, observing no Cycle 1 DLTs in 
9 patients would be expected to occur with probability 0.040 if the true DLT rate is 30%. 


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Table 29: 
Operating Characteristics of Safety Lead-In Criteria for 9 Patients 
Compared to 3+3 Rules 
True Cycle 1 DLT Rate 
Probability of dose declared toxic 
using 3+3 rules 
Probability of observed Cycle 1 
DLT rate ≥ 33%  
in 9 patients 
10% 
0.094 
0.053 
20% 
0.291 
0.262 
30% 
0.506 
0.537 
40% 
0.691 
0.768 
50% 
0.828 
0.910 
If the DMC determines the doses to be tolerable in the first 9 evaluable patients based on 
observing DLTs in < 33% of patients and evaluation of the overall toxicity profile, the Safety 
Lead-in will be expanded by an additional 16-21 patients. A total of 25-30 patients will complete 
the Safety Lead-in (the initial 9 plus the additional patients in the expansion) at the doses 
proposed for the randomized Phase 3 portion of the study. If dose de-escalation is required 
during the Safety Lead-in, additional patients may be necessary.  
A separate safety evaluation of Japanese patients will be conducted once the Japanese Safety 
Lead-In cohort completes 1 cycle of therapy. For this cohort, 6 patients will be enrolled, resulting 
in a total of 31-36 patients for the entire Safety Lead-In study portion.  
11.1.2 Randomized Phase 3 
Overall Survival 
During the randomized Phase 3 portion of the study, eligible patients will be randomized 1:1:1 
such that approximately 205 patients will receive binimetinib + encorafenib + cetuximab (Triplet 
Arm), approximately 205 patients will receive encorafenib + cetuximab (Doublet Arm) and 
approximately 205 patients will receive irinotecan/cetuximab or FOLFIRI/cetuximab (Control 
Arm). The number of 3rd-line patients (those having received 2 prior regimens) randomized to 
the Phase 3 portion of the study will be limited to 215 (35% of the total randomized) in order to 
ensure generalizability of the study. 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. Permitting up to 35% of the randomized patients to have 
received 2 prior regimens ensures a sufficient sample size to adequately generalize the results 
across subgroups when incorporating other relevant stratification factors. Randomization will be 
stratified by ECOG PS (0 vs. 1), prior use of irinotecan (yes vs. no), and cetuximab source 
(US-licensed vs. EU-approved).  
The primary endpoints are OS and ORR (per BICR) of the Triplet Arm vs. Control Arm. 
Historical evidence (Peeters et al. 2014) suggests that the median OS of FOLFIRI combined with 


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another EGFR inhibitor (panitumumab) will be approximately 5 months in BRAF-mutant mCRC. 
Existing published data suggest only modest differences between irinotecan single-agent and 
FOLFIRI efficacy (Clarke et al. 2011). In addition, available data suggests that treatment-eligible 
patients in the 2nd and 3rd-line settings and with or without prior irinotecan have similar PFS and 
OS with standard therapy approaches (DeRoock et al. 2010, Morris et al. 2014, Peeters et al. 
2014). Based on these findings, it is assumed that both control arm options will have an 
approximate median OS of 5 months. 
The number of patients required for the randomized Phase 3 portion of the study is driven by the 
key secondary endpoint of the OS of the Doublet Arm vs. Control Arm. For this comparison, the 
study is powered to detect an improvement of 2.1 months (7.1 months vs. 5 months; HR=0.70). 
With 338 OS events, the study will have approximately 90% power to detect this improvement 
using a group-sequential design and 1-sided α=0.025. Assuming accrual to the randomized Phase 
3 portion of the study increases over a period of time before reaching a maximum of 25 patients 
per month (for an accrual duration of approximately 25 months) and 5% loss to follow-up, 
approximately 615 patients will be randomized to reach 338 events. With 338 events, the null 
hypothesis that the OS in the Doublet Arm is the same or worse than the Control Arm will be 
rejected if the hazard ration (HR) is smaller (i.e., better) than 0.81. 
The final analysis for OS will occur once at least 268 events are observed in the Triplet Arm + 
Control Arm and at least 338 events are observed in the Doublet Arm + Control Arm. This is 
expected to occur approximately 33 months after the first patient is randomized (i.e., 
approximately 8 months after randomization is complete). At the time of the final analysis, it is 
anticipated that approximately 333 OS events will be observed in the Triplet Arm + Control 
Arm, but only the first 268 OS events will be included in the final analysis.  With 268 events, 
there will be approximately 90% power to detect a HR=0.67 (median OS of 7.5 months vs. 5 
months) with 1-sided alpha = 0.025. The null hypothesis that the OS in the Triplet Arm is the 
same or worse than the Control Arm will be rejected if the HR is smaller (i.e., better) than 0.79. 
Overall Response 
During the initial analysis of the study, the primary analysis of Triplet vs. Control ORR by BICR 
will be conducted based on the first 330 randomized patients. Based on historical data, the ORR 
in the control arm is expected to be approximately 10% (Kopetz et al. 2017, Seymour et al. 
2013). A sample size of 110 patients per arm provides 88% power to detect a 20% absolute 
difference in ORR, assuming an ORR of 10% in the Control Arm and an ORR of 30% in the 
Triplet Arm at a 1-sided alpha of 0.005. 


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11.2 Analysis Sets 
11.2.1 Full Analysis Set 
For patients in the Safety Lead-in, the Full Analysis Set (FAS) will consist of all patients who 
receive at least 1 dose of study drug and have at least 1 post-treatment assessment, which may 
include death. 
For patients in the Phase 3 portion, the FAS will consist of all randomized Phase 3 patients. 
Patients will be analyzed according to the treatment arm and stratum they were assigned to at 
randomization. 
11.2.2 Safety Set 
The Safety Set (SS) will consist of all patients who receive at least 1 dose of study drug and have 
at least 1 post-treatment assessment, which may include death. Patients will be analyzed 
according to treatment received. 
11.2.3 Dose-Determining Set 
The dose-determining set (DDS) includes all Safety Lead-In patients from the SS who either 
completed a minimum exposure requirement and have sufficient safety evaluations or 
experienced a DLT. 
A patient is considered to have met the minimum exposure requirement if having received at 
least 75% dose intensity ([Cumulative administered dose in mg in Cycle 1/Cumulative planned 
dose in mg in Cycle 1] x 100) of the planned dose for each of the 3 agents; binimetinib (i.e., 
1890 of the planned 2520 mg dose), encorafenib (i.e., 6300 of the planned 8400 mg dose) or 
cetuximab doses (i.e., 750 of the planned 1000 mg/m2 dose) within the first Cycle of dosing. The 
length of a cycle is 28 days. 
Patients who do not experience DLT during the first cycle will be considered to have sufficient 
safety evaluations if they have been observed for ≥ 28 days following the first dose, and are 
considered by both the Sponsor and Investigators to have enough safety data to conclude that a 
DLT did not occur. 
11.2.4 Safety Lead-in Efficacy Set 
The Safety Lead-in Efficacy Set will consist of all Safety Lead-in patients in the FAS who were 
identified at screening as having a BRAFV600E mutation (per local or central testing).  
11.2.5 Phase 3 Response Efficacy Set 
The Phase 3 Response Efficacy Set will consist of the first 330 patients randomized into the 
Phase 3 portion of the study.  


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11.2.6 Per Protocol Set 
The Per-protocol Set (PPS) will consist of all Phase 3 patients in the FAS who are sufficiently 
compliant with the protocol requirements. A precise definition of the criteria required for 
inclusion in the PPS will be provided in the statistical analysis plan (SAP).  
11.2.7 Pharmacokinetic Set 
The PK set will consist of all patients who receive at least 1 dose of encorafenib, binimetinib or 
cetuximab, and who have at least 1 post-dose PK blood collection with associated bioanalytical 
results. 
11.3 Statistical Analyses and Methods 
11.3.1 General Considerations 
A detailed SAP will be prepared by the Sponsor. This plan may modify the statistical methods 
outlined in the protocol; however, any major modifications of the primary endpoints or key 
secondary endpoint definition or analysis will also be described in a protocol amendment. 
Data analyses from this study will be performed by the Sponsor or designee.  
The primary clinical study report (CSR) will be based on the data generated prior to the data 
cutoff date (see Section 11.3.9). Addendums to the CSR will be written once the end of the study 
has occurred. Additional data cutoff dates for other analyses may be established if requested per 
Health Authorities. 
11.3.2 Patient Characteristics 
The following baseline patient characteristics will be summarized descriptively by treatment 
arm: stratification factors (ECOG PS, prior use of irinotecan, cetuximab source); demographics 
(age, gender and race); histology; prior anticancer agents (chemotherapy, biologics, targeted 
small molecules); best response to prior irinotecan-based therapy; best response to prior 
chemotherapy; prior radiotherapy, prior surgery; primary site of disease; medical history; 
concomitant medication usage; various genes’ mutation status.  
11.3.3 Efficacy Analyses 
The primary efficacy endpoints are OS (Triplet Arm vs. Control Arm) and ORR by BICR 
(Triplet Arm vs. Control Arm) (see Sections 11.3.3.1 and 11.3.3.2). 
The key secondary efficacy endpoint is OS (Doublet Arm vs. Control Arm) and other secondary 
endpoints include ORR (Triplet Arm vs. Control Arm and Doublet Arm vs. Control Arm), PFS 
(Triplet Arm vs. Control Arm and Doublet Arm vs. Control Arm), OS (Triplet Arm vs. Doublet 
Arm), ORR (Triplet Arm vs. Doublet Arm), DOR (Triplet Arm vs. Control Arm, Doublet Arm 


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vs. Control Arm, Triplet Arm vs. Doublet Arm), and time to response (Triplet Arm vs. Control 
Arm, Doublet Arm vs. Control Arm, Triplet Arm vs. Doublet Arm). 
Unless otherwise stated, efficacy analyses will be conducted using the FAS. A supportive 
analysis of the primary endpoints will be conducted using the PPS. For endpoints related to 
tumor evaluations (PFS, ORR, DOR, time to response), the primary analysis will be based on the 
assessments per BICR. The secondary endpoints based on Investigator assessment will each be 
summarized as a supportive analysis. 
The analyses described below for ORR, DOR, and PFS secondary endpoints may also be 
conducted using descriptive statistics if the primary endpoint of ORR is statistically significant at 
the primary analysis. The analyses for OS described below will be conducted only when the 
primary endpoint of OS exceeds the superiority boundary or the study stops for futility. 
The Type I error rate for the primary endpoints will be controlled using a fallback procedure 
described by Wiens and Dmitrienko (2005). One-sided alpha of 0.005 will be assigned to the 
Triplet vs Control ORR endpoint. The remaining 0.020 will be assigned to the Triplet vs Control 
OS endpoint. If the p-value of the Triplet vs Control comparison of ORR at the primary analysis 
is <0.005, then the Triplet vs Control OS comparison will be assigned a total 1-sided alpha of 
0.025. Otherwise, it will remain at 1-sided 0.020. 
The key secondary endpoint and several secondary endpoints may also be formally tested. To 
control the overall Type I error rate, a gatekeeping procedure using hierarchical testing will be 
performed. If the OS of the Triplet Arm vs. Control Arm is found to be significant at either the 
OS interim analysis (Section 11.3.9) or the final analysis, the following tests will then be 
formally conducted sequentially, each at the same total alpha assigned to the Triplet vs Control 
OS endpoint: 
1. 
OS of Doublet Arm vs. Control Arm  
2. 
ORR (per BICR) of Doublet Arm vs. Control Arm 
3. 
PFS (per BICR) of Triplet Arm vs. Control Arm   
4. 
PFS (per BICR) of Doublet Arm vs. Control Arm  
If any of the above tests is found to not be statistically significant, all subsequent comparisons 
will only be summarized using descriptive statistics. 
The overall testing strategy of the study is summarized in Figure 9. 


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Figure 9: 
Testing Strategy for Study ARRAY-818-302 
 
 
Test OS 
(Triplet vs. Control) 
1-sided "= 0.025 
1\PJlo!l~ 205 pts/arm 
[interim Analysis] 
Test ORR per BICR 
(Triplet vs. Control) 
!-sided"= 0.005 
AIUl~ II 0 pts/arm 
Test OS 
(Triplet'"· Control) 
1-sided "= 0.020 
1\PJl>!l~ 205 pts/arm 
[Interim Analysis] 
Does the p.value surpass the O'Brien·Flemin2 efficacy boundary? 
Test subsequent endpoints• 
in hierarchy, using a 
gatekecping: procedure to 
control the overall Type I 
error rate 
APJl~ 205 pts/ann 
No further testing conducted, 
although the contribution of 
binimctinib to efficacy of the 
Triplet combination may be 
further evaluated at a later 
data cutoff 
Test Triplet vs. Control OS 
at final analysis 
Resultsarepo7 
Test subsequent endpoints• 
in hierarchy, using a 
gatekeeping procedure to 
control the o\·erall Type I 
error rate 
A~ 
205 pts/arm 
No furthertestingcondueted 
~tsare negati\·e 
No furthertestingc.onducted 
• Subsequent endpoints would be tested in the following order: Doublet vs. Control OS, Doublet vs. Control ORR 
per BICR, Triplet'" · Control PFS per BICR, and then Doublet,,., Control PFS per BICR. 


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11.3.3.1 Overall Survival 
Overall survival for Phase 3 is defined as the time from randomization to death due to any cause. 
Patients who do not die by the data cutoff date will be censored for OS at their last contact date. 
Overall survival will be calculated for all patients and summarized by treatment arm using the 
Kaplan-Meier (KM) method. Overall treatment arm estimates as well as treatment arm estimates 
by stratum will be provided.  
For the OS primary endpoint, the null hypothesis is that the OS for the Triplet Arm is less than or 
equal to the OS of the Control Arm, i.e., 
H0: SOS,A (t) ≤ SOS,C (t) 
where SOS,A (t) is the OS survival distribution function for the Triplet Arm and SOS,C (t) is the OS 
survival distribution function for the Control Arm. The null hypothesis will be tested using a 
stratified log-rank test against the alpha assigned to the endpoint based on the fallback approach. 
The stratification factors used in the test will be those used for randomization, and will be based 
on the actual randomization (IWRS) information. A stratified Cox proportional hazard model 
will be fit with treatment arm as the covariate to obtain a HR estimate of the treatment effect 
along with 95% CI 
The primary analysis of OS will be based on the intent-to-treat (ITT) principle, with patients in 
the treatment group assigned at randomization. Additional details will be provided in the SAP. 
A similar hypothesis and testing approach will be used for the comparison of the Doublet Arm 
OS to the Control Arm and for the secondary objective of comparing the Triplet Arm OS to that 
of the Doublet Arm.   
At the initial analysis of the study, an interim analysis for superiority or (non-binding) futility of 
the Triplet vs Control OS endpoint will be performed based on all available data (i.e., using the 
FAS). Futility and superiority boundaries for both the OS interim and final analyses will be 
determined using a Lan-DeMets spending function (Lan and DeMets 1983) that approximates 
O’Brien-Fleming stopping boundaries. 
11.3.3.2 Objective Response Rate 
The overall best response (i.e., CR or PR) as assessed by BICR per RECIST v1.1 will be 
determined for each patient. The ORR will be calculated within each treatment arm, where ORR 
is defined as the number of patients achieving an overall best response of CR or PR divided by 
the total number of patients in that treatment arm.  
The ORR will be tested for the primary endpoint Triplet Arm vs. Control Arm comparison using 
the Cochran-Maentel-Haenszel test at a one-sided alpha of 0.005 using the Phase 3 Response 
Efficacy Set. Both confirmed and unconfirmed ORR will be summarized but, for purposes of 


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formal testing, the analysis of the confirmed responses will be used. The stratification factors 
used in the test will be those used for randomization and will be based on the actual 
randomization (IWRS) information. For the primary analysis, ORR will be presented by arm and 
stratum, along with a 95% and 99% CI. 
11.3.3.3 Efficacy Analyses of Secondary Endpoints 
11.3.3.3.1 Progression Free Survival (PFS) 
Progression-free survival is defined as the time from randomization to the earliest documented 
date of disease progression, per RECIST v1.1 and as determined by Investigator, or death due to 
any cause. Progression-free survival will be calculated for all patients and summarized by 
treatment arm using the KM method. The Safety Lead-in Efficacy Set will be used to summarize 
the PFS in Safety Lead-in patients, and the FAS will be used for the randomized Phase 3 
patients.  
Progressive disease and death (from any cause) will be considered as events. If death or PD is 
not observed, the PFS will be censored at the date of last adequate tumor assessment (i.e., at the 
date of last tumor assessment of CR, PR or SD) prior to cutoff date or date a subsequent 
anticancer therapy for mCRC is started (e.g., systemic therapy, non-palliative radiotherapy). 
However, if a PFS event is observed after more than 1 missing or inadequate tumor assessment, 
PFS will be censored at the last adequate tumor assessment. If a PFS event is observed after a 
single missing or non-adequate tumor assessment, the actual date of event will be used. 
When a patient discontinues treatment for “disease progression” but without documentation of 
radiological and/or pathological evidence of progression based on RECIST it will not be counted 
as a PFS event. The patient will continue to be followed for PFS until disease progression, 
withdrawal of consent, initiation of subsequent anticancer therapy, the patient is lost to follow-up 
or until death. If a PFS event occurs during this follow-up, the date of the event will be included 
in the analysis. If the patient does not have a PFS event during this time, the patient will be 
censored at the last assessment date. 
Progression-free survival of the arms will be compared using a stratified log-rank test. The 
stratification factors used in the test will be those used for randomization, and will be based on 
the actual randomization (IWRS) information. A stratified Cox model will be fit with treatment 
arm as the covariate to obtain an HR estimate of the treatment effect along with 95% CI. 
Additional sensitivity analyses examining alternative censoring rules will be described in the 
SAP. 
11.3.3.3.2 Objective Response Rate 
The overall best response (i.e., CR or PR) as assessed by the Investigator and retrospectively by 
BICR per RECIST v1.1 will be determined for each patient. The ORR will be calculated within 


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each treatment arm, where ORR is defined as the number of patients achieving an overall best 
response of CR or PR divided by the total number of patients in that treatment arm. The Safety 
Lead-in Efficacy Set will be used to summarize the ORR in Safety Lead-in patients, and both the 
Phase 3 Response Efficacy Set and FAS will be used for the randomized Phase 3 patients.  
The ORR will be compared between treatment arms using the Cochran-Maentel-Haenszel test. 
Both confirmed and unconfirmed ORR will be summarized, but for purposes of the hierarchical 
testing, the analysis of the confirmed responses will be used. The stratification factors used in the 
test will be those used for randomization and will be based on the actual randomization (IWRS) 
information. The ORR along with a 95% CI will be presented by arm.   
11.3.3.3.3 Duration of Response 
Duration of response is defined as the time from first radiographic evidence of response to the 
earliest documented PD or death and is calculated for responders only. Responders who do not 
have a PD or death date by the data cutoff date will be censored for DOR at their last adequate 
radiological assessment (i.e., at the date of last tumor assessment of CR, PR or SD) prior to 
cutoff date or date a subsequent anticancer therapy for mCRC is started. The Safety Lead-in 
Efficacy Set will be used to summarize the DOR in Safety Lead-in patients, and both the Phase 3 
Response Efficacy Set and FAS will be used for the randomized Phase 3 patients. Duration of 
response will be summarized by arm using the KM method.   
11.3.3.3.4 Time to Response 
Time to response (CR or PR) is defined as the time from date of randomization to date of first 
radiographic evidence of response. Patients who do not have a CR or PR by the data cutoff date 
will be censored for time to response at their last radiological assessment. Patients who receive 
subsequent anticancer therapy prior to response will be censored at their last radiological 
assessment prior to initiation of subsequent anticancer therapy. The Safety Lead-in Efficacy Set 
will be used to summarize the time to response in Safety Lead-in patients, and both the Phase 3 
Response Efficacy Set and FAS will be used for the randomized Phase 3 patients. Time to 
response will be summarized by arm using the KM method.  
11.3.3.4 Assessment of the Binimetinib Contribution to Efficacy 
To adequately assess the efficacy benefit that binimetinib contributes to the triplet combination, 
comparisons of the Triplet Arm to the Doublet Arm will be conducted for each efficacy endpoint 
using the FAS. 
A comparison of the OS distributions for the Triplet Arm and the Doublet Arm will be described 
in tabular and graphical format by treatment arm using KM methods. A Cox regression model 
stratified by randomization stratification factors will be also used to estimate the HR of OS, 
along with 95% CI based on the Wald test. Nominal p-values will be provided. 


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In addition to the response rates reported by treatment arms with exact binomial confidence 
intervals, the Cochran-Mantel-Haenszel test will be used to compare ORR between the Triplet 
Arm and the Doublet Arm. The stratification factors used in the test will be those used for 
randomization, and will be based on the actual randomization (IWRS) information. Nominal 
p-values will be provided. Separate summaries for confirmed responses and all responses 
(confirmed and unconfirmed) will be generated. 
The PFS of the Triplet Arm and the Doublet Arm will be summarized using the KM method. 
Nominal p-values will be provided. Time to response and DOR of the two arms will also be 
summarized using the KM method. 
11.3.4 Pharmacokinetic Analysis 
Plasma concentrations of encorafenib, binimetinib and the active metabolite of binimetinib 
(AR00426032) and serum concentrations of cetuximab will be determined using validated 
assays. Descriptive statistics of concentrations will be reported and summarized graphically.  
Pharmacokinetic parameters from the Safety Lead-in will be generated by noncompartmental 
and/or compartmental approaches as appropriate. No noncompartmental PK parameters will be 
estimated in the Phase 3 portion of the study due to sparse sampling. Phase 3 PK parameters will 
be estimated for encorafenib, cetuximab, binimetinib and the active metabolite of binimetinib 
(AR00426032) as appropriate using a population model-based approach for patients in the Safety 
Lead-in, Triplet, Doublet, and Control Arms, as appropriate, to determine appropriate model-
based PK parameters and their respective variability, if deemed appropriate. Pharmacokinetic 
data may be analyzed in at least 2 ways:  
• Data from this study will be analyzed alone based on the previously described population 
PK model. The structure of the model will remain similar but parameters (fixed and 
random effects) will be estimated based on the current population. 
• If needed, prior knowledge from other studies with intensive sampling may be introduced 
in the analysis by either fixing the population parameters to the value estimated 
previously or by adding data from the previous studies to the dataset to estimate 
population parameters and derive Empirical Bayes Estimates of PK parameters for 
patients in this study. 
Assessments for potential drug interactions between encorafenib, cetuximab, binimetinib and the 
active metabolite (AR00426032) will be conducted by comparison to historical results for all 
3 study drugs and by covariate modeling as part of the population PK analysis, as appropriate. 
The following effects will be assessed:  encorafenib exposure affecting cetuximab exposure, 
binimetinib exposure affecting cetuximab exposure and encorafenib exposure affecting 
binimetinib exposure. The effect of clinical source of cetuximab study drug on cetuximab PK 
may also be assessed. Additional assessments may be performed as appropriate. 


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11.3.7.2 Concomitant Medications 
Concomitant medications will be listed and summarized by Anatomical Therapeutic 
Classification System term, preferred term and treatment arm. These summaries will include 
medications starting on or after the start of study treatment or medications starting prior to the 
start of study treatment and continuing after the start of study treatment. 
11.3.7.3 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Incidence tables will be presented for all AEs by maximum grade. Adverse events, 
SAEs, AEs assessed as related to study drug and AEs resulting in dose reduction, interruption or 
discontinuation of study drug will be tabulated, as well as AEs leading to additional therapy.  
Summaries for deaths on-study will be provided by system organ class, preferred term, and 
treatment arm. 
Adverse events of special interest for both encorafenib and binimetinib will be identified and 
additional analyses, including time to onset and duration, may be estimated for these events. 
Such categories consist of 1 or more well-defined safety events which are similar in nature and 
for which there is a specific clinical interest in connection with the study treatment. For each 
specific category, number and percentage of patients with at least 1 event will be reported.  
For this study, the categories for encorafenib include the following (based on grouping of 
selected AEs and laboratory parameters) and may be updated during the course of the study 
based on accumulating safety data:  
• Acute renal failure  
• Dermatologic events (rash and skin except rash) 
• Facial paresis 
• Fatigue/asthenia 
• Gastrointestinal events 
• Headache 
• Heart rate increased events 
• Myopathy/rhabdomyolysis events 
• Ophthalmic events (retinal, vascular and other eye events) 


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• QTc prolongation 
• Secondary neoplasms 
The categories for binimetinib include the following (based on grouping of selected AEs and 
laboratory parameters) and may be updated during the course of the study based on 
accumulating safety data:  
• Cardiac events (i.e., LVEF decrease) 
• Dermatologic events (rash and skin except rash) 
• Edema events 
• Fatigue and asthenia 
• Gastrointestinal events 
• Hepatic events 
• Hemorrhage 
• Hypertension 
• Ophthalmic events (retinal, vascular and other eye events) 
• Myopathy/rhabdomyolysis events 
• Pneumonitis 
• QTc prolongation 
• Thrombotic/embolic events 
Adverse events of special interest do not require special reporting to the Sponsor unless the 
event(s) meets SAE reporting criteria (see Section 10.9). 
11.3.7.4 Laboratory Parameters 
Hematology and chemistry laboratory parameters will be presented in shift tables of Baseline 
grade vs. maximum grade on study. For laboratory parameters that are not gradable by CTCAE, 
shift tables of normal-abnormal will be provided. Laboratory measurements will be summarized 
descriptively by visit and treatment arm, and plots of measurements over time will be generated 
for selected parameters.  


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Both central and local laboratory values will be considered for summaries and both will be 
presented in listings.  
11.3.7.5 Electrocardiograms 
Electrocardiogram values will be summarized descriptively and/or with shift tables by treatment 
arm. 
11.3.7.6 Other Safety Data 
Vital signs, body weight, ECOG PS, dermatologic and ophthalmic examination data will be 
summarized descriptively by visit and/or with shift tables by treatment arm. Summaries of 
clinically notable measurements will also be provided. Definitions of “clinically notable” will be 
provided in the SAP. 
11.3.7.7 Patient-Reported Outcomes 
Quality-of-life data will be analyzed on the FAS. 
The EORTC QLQ-C30, FACT-C, EQ-5D-5L and PGIC will be used to assess QoL. For 
EORTC-QLQ-C30, the global health status/QoL scale score is identified as the primary 
patient-reported outcome variable of interest; physical functioning, emotional functioning and 
social functioning scale scores of the QLQ-C30 are considered as secondary. For FACT-C, the 
functional well-being score is the primary patient-reported outcome variable of interest; the 
physical well-being, social/family well-being, emotional well-being, and additional concern 
scores are considered as secondary. The EQ-5D-5L contains 1 item for each of 5 dimensions 
health-related quality of life (i.e., mobility, self-care, usual activities, pain or discomfort, and 
anxiety or depression). Response options for each item vary from having no problems, moderate 
problems, or extreme problems.    
The EORTC QLQ-C30, FACT-C, EQ-5D-5L and PGIC will be scored according to respective 
scoring manuals, respectively. The number of patients completing the questionnaires and the 
number of missing or incomplete assessments will be summarized by each treatment arm for 
each scheduled assessment time point. 
Descriptive statistics will be used to summarize the scored scales at each scheduled assessment. 
Additionally, change from baseline in the domain scores at the time of each assessment will be 
summarized. Patients with an evaluable baseline score and at least 1 evaluable post-baseline 
score during the treatment period will be included in the change from baseline analyses. In 
addition, a repeated measurement analysis model may be used to compare the 2 treatment arms 
with respect to changes in the domain scores longitudinally over time. Full details of the 
modeling analysis will be provided in the SAP. 


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Time to definitive deterioration in the QoL domains will be assessed in the treatment arms in the 
FAS. The time to definitive deterioration is defined as the time from the date of randomization to 
the date of event, which is defined as at least 10% worsening relative to Baseline of the 
corresponding scale score with no later improvement above this threshold observed during the 
course of the study or death due to any cause. If a patient has not had an event prior to analysis 
cutoff or start of another anticancer therapy, time to deterioration will be censored at the date of 
the last adequate QoL evaluation. The distribution will be presented descriptively using KM 
curves. Median time to definitive deterioration along with 2-sided 95% CI will be provided. 
Additionally, time to definitive deterioration with different cutoff definitions (e.g., 5%, 15%) 
may be specified in the SAP as deemed appropriate. A Cox model will be fit with treatment arm 
and stratification factors as the covariates to obtain a HR estimate of the treatment effect along 
with 95% CI. The stratification factors used in the test will be precisely those used for 
randomization, and will be based on the actual randomization (IWRS) information. 
11.3.8 Interim Safety Reviews 
The independent DMC will review the available safety information after the first 30 patients in 
the randomized Phase 3 portion of the study (i.e., approximately 10 patients in each arm) have 
had the opportunity to complete at least 1 cycle of treatment to confirm tolerability. Subsequent 
DMC safety data reviews will occur at regular intervals. Additional details will be outlined in the 
DMC Charter. 
11.3.9 Initial Efficacy Analyses 
An initial analysis of the study will be performed when all three of the following criteria have 
been met: 
• approximately 9 months after randomization of the 330th patient (i.e., approximately 
110 patients per arm), to allow a majority of responders among the 330 Phase 3 patients 
to have the opportunity to be followed for approximately 6 months or longer after their 
first response 
• at least 188 OS events have occurred in the Triplet and Control arms combined 
(i.e., approximately 70% information) 
• at least 169 OS events have occurred in the Doublet and Control arms combined 
(i.e., approximately 50% information) 
The primary endpoint of Triplet vs. Control ORR (per BICR) will be formally tested first at this 
analysis and will be based on the first approximately 330 randomized patients (any additional 
patient[s] randomized on the same day as the 330th randomized patient will be included in the 
analysis). If the Triplet vs. Control ORR comparison is positive (i.e., p < 0.005), then based on 
the fallback procedure, the OS endpoint of Triplet vs. Control will be assigned a total 1-sided 
alpha = 0.025. Otherwise, the Triplet vs. Control OS will be assigned a total 1-sided alpha 
= 0.020. 


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An interim analysis for superiority or (non-binding) futility of the Triplet vs Control OS endpoint 
will be also performed at the time of the primary ORR analysis based on all available data. 
Futility and superiority boundaries for both the OS interim and final analyses will be determined 
using a Lan-DeMets spending function that approximates O’Brien-Fleming stopping boundaries.  
If the p-value for the Triplet Arm vs Control Arm OS comparison exceeds the superiority 
boundary at the interim analysis, testing of the endpoints included in the hierarchical approach 
described in Section 11.3.3 will be conducted. For each endpoint in the hierarchy, a Lan-DeMets 
spending function that approximates the O’Brien-Fleming stopping boundaries will be used with 
data from all available patients. The total alpha assigned to each endpoint will be either 0.025 (if 
the Triplet Arm vs. Control Arm ORR comparison was p < 0.005) or 0.020 (if the Triplet Arm 
vs. Control Arm ORR comparison was p ≥ 0.005). 
If the p-value for the Triplet Arm vs Control Arm OS comparison does not exceed the superiority 
boundary at the interim analysis, OS of Triplet Arm vs. Control Arm will be tested again at the 
final analysis (i.e., when at least 268 OS events in Triplet and Control and at least 338 OS events 
in Doublet and Control have occurred). Table 30 provides the number of expected events, the 
cumulative alpha spent, and the cumulative power to reject the null hypothesis at the expected 
analysis timepoints for the Triplet vs Control OS analysis. 
Table 30: 
Expected Number of OS Events and Cumulative Power at Expected OS 
Analysis Timepoints for the Triplet vs Control Comparison 
 
 
OS Analysis 
 
 
Triplet vs 
Control OS 
Analysis 
Cumulative 
Number of OS 
Events 
Cumulative 
Alpha Spent on 
OS 
Cumulative 
Power to Reject 
H0 for OS (%) 
Triplet vs Control ORR is 
statistically significant  
(i.e., one-sided p<0.005) 
Interim 
188 
0.0074 
61.5 
Final 
268 
0.0250 
88.3 
Triplet vs Control ORR is not 
statistically significant  
(i.e., one-sided p>0.005) 
Interim 
188 
0.0055 
57.4 
Final 
268 
0.0200 
86.3 
Note: All values were calculated using East® v6.4, assuming 70% information at the OS interim analysis. Boundaries will be 
adjusted according to the actual information fraction observed at the interim analysis. Cumulative power values were estimated 
using simulations within East® under the alternative hypothesis.  
Efficacy and futility are determined using Lan-DeMets approximation of O’Brien-Fleming alpha- and (non-binding) 
beta-spending boundaries, respectively. 
 


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12.0 DATA RECORDING, RETENTION AND MONITORING 
12.1 Data Management 
Data will be collected using an electronic data capture system (EDC) at the clinical site. The 
Investigator or designee will record data specified in the protocol using eCRFs. Changes or 
corrections to eCRFs will be made by the Investigator or an authorized member of the study staff 
according to the policies and procedures at the site. 
It is the Investigator’s responsibility to ensure eCRFs are complete and accurate. Following 
review and approval, the Investigator will electronically sign and date the pages. This signature 
certifies that the Investigator has thoroughly reviewed and confirmed all data on the eCRF. 
A portable document format (PDF) file of the eCRFs will be provided to the site after all data 
have been monitored and reconciled. An electronic copy will be archived at the site. 
12.2 Data Monitoring 
This study will be closely monitored by representatives of the Sponsor throughout its duration. 
Monitoring will include personal visits with the Investigator and study staff as well as 
appropriate communications by telephone, fax, mail, email or use of the EDC system, if 
applicable. It is the monitor’s responsibility to inspect eCRFs at regular intervals throughout the 
study to verify the completeness, accuracy and consistency of the data and to confirm adherence 
to the study protocol and to Good Clinical Practice (GCP) guidelines. The Investigator agrees to 
cooperate with the monitor to ensure that any problems detected during the course of this study 
are resolved promptly. The Investigator and site will permit study-related monitoring, audits, EC 
review and regulatory inspection, including direct access to source documents. 
It is understood that study monitors and any other personnel authorized by the Sponsor may 
contact and visit the Investigator and will be permitted to inspect all study records (including 
eCRFs and other pertinent data) on request, provided that patient confidentiality is maintained 
and that the inspection is conducted in accordance with local regulations. 
Every effort will be made to maintain the anonymity and confidentiality of patients during this 
study. However, because of the experimental nature of this treatment, the Investigator agrees to 
allow representatives of the Sponsor, the development partner of the Sponsor, as well as 
authorized representatives of regulatory authorities to inspect the facilities used in the conduct of 
this study and to inspect, for purposes of verification, the hospital or clinic records of all patients 
enrolled in the study. 


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12.3 Quality Control and Quality Assurance 
Quality control procedures will be conducted according to the Sponsor’s internal procedures. 
The study site may be audited by a quality assurance representative of the Sponsor. All necessary 
data and documents will be made available for inspection. 


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13.0 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
13.1 Good Clinical Practice 
The study will be performed in accordance with the protocol, guidelines for GCP established by 
the International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and applicable local regulatory requirements and laws 
and in accordance with European Clinical Trials Directive. 
13.2 Ethics Committee Approval 
The Investigator must inform and obtain approval from the EC for the conduct of the study at 
named sites, the protocol, informed consent documents and any other written information that 
will be provided to the patients and any advertisements that will be used. Written approval must 
be obtained prior to recruitment of patients into the study and shipment of study drug. 
Proposed amendments to the protocol and aforementioned documents must be submitted to the 
Sponsor for review and approval, then to the EC. Amendments may be implemented only after a 
copy of the approval letter from the EC has been transmitted to the Sponsor. Amendments that 
are intended to eliminate an apparent immediate hazard to patients may be implemented prior to 
receiving Sponsor or EC approval. However, in this case, approval must be obtained as soon as 
possible after implementation. 
Per GCP guidelines, the Investigator will be responsible for ensuring that an annual update is 
provided to the EC to facilitate continuing review of the study and that the EC is informed about 
the end of the study. Copies of the update, subsequent approvals and final letter must be sent to 
the Sponsor. 
13.3 Regulatory Authority Approval 
The study will be performed in accordance with the requirements of each country’s regulatory 
authorities (e.g., FDA, European Medicines Agency (EMA) and Health Canada) and will also 
meet all of the requirements of ICH GCP guidance. Amendments to the protocol will be 
submitted to the relevant authorities (e.g., FDA, EMA or Health Canada) for approval prior to 
implementation in accordance with applicable regulations. 
13.4 Other Required Approvals 
In addition to EC and regulatory authority approval, all other required approvals (e.g., approval 
from the local research and development board or scientific committee) will be obtained prior to 
recruitment of patients into the study and shipment of study drug. 


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13.5 Informed Consent 
Informed consent is a process that is initiated prior to the patient’s agreeing to participate in the 
study and continues throughout the patient’s study participation. It is the Investigator’s 
responsibility (or designee) to obtain written informed consent from each patient after adequate 
explanation of the aims, methods, anticipated benefits and potential hazards of the study and 
before any study procedures are initiated. Each patient should be given a copy of the informed 
consent document and associated materials. The original copy of the signed and dated informed 
consent document must be retained at the site and is subject to inspection by representatives of 
the Sponsor or regulatory authorities. If any amendments occur throughout the course of the 
study that affect the ICF (i.e., when new study procedures or assessments have been added), all 
active patients should be reconsented using the same process for the initial consent. 
13.6 Patient Confidentiality 
The Investigator must ensure that the patient’s privacy is maintained. On the eCRF or other 
documents submitted to the Sponsor, patients will be identified by a patient number only. 
Documents that are not submitted to the Sponsor (e.g., signed informed consent documents) 
should be kept in a confidential file by the Principal Investigator. 
The Investigator shall permit authorized representatives of the Sponsor, regulatory authorities 
and ethics committees to review the portion of the patient’s medical record that is directly related 
to the study. As part of the required content of informed consent documents, the patient must be 
informed that his/her records will be reviewed in this manner. 
13.7 Disclosure of Information 
Information concerning the study, patent applications, processes, scientific data or other pertinent 
information is confidential and remains the property of the Sponsor. The Principal Investigator 
may use this information for the purposes of the study only. 
It is understood by the Principal Investigator that the Sponsor will use information obtained in 
this clinical study in connection with the clinical development program, and therefore may 
disclose it as required to other clinical investigators and to regulatory authorities. In order to 
allow the use of the information derived from this clinical study, the Principal Investigator 
understands that he/she has an obligation to provide complete test results and all data obtained 
during this study to the Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting should only 
be undertaken with written consent from the Sponsor. 


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13.8 Publication of Study Data 
The conditions regulating dissemination of the information derived from this study are described 
in the Clinical Trial Agreement. 


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14.0 ADHERENCE TO THE PROTOCOL 
Investigators must apply due diligence to avoid protocol deviations, and the Sponsor (and 
designee[s]) will not pre-authorize deviations. If the Investigator believes a change to the 
protocol would improve the conduct of the study, this must be considered for implementation in 
a protocol amendment. Protocol deviations will be recorded. 
14.1 Amendments to the Protocol 
Only the Sponsor may modify the protocol. The only exception is when the Investigator 
considers that a patient’s safety is compromised without immediate action. In these 
circumstances, immediate approval of the chairman of the EC must be sought, and the 
Investigator should inform the Sponsor and the full EC within 5 working days after the 
emergency occurred. All amendments that have an impact on patient risk or the study objectives 
or require revision of the informed consent document must receive approval from the EC prior to 
implementation. 


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15.0 REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;3;85(5):365-76. 
American Society for Clinical Pathology (ASCP), the College of American Pathologists (CAP), 
American Society of Clinical Oncology (ASCO) and the Association for Molecular Pathology 
(AMP): Guideline on the Evaluation of Molecular Markers for Colorectal Cancer Expert Panel 
Draft Recommendations Summary for Open Comment Period. Available at: 
http://www.amp.org/committees/clinical_practice/documents/20150327CRCMMDraftRecomme
ndationsforOCP-UPDATEDfinaldraft_001.pdf. Accessed April, 2016. 
Amir E, Seruga B, Kwong R, et al. Poor correlation between progression-free and overall 
survival in modern clinical trials: Are composite endpoints the answer? Eur J Cancer. 
2012;48(3):385-8. 
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Appendix 1: Recommended Guidelines for the Management of Cetuximab-induced, 
Encorafenib-induced and/or Binimetinib-induced Skin Toxicity 
Clinical judgment and experience of the treating physician should guide the management plan of 
each patient. In general, the following interventions are in addition to the cetuximab-induced 
rash and the encorafenib-induced and/or binimetinib-induced rash dosing guidelines provided in 
Table 17 and Table 16, respectively, of the protocol. 
The Initial Rash Treatment Regimen may be initiated as prophylactic treatment 24 hours prior to 
the first treatment, or later as needed to treat mild rash (CTCAE Grade 1). 
Initial Rash Treatment Regimen: 
• Application of topical agents to the most commonly affected skin areas such as face, 
scalp, neck, upper chest and upper back. Topical agents include the following: 
o Non-oily sunscreen (PABA-free, SPF ≥ 30, UVA/UVB protection); 
o Topical steroids, preferably mometasone cream (e.g., Elocon®); 
o Topical erythromycin (e.g., Eryaknen®); 
o Topical pimocrolimus. 
Note: Topical agents should be applied on a daily basis starting on Day 1 of study treatment or 
24 hours prior to first treatment, and more often as needed. 
• Possibly oral doxycycline (100 mg daily) for the first 2 to 3 weeks of study drug 
administration. 
Other effective medications are antihistamines, other topical corticosteroids, other topical 
antibiotics and low-dose systemic corticosteroids. 
The treatment algorithm based on CTCAE grade is as follows: 
Mild Rash (CTCAE Grade 1) Treatment Regimen: 
• Initiate Initial Rash Treatment Regimen, if not already started. 
• Use of topical corticosteroid (e.g., mometasone cream) and/or topical antibiotic (e.g., 
erythromycin 2%) is recommended. 
• The patient should be reassessed within a maximum of 2 weeks, or as per Investigator 
opinion. 


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Moderate Rash (CTCAE Grade 2) Treatment Regimen: 
• Use of topical erythromycin or clindamycin (1%) plus topical mometasone or topical 
pimecrolimus (1% cream) plus oral antibiotics, such as lymecycline (408 mg QD), 
doxycycline (100 mg BID) or minocycline (50 to 100 mg BID). 
• Although there has been no evidence of phototoxicity or photosensitivity in patients 
treated with binimetinib, doxycycline (or minocycline as second line) should be used 
with thorough UV protection (i.e., avoidance of direct exposure to sunlight, use of 
sunscreen and sunglasses, etc.). 
• Use of acitretin is not recommended. 
Severe Rash (CTCAE Grade 3-4) Treatment Regimen: 
CTCAE Grade 3: 
• In addition to the interventions recommended for moderate rash, consider oral 
prednisolone at a dose of 0.5 mg/kg. Upon improvement, taper the dose in a stepwise 
manner (25 mg for 7 days, subsequently decreasing the dose by 5 mg/day every day). 
• Alternatively, in addition to the interventions recommended for moderate rash, consider 
oral isotretinoin (low dose, i.e., 0.3 to 0.5 mg/kg) (Lacouture et al. 2011). 
• Use of acitretin is not recommended. 
CTCAE Grade 4 Treatment Regimen: 
• Immediately discontinue the patient from study drug and treat the patient with oral or 
topical medications (see recommendation CTCAE Grade 3). 
Symptomatic Treatment Regimen: 
It is strongly recommended that patients who develop rash/skin toxicities receive symptomatic 
treatment: 
• For pruritic lesions: use cool compresses and oral antihistamine agents. 
• For fissuring: use Monsel’s solution, silver nitrate or zinc oxide cream. If not sufficient, 
use mild corticosteroid ointments or ointments containing a combination of corticosteroid 
and antibiotic such as Fucicort®. 
• For desquamation: use emollients that are mild pH 5/neutral (recommended to contain 
10% urea). 


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• For paronychia: use antiseptic bath and local potent corticosteroids, use oral antibiotics, 
and, if no improvement is seen, refer to a dermatologist or surgeon. 
• For infected lesions: obtain bacterial and fungal cultures and treat with topical or 
systemic antibiotics, if indicated, based on sensitivity of culture. 
References: 
Lacouture ME, Anadkat MJ, Bensadoun RJ et al. Clinical practice guidelines for the prevention 
and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 
2011;19:1079–95. 


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Appendix 2: Recommended Guidelines for the Management of Encorafenib-induced 
Hand-foot skin reactions (HFSR) 
Clinical judgment and experience of the treating physician should guide the management plan of 
each patient. In addition to the HFSR dosing guidelines in Table 16 of the protocol, the following 
algorithm is recommended for the management of HFSR based on the severity (CTCAE grading, 
see Table 14) of HFSR (adapted from Nardone et al. 2012). 
Algorithm for the Management of HFSR Based on the Severity of HFSR 
HFSR severity 
Intervention 
No HFSR 
Maintain Frequent Contact with physician to ensure early 
diagnosis of HFSR 
Therapy initiation 
Full body-skin examination, pedicure, evaluation by podiatrist or 
orthotist; wear thick cotton gloves and/or socks; avoid hot water, 
constrictive footwear and excessive friction 
If symptoms develop, proceed to next step 
 
Grade 1 
Maintain current dose of BRAF inhibitor; monitor patient for 
change in severity 
Minimal skin changes or dermatitis without 
pain e.g.: 
 
● Numbness 
● Tingling 
● Dysesthesia 
● Paresthesia 
● Erythema 
● Edema 
● Hyperkeratosis 
 
No interference with ADL 
Avoid hot water; use moisturizing cream for relief; wear thick cotton 
gloves and/or socks; use a 20-40% urea , salicylic acid 3-6%; 
ammonium lactate 12 % or lactic acid 12 % based creams to aid 
exfoliation. 
If symptoms worsen, proceed to next steps 
 
Grade 2 
Maintain current dose of BRAF inhibitor; monitor patient for 
change in severity 
Skin changes with pain e.g. 
Peeling 
● Blisters 
● Bleeding 
● Edema 
● Hyperkeratosis 
Limited instrumental ADL 
Treat as with Grade 1 toxicity, with the following additions: 
clobetasol 0.05% ointment, 2-4% lidocaine, opiates, NSAIDS, or 
GABA agonists for pain; follow dose modifications listed in Table 16 
If no improvement within 15 days, proceed to next steps. 
 
Grade 3 
Interrupt dose until improvement to Grade 0-1 
Severe skin changes with pain e.g. 
Treat as in Grades 1 and 2 


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The following supportive care measures for the prevention, and/or management of HFSR 
summarized in the table below should be instituted along with proper patient education. 
Supportive Care for the Prevention and Management of HFSR 
Stage 
Recommendations 
Prior to initiation of study treatment 
Educate the patient about the early signs and symptoms of HFSR 
and discuss the importance of early reporting. HFSR could start as 
early as 2-5 days after study drug initiation, and mostly expected to 
occur during the first 2 months of treatment. 
Prevention of HFSR for the first 2 months of 
treatment with encorafenib 
Monitor the patient for signs and symptoms of HFSR. Instruct the 
patient to: 
- Apply emollient cream regularly to hands and feet: use 20-40% 
urea , salicylic acid 3-6%; ammonium lactate 12% or lactic acid 
12 % based creams 
- Wear cotton socks or gloves to bed to enhance the absorption of 
creams 
- Avoid tight, irritating or ill-fitting clothing and shoes 
- Avoid repetitive activity or staying in one position for long 
periods of time 
- Pat (do not rub) skin dry with towels 
- Avoid extremes of temperature, pressure and friction 
- Avoid performing mechanically stressful manual work 
- Cushioning of callused areas 
- Use of moisturizing and keratolytic creams to control existing 
palmar and plantar hyperkeratosis 
Treatment of HFSR 
1) Ensure that patient follows treatment interruption or dosage 
reduction guidelines 
2) Monitor the patient for worsening/resolution of HFSR (Normal 
frequency monthly, except if patient has Grade 2 or 3 HFSR, where 
bi weekly- visits are recommended) 
3) Prescribe analgesics if necessary 
4) Instruct the patient to: 
- Continue the use of prevention strategies 
- Cushion sore skin 
- For control or relief of pain symptoms, patient may submerge 
hands and feet in cool water baths or apply cold compresses for 
relief 
a Wear loose-fitting clothing made of soft, natural fabrics and shoes that are wide and comfortable. Avoid tight belts, 
panties and bras. 
This table is adapted from (van Moos et al. 2008). 
Peeling 
● Blisters 
● Bleeding 
● Edema 
● Hyperkeratosis 
Limiting self-care ADL 
 
Follow dose modifications listed in Table 16  
 
 


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References: 
Nardone B, Hensley JR, Kulik L, et al. (2012). The effect of hand-foot skin reaction associated 
with the multikinase inhibitors sorafenib and sunitinib on health-related quality of life. Journal of 
Drugs in Dermatology Nov 2011: 11;11:e61-5. 
Van Moos R, Thuerlimann B, Chair M, etal. (2008) Pegylated liposomal doxorubicin-associated 
hand-foot syndrome: Recommendations of an international panel of experts. Eur J Cancer: 
1016:1-10. 
 


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Appendix 3: Recommended Guidelines for the Management of Binimetinib-induced 
Diarrhea 
Proactively Investigate for Occurrence of Diarrhea and Educate Patient: 
1. 
Remind patients at each visit to contact the Investigator immediately upon the first sign 
of loose stool or symptoms of abdominal pain. Additionally, at each study visit, each 
patient should be asked regarding occurrence of diarrhea or diarrhea-related symptoms. If 
the patient has had symptoms, the patient should be asked regarding the actions taken for 
these symptoms and re-instruct if indicated. 
2. 
Patients should be instructed on dietary modification and early warning signs of diarrhea 
and potentially life-threatening illnesses (e.g., severe cramping might be a sign of severe 
diarrhea; fever with diarrhea might be a sign of infection; fever and dizziness on standing 
might be a sign of shock).  
3. 
Patients should be educated about what to report to the Investigator (i.e., number of 
stools, stool composition, stool volume). 
Anti-diarrhea Therapy: 
In order to effectively manage diarrhea and mitigate the escalation in severity or duration of 
diarrhea, patient education as outlined above, as well as proper management of diarrhea is 
important.  
Management of diarrhea should be instituted at the first sign of abdominal cramping, loose stools 
or overt diarrhea. All concomitant therapies /used for treatment of diarrhea must be recorded on 
the eCRF. It is recommended that patients be provided loperamide tablets and be instructed on 
the use of loperamide on the first day of binimetinib dosing. In addition to the binimetinib-
induced diarrhea dosing guidelines provided in Table 16 of the protocol, these instructions 
should be provided at each visit and the site should ensure that the patient understood the 
instructions.  
See Table 15 in the protocol to explain the frequency of diarrhea and its relationship to NCI 
CTCAE, v.4.03 grading and to determine if diarrhea is complicated or uncomplicated. 
Rule out Other or Concomitant Causes: 
These may include: 
• Infection with Candida, Salmonella, Clostridium difficile, Campylobacter. Giardia, 
Entamoeba or Cryptosporidium species, which can lead to severe infections in 
immunosuppressed patients. 
• Medication-induced diarrhea. 


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• Malabsorption/lactose intolerance. 
• Fecal impaction, partial bowel obstruction. 
For Uncomplicated Grade 1/2 Diarrhea: 
• Stop all lactose-containing products and alcohol, and eat frequent small meals that 
include bananas, rice, applesauce or toast. 
• Stop laxatives, bulk fiber (e.g., Metamucil®), and stool softeners (e.g., docusate sodium, 
Colace®). 
• Stop high-osmolar food supplements (e.g., Ensure® Plus, Jevity® Plus [with fiber]). 
• Drink 8 to 10 large glasses of clear liquids per day (e.g., water, Pedialyte®, Gatorade®, 
broth). 
• Consider administration of a standard dose of loperamide: initial administration 4 mg, 
then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool. 
• Discontinue loperamide after 12-hours diarrhea-free (Grade 0) interval. 
• Consider temporary interruption of binimetinib until resolved to Grade ≤ 1. Re-treatment 
may then be resumed at current dose level. 
• If uncomplicated Grade 1 to Grade 2 diarrhea persists for more than 24 hours, escalate to 
high-dose loperamide: 2 mg every 2 hours (maximum of 16 mg/day) or after each 
unformed stool. 
Note: Oral antibiotics may be started as prophylaxis for infections under the discretion of the 
physician. 
• If uncomplicated Grade 1 to Grade 2 diarrhea persists after 48 hours of treatment with 
loperamide, discontinue loperamide and begin a second-line agent which can be an opiate 
(opium tincture or paregoric), octreotide acetate or steroid (budesonide). 
For Complicated Grade 1/2 Diarrhea or Any Grade 3/4 Diarrhea: 
• The patient must call the Investigator immediately. 
• Temporarily interrupt binimetinib treatment until resolved to Grade ≤ 1. Restart 
binimetinib at a reduced dose level. 


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• If loperamide has not been intitiated, initiate loperamide immediately. Initial 
administration 4 mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each 
unformed stool. 
• Administer IV fluids and electrolytes as needed. In case of severe hydration, replace 
loperamide with octreotide acetate. 
• Monitor/continue IV fluids and antibiotics as needed. Intervention should be continued 
until the patient is diarrhea-free for at least 24 hours. 
• Hospitalization may need to be considered. 
 
 


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Appendix 4: Snellen Equivalence (Visual Acuity Conversion Chart) 
 
References: 
Holladay JT. Visual acuity measurements. J Cataract Refract Surg. 2004;30:287-90. 
 
 


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Appendix 5: List of Concomitant Medications 
Table A: 
List of CYP450 Substrates to be Used with Caution* 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A** 
Amodiaquine 
Acenocoumarol 
Clopidogrel 
Alfentanil 1,2 
Ergotamine 2 
Cerivastatin 
Celecoxib 
Diazepam 
Alpha-dihydroergocryptine 1 
Everolimus 1 
Repaglinide 
Diclofenac 
Esoprazole 
Alprazolam 
Felodipine 1 
Rosiglitazone 
Glipizide 
Lansoprazole 
Amlodipine 
Fentanyl 2 
Torasemide 
Irbesartan 
Moclobemide 
Aplaviroc 
Fluticasone 1 
 
Losartan 
Omeprazole 
Aprepitant 1 
Indinavir 1 
Phenytoin 2 
Pantoprazole 
Aripiprazole 
Lopinavir 1 
Piroxicam 
Phenobarbitone 
Atorvastatin 
Lovastatin 1 
S-ibuprofen 
Phenytoin 2 
Boceprevir 
Maraviroc 1 
Sulfamethoxazole 
Proguanil 
Brecanavir 
Midazolam 1 
Tolbutamide 
Rabeprazole 
Brotizolam 1 
Nifedipine 
Torasemide 
S-mephenytoin 
Budesonide 1 
Nisoldipine 
 
 
Buspirone 1 
Nitrendipine 
capravirine 
Perospirone 1 
casopitant 
Quinine 
Conivaptan 1 
Saquinavir 1 
Cyclosporine 2 
Sildenafil 1 
Darifenacin 1 
Simvastatin 1 
Darunavir 1 
Sirolimus 1,2 
Diazepam 
Telaprevir 
Diergotamine 2 
Tipranavir 1 
Diltiazem 
Tolvaptan 
Ebastine 1 
Triazolam 1 
Eletriptan 1 
Verapamil 
Eplerenone 1 
 
*Table was compiled from the Indiana University School of Medicine’s “Clinically Relevant” table, a list by the United States 
Food and Drug Administration (FDA) 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm, and the 
University of Washington’s Drug Interaction Database. 
1 Sensitive substrates: Drugs whose plasma area under concentration-time curve (AUC) values have been shown to increase 5-
fold or higher when co-administered with a potent inhibitor of the respective enzyme. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their exposure 
levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., TdP). 
 


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Table B: 
List of CYP450 Substrates to be Used with Caution – CYP2B6 
CYP2B6* 
bupropion 1 
cyclophosphamide 
Efavirenz 1 
Ifosfamide 
Methadone 
Thiotepa 
*Table was compiled from the Indiana University School of Medicine’s “Clinically Relevant” table, a list by the FDA 
(http://.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm) and the 
University of Washington’s Drug Interaction Database. 
1 Sensitive substrates: The area under the concentration-time curves (AUCs) of these substrates were not increased 
by 5-fold or more with a CYP2B6 inhibitor, but they represent the most sensitive substrates studied with available 
inhibitors evaluated to date. 
 
Table C: 
Strong/Moderate CYP3A4 Inhibitors and CYP3A4 Inducers to be Prohibited 
or Administered with Caution when Co-administered with Encorafenib 
Strong Inhibitors (prohibited) 
boceprevir  
nefazodone  
Clarithromycin 
Nelfinavir 
Conivaptan 
posaconazole 
Indinavir 
Ritonavir 
Itraconazole 
Saquinavir 
Ketoconazole 
telithromycin 
Lopinavir 
troleandomycin 
Telaprevir 
Grapefruit juice (citrus paradisi fruit juice) 
Mibefradil 
Voriconazole 
Moderate inhibitors (use with caution)  
Ciprofloxacin 
Erythromycin 
Fluconazole 
Amprenavir 
Verapamil 
Imatinib 
Atazanavir 
Schisandra sphenanthera 
Aprepitant 
Casopitant 
Cyclosporine 
Cimetidine 
Tofisopam 
Dronedarone 
Fosamprenavir 
Darunavir 
Diltiazem 
 
Strong Inducers (use with caution) 
Avasimibe 
Rifampin 
Carbamazepine 
St. John’s wort 
Phenytoin 
 
Reproduced from 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm 
 


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Table D: 
Substrates of BCRP, OAT, OCT s and OATPs to be Administered with 
Caution 
 
Substrates 
BCRP 
imatinib, irrinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan 
P-gp 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, 
maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan  
OCT2 
Amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, procainamide, 
ranitidine, varenicline, oxaliplatin 
OAT1 
Adefovir, captopril, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, zalcitabine, zidovudine 
OAT3 
Acyclovir, bumetanide, ciprofloxacin, famotidine, furosemide, methotrexate, zidovudine, oseltamivir acid, (the 
active metabolite of oseltamivir), penicillin G, pravastatin, rosuvastatin, sitagliptin 
OATP1B1 
Atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 (active metabolite of irinotecan), 
rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, rifampin, valsartan, olmesartan 
OATP1B3 
Atorvastatin, rosuvastatin, pitavastatin, telmisartan, valsartan, olmesartan 
Reproduced from 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm 
 
Table E: 
Pg-P and BCRP Inhibitors/Inducers to be Used with Caution 
Transporter 
Gene 
Inhibitor 1 
Inducer 2 
P-gp 
ABCB1 
Amiodarone, azithromycin,captopril, carvedilol, 
clarithromycin, conivaptan, cyclosporine, diltiazem, 
dronedarone, erythromycin, felodipine, itraconazole, 
ketoconazole, lopinavir and ritonavir, quercetin, 
quinidine, ranolazine, verapamil 
Avasimibe,carbamazepine,phenytoin, 
rifampin, St John’s wort, 
tipranavir/ritonavir 
BCRP 
ABCG2 
Cyclosporine, elacridar (GF120918), eltrombopag, 
gefitinib 
Not known 
Reproduced from 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm 
1 Inhibitors listed for P-gp are those that showed > 25% increase in digoxin area under the concentration-time curve (AUC) or 
otherwise indicated if substrate is other than digoxin. 
2 Inducers listed for P-gp are those that showed > 20% decrease in digoxin AUC or otherwise indicated if substrate is other than 
digoxin. 
 
Table F: 
List of Inhibitors of UGT1A1 to be Used with Caution 
Inhibitors of UGT1A1 
atazanavir, erlotinib, flunitrazepam, gemfibrozil, indinavir, ketoconazole, nilotinib, 
pazopanib, propofol, regorafenib, sorafenib 
 
Table G: 
List of Potential QT Prolonging Drugs1 
Drug 
QT risk2 
Comment 
Alfuzosin 
possible risk 
  
Amantadine 
possible risk 
  
Amiodarone 
known risk  
Females > Males, TdP risk regarded as low 
Amitriptyline 
conditional risk 
Risk of TdP with overdosage. Substrate of CYP2C19 


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Drug 
QT risk2 
Comment 
Arsenic trioxide 
known risk  
  
Astemizole 
known risk  
No Longer available in U.S. Substrate for 3A4 
Atazanavir 
possible risk 
  
Azithromycin 
possible risk 
Rare reports 
Bepridil 
known risk  
Females > Males 
Chloral hydrate 
possible risk 
  
Chloroquine 
known risk  
  
Chlorpromazine 
known risk  
  
Ciprofloxacin 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Cisapride 
known risk  
No longer available in the U.S.; available in Mexico. Substrate for 3A4 
Citalopram 
known risk  
  
Clarithromycin 
known risk  
Substrate for 3A4 
Clomipramine 
conditional risk 
  
Clozapine 
possible risk 
  
Desipramine 
conditional risk 
Risk of TdP with overdosage 
Diphenhydramine 
conditional risk 
Risk of QT increase/TdP in overdosages 
Disopyramide 
known risk  
Females > Males 
Dofetilide 
known risk  
  
Dolasetron 
possible risk 
  
Domperidone 
known risk  
Not available in the U.S. 
Doxepin 
conditional risk 
  
Dronedarone 
possible risk 
Substrate for 3A4 
Droperidol 
known risk  
  
Eribulin 
possible risk 
  
Erythromycin 
known risk  
Females>Males. Substrate for 3A4 
Escitalopram 
possible risk 
  
Famotidine 
possible risk 
  
Felbamate 
possible risk 
  
Fingolimod 
possible risk 
  
Flecainide 
known risk  
  
Fluconazole 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Fluoxetine 
conditional risk 
  
Foscarnet 
possible risk 
  
Fosphenytoin 
possible risk 
  
Galantamine 
conditional risk 
  
Gatifloxacin 
possible risk 
  
Gemifloxacin 
possible risk 
  
Granisetron 
possible risk 
  
Halofantrine 
known risk  
Females>Males 
Haloperidol 
known risk  
When given intravenously or at higher-than- recommended doses, risk of 
sudden death, QT prolongation and torsades increases. Substrate for 3A4 


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Drug 
QT risk2 
Comment 
Ibutilide 
known risk  
Females>Males 
Imipramine 
conditional risk 
Risk of TdP in overdosage 
Indapamide 
possible risk 
  
Isradipine 
possible risk 
  
Itraconazole 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Ketoconazole 
conditional risk 
Drug metabolism inhibitor 
Levofloxacin 
possible risk 
  
Levomethadyl 
known risk  
Not available in the U.S. 
Lithium 
possible risk 
  
Mesoridazine 
known risk  
  
Methadone 
known risk  
Females>Males. Substrate for 3A4 
Moexipril/HCTZ 
possible risk 
  
Moxifloxacin 
known risk  
  
Nicardipine 
possible risk 
  
Nortriptyline 
conditional risk 
  
Octreotide 
possible risk 
  
Ofloxacin 
possible risk 
  
Ondansetron 
possible risk 
  
Oxytocin 
possible risk 
  
Paliperidone 
possible risk 
  
Paroxetine 
conditional risk 
  
Pentamidine 
known risk  
Females > Males 
Perflutren lipid 
microspheres 
possible risk 
  
Pimozide 
known risk  
Females > Males. Substrate for 3A4 
Probucol 
known risk  
No longer available in U.S. 
Procainamide 
known risk  
  
Protriptyline 
conditional risk 
  
Quetiapine 
possible risk 
Substrate for 3A4 
Quinidine 
known risk  
Females > Males. Substrate for 3A4 
Ranolazine 
possible risk 
  
Risperidone 
possible risk 
  
Ritonavir 
conditional risk 
Substrate for 3A4 
Roxithromycin* 
possible risk 
*not available in the United States 
Sertindole 
possible risk 
  
Sertraline 
conditional risk 
  
Solifenacin 
conditional risk 
  
Sotalol 
known risk  
Females > Males 
Sparfloxacin 
known risk  
  
Tacrolimus 
possible risk 
Substrate for 3A4 
Telithromycin 
possible risk 
Substrate for 3A4 


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Drug 
QT risk2 
Comment 
Terfenadine 
known risk  
No longer available in U.S.Substrate for 3A4 
Thioridazine 
known risk  
  
Tizanidine 
possible risk 
  
Trazodone 
conditional risk 
Substrate for 3A4 
Trimethoprim-Sulfa 
conditional risk 
  
Trimipramine 
conditional risk 
  
Vandetanib 
known risk  
  
Vardenafil 
possible risk 
Substrate for 3A4 
Venlafaxine 
possible risk 
  
Voriconazole 
possible risk 
  
Ziprasidone 
possible risk 
  
1 Additional agents can be found at https://www.crediblemeds.org  
2 Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 


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Appendix 6: Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 
1.0 
MEASURABILITY OF TUMOUR AT BASELINE 
1.1 
Definitions 
At baseline, tumour lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1.1.1 Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm); 
• 10 mm caliper measurement by clinical examination (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable); 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
1.1.2 Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
1.1.3 Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 


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• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic mestastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions with prior local treatment: 
• Tumour lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
1.2 
Specifications by Methods of Measurements 
1.2.1 Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
1.2.2 Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin 
lesions, documentation by colour photography including a ruler to estimate the size of the lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical examination and 


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2.0 
TUMOUR RESPONSE EVALUATION 
2.1 
Assessment of Overall Tumour Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumour 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion (as detailed above).  
2.2 
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved, a maximum of two and 
four lesions respectively will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumour. As previously noted, pathological nodes 
which are defined as measurable and may be identified as target lesions must meet the criterion 
of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the 
baseline sum. The short axis of the node is the diameter normally used by radiologists to judge if 
a node is involved by solid tumour. Nodal size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, saggital, or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm X 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm 
should be recorded as the node measurement. All other pathological nodes (those with short axis 
≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that have a short axis 
< 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as previously noted, only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumour 
regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 


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these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
2.3 
Response Criteria 
This section provides the definitions of the criteria used to determine objective tumour response 
for target lesions. 
2.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered 
progression. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.3.2 Special Notes on the Assessment of Target Lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. Case report 
forms (CRFs) or other data collection methods may therefore be designed to have target nodal 
lesions recorded in a separate section where, in order to qualify for CR, each node must achieve 
a short axis < 10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to 
be included in the sum of target lesion. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small to 


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measure’. When this occurs it is important that a value be recorded on the CRF. If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false responses 
or progressions based upon measurement error. If the radiologist is able to provide an actual 
measurement, that should be recorded, even if below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2.3.2 Evaluation of Non-Target Lesion 
This section provides the definitions of the criteria used to determine the tumour response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumour 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumour 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. The 
appearance of one or more new lesions is also considered progression. 
2.3.3 Special Notes on Assessment of Progression of Non-Target Disease 
The concept of progression of non-target disease requires additional explanations as follows: 
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumour burden has increased sufficiently to merit discontinuation of therapy. A modest 


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‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.  
When the patient has only non-measurable disease. This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as previously noted, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified, a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease: i.e., an 
increase in tumour burden representing an additional 73% increase in ‘volume’ (which is 
equivalent to a 20% increase in diameter in a measurable lesion). Examples include an increase 
in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to 
widespread, or may be described in protocols as ‘sufficient to require a change in therapy’. If 
‘unequivocal progression’ is seen, the patient should be considered to have had overall PD at that 
point. While it would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so, therefore the increase must be 
substantial. 
2.3.4 New Lesions 
The appearance of new malignant lesions denotes disease progression. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal: i.e., not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumour. This is 
particularly important when the patient’s baseline lesions show partial or complete response. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain scan 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan.  
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 


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progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imagine 
can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. A ‘positive’ FDG-PET scan lesion is one which is 
FDG avid with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that time (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD. 
2.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in non-randomised trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall 
response’.  
2.4.1 Time Point Response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 


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Table 1: 
Time Point Response: Patients With Target (± Non-Target) Disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, NE=inevaluable 
 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
Table 2: 
Time Point Response: Patients With Non-Target Disease Only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised. 
 


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2.4.2 Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless convincing argument 
can be made that the contribution of the individual missing lesion(s) would not change the 
assigned time point response. This would be most likely to happen in the case of PD.  
2.4.3 Best Overall Response: All Time Points 
The best overall response is determined once all the data for the patient is known.  
Best response is defined as the best response across all time points (for example, a patient who 
has SD at first assessment, PR at second assessment, and PD on last assessment has a best 
overall response of PR). When SD is believed to be the best response, it must also meet the 
protocol specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best time point response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same patient lost to follow-
up after the first SD assessment would be considered inevaluable.  
2.4.4 Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on the increase in size of the nodes. As noted earlier, this means that patients with CR may 
not have total sum of ‘zero’ on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease. 
Conditions that define ‘early progression, early death and inevaluability’ are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar to 


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a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesion), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
References: 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. 
 
 


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Appendix 7: Patient Global Impression of Change 
Patients will be asked the following:  
Since starting treatment, my colorectal cancer symptoms are: 
(1) Very much improved 
(2) Much improved 
(3) Minimally improved 
(4) No change 
(5) Minimally worse 
(6) Much worse 
(7) Very much worse 
References: 
Mesa AM, Gotlib J, Gupta V, et. al. Effect of ruxolitinib therapy on myelofibrosis-related 
symptoms and other patient-reported outcomes in COMFORT-1: A randomized, double-blind, 
placebo-controlled trial. J Clin Oncol. 2013;31:1285-92. 
 


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Appendix 8: Recommended Guidelines for the Management of Binimetinib-associated 
Interstitial Lung Disease 
Clinical judgment and experience of the treating physician should guide the management plan of 
each patient. In general, the following interventions are in addition to the binimetinib-associated 
interstitial lung disease (ILD) dosing guidelines provided in Table 16 of the protocol. 
Drug-associated ILD or pneumonitis is a clinical diagnosis based on clinical signs and 
symptoms, radiological changes, pulmonary function tests (PFT) and exclusion of other possible 
etiologies of parenchymal lung disease. The most common symptoms of ILD are nonspecific and 
include dyspnea, dry cough, fever, fatigue, hypoxia, and occasional hemoptysis. The CTCAE 
v.4.03 criteria for ILD (pneumonitis) are provided below. 
CTCAE v. 4.03 Criteria for Pneumonitis 
 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Pneumonitis 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care 
ADL; oxygen 
indicated 
Life-threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated (e.g., 
tracheotomy or 
intubation) 
Death 
Definition: A disorder characterized by inflammation or diffusely affecting the lung parenchyma. 
 
All patients should be instructed to immediately report new or worsening respiratory symptoms. 
Diagnostic procedures include PFT and high-resolution CT scans. The principal management of 
ILD consists of drug interruption and/or dose reduction and treatment with steroids as specified 
below. Empirical antibiotics directed at likely pathogens should also be considered while the 
results of diagnostic procedures and cultures are pending.  
• Prednisolone 40 mg oral, daily 
o Reduce dose by 10 mg every 2 weeks × 2 (until dose reduced to 20 mg oral, daily) 
o Reduce dose by 5 mg weekly × 4 weeks 
• Combine with empirical antimicrobial therapy while awaiting results of diagnostic 
procedures 
References: 
Shah R. Tyrosine kinase inhibitor-induced interstitial lung disease: Clinical features, diagnostic 
challenges, and therapeutic dilemmas. Drug Saf 2016;39:1073-1091.