Clinical trial NCT03911869
Conditions: Brain Metastases
Keywords: BRAFV600-mutant melanoma brain metastasis
Sponsor: Pfizer
Start date: 2019-04-30; Completion date: 2022-01-27
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a multicenter, randomized open-label Phase 2 study to assess the safety, efficacy and pharmacokinetic (PK) of 2 dosing regimens of encorafenib + binimetinib combination in patients with BRAFV600-mutant melanoma with brain metastasis. Approximately 100 patients will be enrolled, including 9 patients in a Safety Lead-in of the high-dose treatment arm. After a Screening Period, treatment will be administered in 28-day cycles and will continue until disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent anticancer therapy, death.

Detailed description:

Arms: arm 1: Patients in the standard-dose treatment arm will receive encorafenib and binimetinib in 28-day cycles.

* 450 mg encorafenib orally once a day (QD)
* 45 mg binimetinib orally twice a day (BID)

Patients who are able to tolerate the standard dose during the first 4 weeks of treatment (Cycle 1) should be dose-escalated to 600 mg encorafenib QD plus 45 mg binimetinib BID provided they meet protocol-defined criteria. arm 2: Patients in the high-dose treatment arm will receive encorafenib and binimetinib in 28-day cycles.

* 300 mg encorafenib orally twice a day (BID)
* 45 mg binimetinib orally twice a day (BID)
Interventions: intervention 1: encorafenib intervention 2: binimetinib
Intervention descriptions: intervention 1: taken orally intervention 2: taken orally

Protocol documents:
Prot_000.pdf: 
Encorafenib + Binimetinib
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Page 1
CLINICAL STUDY ARRAY-818-201 / C4221006
Protocol Title:
A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib
Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-Mutant 
Melanoma Brain Metastasis
Protocol Number:
ARRAY-818-201
Compound:
Encorafenib + Binimetinib in Combination
Study Phase:
Phase 2
Original Protocol:
14 November 2018
Version 1:
08 April 2019
Version 2:
13 March 2020
Version 3:
07 August 2020
Version 4:
04 January 2021
Sponsor:
Array BioPharma Inc.
(a wholly owned subsidiary of Pfizer Inc.)
3200 Walnut Street
Boulder, CO 80301
Phone: (303) 381-6600
Fax: (303) 386-1240
IND Number:
113850
EudraCT Number:
2018‐004555‐21
CONFIDENTIAL INFORMATION
This document contains trade secrets and other confidential and proprietary information belonging to 
Array BioPharma Inc. Except as otherwise agreed to in writing, by accepting or reviewing this 
document you agree to hold this information in confidence and not to disclose it to others (except 
where required by applicable law) or to use it for unauthorized purposes. In the event of any actual or 
suspected breach of this obligation, Array BioPharma Inc. should be promptly notified.


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................7
APPENDICES ...........................................................................................................................8
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..............................................9
1. PROTOCOL SUMMARY...................................................................................................14
1.1. Synopsis ..................................................................................................................14
1.2. Schema ....................................................................................................................19
1.3. Schedule of Activities (SoA)...................................................................................20
2. INTRODUCTION ...............................................................................................................24
2.1. Background .............................................................................................................24
2.1.1. Overview of Melanoma Brain Metastasis ..................................................24
2.1.2. Local Treatment for BRAF-mutant Melanoma Brain Metastasis...............24
2.1.3. Systemic Treatment for BRAF-mutant Melanoma Brain Metastasis .........25
2.2. Overview of Encorafenib and Binimetinib .............................................................26
2.2.1. Encorafenib.................................................................................................26
2.2.2. Binimetinib .................................................................................................27
2.2.3. Clinical Safety of Combination Encorafenib and Binimetinib...................27
2.2.4. Clinical Safety of Encorafenib as a Single Agent in the COLUMBUS 
Study ................................................................................................................29
2.2.5. Clinical Safety of Encorafenib 600 mg QD in the CMEK162X2110 
Study ................................................................................................................29
2.3. Study Rationale .......................................................................................................30
2.4. Benefit/Risk Assessment.........................................................................................30
3. OBJECTIVES AND ENDPOINTS.....................................................................................31
4. STUDY DESIGN.................................................................................................................34
4.1. Overall Design.........................................................................................................34
4.2. Discussion of Study Design ....................................................................................35
4.3. Justification for Dose ..............................................................................................35
4.3.1. Binimetinib Regimen..................................................................................36
4.3.2. High-dose Encorafenib ...............................................................................36
4.4. End of Study Definition ..........................................................................................37
4.5. Study Termination...................................................................................................37


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5. STUDY POPULATION......................................................................................................38
5.1. Inclusion Criteria.....................................................................................................38
5.2. Exclusion Criteria....................................................................................................40
5.3. Lifestyle Considerations..........................................................................................43
5.3.1. Meals and Dietary Restrictions...................................................................43
5.3.2. Activity .......................................................................................................43
5.4. Screen Failures ........................................................................................................43
6. STUDY TREATMENT.......................................................................................................44
6.1. Study Treatments Administered..............................................................................44
6.2. Preparation/Handling/Storage/Accountability ........................................................45
6.3. Randomization ........................................................................................................46
6.3.1. Patient Numbering......................................................................................47
6.4. Study Treatment Compliance..................................................................................47
6.5. Concomitant Therapy..............................................................................................47
6.5.1. Permitted Concomitant Therapy Requiring Caution and/or Action...........48
6.5.1.1. CYP and UGT Substrates and Inhibitors ..................................48
6.5.1.2. Transporter Substrates and Inhibitors .......................................48
6.5.1.3. Drugs with a Known Conditional or Possible Risk to 
Prolong QT Interval and/or Induce Torsade de Pointes ....................49
6.5.2. Prohibited Concomitant Therapy................................................................49
6.6. High-dose Safety Assessment .................................................................................50
6.6.1. Management and Follow up of Reviewable Toxicities..............................52
6.6.2. Procedure for High-dose Safety Review ....................................................52
6.7. Dose Modification...................................................................................................52
6.7.1. General Procedures for Dose Modification ................................................52
6.7.2. Intra-Patient Dose Escalation of Encorafenib.............................................54
6.7.3. Renal Changes in Dose Modification.........................................................55
6.8. Criteria for Permanent Discontinuation of Study Treatment ..................................55
6.9. Patient Discontinuation/Withdrawal from the Study ..............................................56
6.10. Intervention After the End of the Study................................................................57
6.11. Replacement of Patients........................................................................................57
6.12. Lost to Follow up ..................................................................................................57
6.13. Withdrawal Consent..............................................................................................58


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7. STUDY ASSESSMENTS AND PROCEDURES...............................................................58
7.1. Screening Procedures ..............................................................................................58
7.1.1. Baseline Documentation of Intracranial Target and non-Target 
Lesions .............................................................................................................59
7.1.2. Baseline Documentation of Extracranial Target and non-Target 
Lesions .............................................................................................................59
7.2. Efficacy Assessments..............................................................................................59
7.2.1. Radiological Tumor Evaluation..................................................................59
7.2.2. Imaging Assessments for RECIST v1.1 and mRECIST v1.1 ....................61
7.2.3. Blinded Independent Central Review.........................................................61
7.2.4. Post-treatment Follow up............................................................................61
7.2.4.1. 30-Day Safety Follow Up .........................................................61
7.2.4.2. Disease Follow Up ....................................................................61
7.2.4.3. Survival Follow up....................................................................62
7.2.5. Performance Status.....................................................................................62
7.2.6. BRAF Testing..............................................................................................63
7.3. Safety Assessments .................................................................................................64
7.3.1. Patient Demographics and Other Baseline Characteristics ........................64
7.3.2. Disease Characteristics and Treatment History..........................................64
7.3.3. Physical Examinations................................................................................64
7.3.4. Dermatological Examinations ....................................................................64
7.3.5. Vital Signs ..................................................................................................65
7.3.6. Electrocardiograms.....................................................................................65
7.3.7. Clinical Safety Laboratory Assessments ....................................................66
7.3.8. Pregnancy Testing ......................................................................................67
7.3.9. Renal Function Monitoring.........................................................................68
7.3.10. Serology....................................................................................................68
7.3.11. Echocardiogram/Multi-gated Acquisition ................................................68
7.3.12. Ophthalmic Examination..........................................................................68
7.3.12.1. Testing at Screening and During the Treatment Period ..........68
7.3.12.2. Additional Testing...................................................................69
7.4. Adverse Events and Serious Adverse Events..........................................................69
7.4.1. Time Period and Frequency for Collecting AE and SAE Information.......69


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7.4.1.1. Reporting SAEs to Pfizer Safety...............................................70
7.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................70
7.4.2. Methods of Detecting AEs and SAEs.........................................................70
7.4.3. Follow-up of AEs and SAEs.......................................................................71
7.4.4. Regulatory Reporting Requirements for SAEs...........................................71
7.4.5. Exposure During Pregnancy or Breastfeeding and Occupational 
Exposure ..........................................................................................................72
7.4.5.1. Exposure During Pregnancy......................................................72
7.4.5.2. Exposure during Breastfeeding .................................................73
7.4.5.3. Occupational Exposure .............................................................74
7.4.6. Cardiovascular and Death Events...............................................................74
7.4.7. Disease-Related event and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................74
7.4.8. Adverse Events of Special Interest.............................................................74
7.4.8.1. Lack of Efficacy........................................................................74
7.4.9. Medical Device Deficiencies......................................................................74
7.4.10. Medication Errors.....................................................................................74
7.5. Product Complaints.................................................................................................75
7.6. Treatment of Overdose............................................................................................75
7.7. Pharmacokinetic Assessments.................................................................................76
7.7.1. Blood Sample Collection............................................................................76
7.8. Pharmacodynamics..................................................................................................78
7.10. Patient-reported Outcomes....................................................................................79
7.11. Unscheduled Visits................................................................................................80
7.12. End of Treatment and/or Early Termination.........................................................80
8. STATISTICAL CONSIDERATIONS ................................................................................80
8.1. Statistical Hypotheses .............................................................................................80
8.2. Sample Size Determination.....................................................................................80
8.3. Analyses Sets...........................................................................................................81
8.4. Statistical Analyses .................................................................................................82
8.4.1. Primary Analyses........................................................................................83
CCI


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8.4.2. Secondary Analyses....................................................................................83
8.4.2.1. Extracranial Response Rate.......................................................83
8.4.2.2. Global Response Rate ...............................................................83
8.4.2.3. Disease Control Rate.................................................................83
8.4.2.4. Duration of Response................................................................84
8.4.2.5. Progression-free Survival..........................................................84
8.4.2.6. Overall Survival ........................................................................84
8.4.2.7. Brain Metastasis Response Rate for Safety Lead-in .................84
8.4.3. Safety Analyses ..........................................................................................84
8.4.4. Pharmacokinetic Analysis ..........................................................................85
8.5. Interim Analyses .....................................................................................................85
9. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......86
9.1. Regulatory, Ethical, and Study Oversight Considerations......................................86
9.2. Investigator Responsibilities ...................................................................................86
9.3. Financial Disclosure................................................................................................87
9.4. Informed Consent Process.......................................................................................87
9.5. Data Protection........................................................................................................88
9.6. Committees..............................................................................................................88
9.6.1. Steering Committee ....................................................................................88
9.7. Dissemination of Clinical Study Data.....................................................................89
9.7.1. Data Sharing ...............................................................................................89
9.8. Data Quality Assurance...........................................................................................89
9.9. Source Documents...................................................................................................91
9.10. Study and Site Closure ..........................................................................................91
9.11. Publication Policy .................................................................................................91
10. REFERENCES ..................................................................................................................92
CCI


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LIST OF TABLES
Table 1.
Primary and Select Secondary Objectives and Endpoints........................14
Table 2.
Key Study Design Elements.....................................................................17
Table 3.
Schedule of Activities...............................................................................20
Table 4.
Objectives and Endpoints .........................................................................31
Table 5.
Planned Treatment Arms..........................................................................34
Table 6.
Study Treatments......................................................................................45
Table 7.
Criteria for Defining Dose-limiting Toxicities.........................................51
Table 8.
Dose Reductions for Encorafenib and Binimetinib..................................53
Table 9.
Performance Status Scoring......................................................................62
Table 10.
Timing of ECGs........................................................................................66
Table 11.
Summary of Clinical Laboratory Tests.....................................................67
Table 12.
Pharmacokinetic Blood Sample Timing in the Safety Lead-in 
Portion and in the Phase 2 Portion When the High Dose Regimen is 
Tested........................................................................................................77
Table 13.
Pharmacokinetic Blood Sample Timing in the Phase 2 Portion 
When Only the Standard Dose Regimen is Tested...................................78
Table 14.
Characteristics of Safety Lead-in Criteria for Cycle 1 Dose-limiting 
Toxicity Rate ............................................................................................80
Table 15.
Populations for Analysis...........................................................................82
LIST OF FIGURES
Figure 1.
Study Schema ...........................................................................................19


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APPENDICES
Appendix 1. Contraceptive Guidance......................................................................................97
Appendix 2. Recommended Dose Modifications for Encorafenib-related* Adverse 
Events .....................................................................................................100
Appendix 3. Recommended Dose Modifications for Binimetinib-related* Adverse 
Events .....................................................................................................104
Appendix 4. Response Evaluation Criteria in Solid Tumours (RECIST), Version 1.1.........107
Appendix 5. Modified Response Evaluation Criteria in Solid Tumors (mRECIST), 
Version 1.1..............................................................................................117
Appendix 6. Criteria for Evaluation of Global Response......................................................120
Appendix 7. Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.......................................................................123
Appendix 8. Liver Safety: Suggested Actions and Follow-up Assessments.........................130
Appendix 9. ECG Findings of Potential Clinical Concern....................................................132
Appendix 10. ALTERNATIVE MEASURES DURING PUBLIC EMERGENCIES..........134
Appendix 11. Protocol Amendment Summary of Changes...................................................138


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study protocol.
Abbreviation or 
special term
Explanation
ACR
albumin-to-creatinine ratio
AE
adverse event
AESI
adverse event of special interest
AJCC
American Joint Committee on Cancer
ALP
alkaline phosphatase
ALT 
alanine aminotransferase 
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST 
aspartate aminotransferase 
ATP
adenosine triphosphate
AUC
area under the plasma concentration-time curve
AUClast
area under the plasma concentration-time curve from time zero to Tlast
AV
atrioventricular
BBB
blood-brain barrier
BCRP
breast cancer resistance protein
BICR
Blinded Independent Central Review 
BID
twice daily
BMRR
brain metastasis response rate
BRAF
B-RAF proto-oncogene, serine/threonine kinase
BRAFV600E
B-RAF proto-oncogene, V600E mutant
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
Cmax
maximum observed plasma concentration after drug administration
Cmin
measured concentration at the end of a dosing interval at steady state (from predose 
PK sample) 
COLUMBUS
Oncology Clinical Trial Protocol CMEK162B2301
COLUMBUS – Combined LGX818 Used with MEK162 in BRAF mutant 
Unresectable Skin cancer. A 2-part phase III randomized, open label, multicenter 
study of LGX818 plus MEK162 versus vemurafenib and LGX818 monotherapy in 


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Abbreviation or 
special term
Explanation
patients with unresectable or metastatic BRAF V600 mutant melanoma. 
ClinicalTrials.gov Identifier: NCT 01909453
COVID-19
coronavirus disease 2019
CPK
creatine phosphokinase
CR
complete response
CRF
case report form
CSR
Clinical Study Report
CT
computed tomography; clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CXDX
C = cycle, D = day and X = number of cycle or day number on a cycle
DCR
disease control rate
DILI
drug-induced liver injury
dL
deciliter(s)
DLT
dose-limiting toxicity
DOR
duration of response
DVT
deep vein thrombosis
EC
ethics committee (includes institutional review board, research ethics board and 
institutional ethics committee)
EC50
half-maximal effective concentration
ECG
electrocardiogram
ECOG PS
Eastern Cooperation Oncology Group Performance Status
ECHO
echocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EDP
exposure during pregnancy
EOT
end of treatment
ERK
extracellular signal-regulated kinase
EU
European Union
FAS
Full Analysis Set
FDA
U.S. Food and Drug Administration
FDG-PET
fluorodeoxyglucose-positron emission tomography
FSH
follicle stimulating hormone
CCI


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Abbreviation or 
special term
Explanation
g
gram(s)
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
H0
null hypothesis
HBV
hepatitis B virus
HCV
hepatitis C virus
HFSR
hand foot skin reaction
HIPAA
Health Information Portability and Accountability Act of 1996
HIV
human immunodeficiency virus
HRT
hormonal replacement therapy
IA
interim analysis
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IWRS
Interactive Voice/Web Response System
L
liter(s)
LDH
lactate dehydrogenase
LFT
liver function test
LH
luteinizing hormone
LLN
lower limit of normal
LV
left ventricular
LVEF
left ventricular ejection fraction
MAPK
mitogen-activated protein kinase
MedDRA
Medical Dictionary for Regulatory Activities
MEK
mitogen-activated protein kinase kinase
mg
milligram(s)


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Abbreviation or 
special term
Explanation
mL
milliliter(s)
mm
millimeter
mRECIST v1.1
modified Response Evaluation Criteria in Solid Tumors version 1.1
MRI
magnetic resonance imaging
ms
millisecond(s)
MTD
maximum tolerated dose
MUGA
multi-gated acquisition
NA
not applicable
NCI
National Cancer Institute
NE
inevaluable or not evaluable
nM
nanomolar
OCT
optical coherence tomography
ORR
overall response rate
OS
overall survival
P-gp
P-glycoprotein
PD
progressive disease
PDF
portable document format
PE
pulmonary embolism
pERK
phosphorylated ERK
PET
positron emission tomography
PET-CT
positron emission tomography-computed tomography
PFS
progression-free survival
pH
hydrogen ion concentration
PK
pharmacokinetic(s)
PKS
Pharmacokinetics (PK) Set
pMEK
phosphorylated MEK
PO
oral
PPS
Per-protocol Set
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
PVC
premature ventricular contraction
Q8W
every 8 weeks
Q12W
every 12 weeks


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Abbreviation or 
special term
Explanation
QD
once daily
QTcF
QT interval corrected for heart rate using Fridericia’s formula.
RANO-BM
Response Assessment in Neuro-Oncology Brain Metastases
RAUC
accumulation ratio calculated as AUClast,ss/AUClast
RBC
red blood cell(s)
RECIST v1.1
Response Evaluation Criteria in Solid Tumours version 1.1
RP2D
recommended Phase 2 dose
RPED
retinal pigment epithelial detachment
RVO
retinal vein occlusion
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
stable disease
SoA
schedule of activities
SOP
standard operating procedure
SRS
stereotactic radiosurgery
SRT
stereotactic radiotherapy
SUSAR
suspected unexpected serious adverse reaction
t1/2
TLF
terminal half-life
tables, listings, and figures
TBili
total bilirubin
TDP
torsades de pointes
Tlast
time of last PK sample
Tmax
time to reach Cmax
ULN
upper limit of normal
US
United States
vs.
versus
WBC
white blood cell(s)
WOCBP
woman of childbearing potential


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1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title:
A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib 
Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-mutant 
Melanoma Brain Metastasis
Protocol Number: ARRAY-818-201
Rationale:
Treatment with BRAF + MEK inhibitors has been shown to result in shrinkage of 
BRAFV600-mutant melanoma brain metastasis, albeit with a relatively short duration of 
response.
The pivotal COLUMBUS study demonstrated favorable efficacy and safety of combination 
encorafenib + binimetinib for patients with BRAFV600-mutant melanoma. Patients with 
asymptomatic brain metastasis have not been evaluated in a dedicated study with encorafenib 
+ binimetinib. The aim of the present study is to evaluate the benefits of encorafenib and 
binimetinib specifically in a population of patients with BRAFV600-mutated melanoma brain 
metastasis. Moreover, the blood-brain barrier can limit concentrations of anti-cancer agents 
at the target for treatment of brain metastases; for this reason, a higher dose of combination 
therapy may potentially demonstrate greater efficacy without compromising safety for 
patients with BRAFV600 melanoma brain metastasis. 
Objectives and Endpoints:
Table 1 presents the primary and major/select secondary endpoints and objectives.
Table 1.
Primary and Select Secondary Objectives and Endpoints
Objectives
Endpoints
Primary
Safety Lead-in

Evaluate the safety of a high-dose 
regimen of encorafenib + binimetinib 
combination therapy in patients with 
BRAFV600-mutant melanoma who 
have asymptomatic brain metastasis 
Safety Lead-in

Incidence of DLTs 

Incidence and severity of AEs graded 
according to the NCI CTCAE version 
4.03 and changes in clinical laboratory 
parameters, vital signs and ECGs

Incidence of dose interruptions, dose 
modifications and discontinuations due 
to AEs 


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Table 1.
Primary and Select Secondary Objectives and Endpoints
Objectives
Endpoints
Phase 2
If the high-dose regimen is determined to 
be safe based on the results of the Safety 
Lead-in phase, then

Evaluate the antitumor activity in brain 
metastases of the standard and high-
dose regimens of encorafenib + 
binimetinib combination therapy in 
patients with BRAFV600-mutant 
melanoma who have asymptomatic 
brain metastasis
If the high-dose regimen is determined not 
to be safe based on the results of the Safety 
Lead-in phase, then

Evaluate the antitumor activity in brain 
metastases of the standard dosing 
regimen of encorafenib + binimetinib 
combination in patients with 
BRAFV600-mutant melanoma who 
have asymptomatic brain metastasis
Phase 2

BMRR per mRECIST v1.1
Secondary

Further evaluate the antitumor activity 
of encorafenib + binimetinib 
combination therapy in patients with 
BRAFV600-mutant melanoma who 
have asymptomatic brain metastasis

Extracranial response rate per RECIST 
v1.1

Global response rate (brain metastasis 
response per mRECIST v1.1 and 
extracranial response per RECIST v1.1)

DCR
o
for brain metastasis response 
per mRECIST v1.1 criteria
o
for extracranial response per 
RECIST v1.1
o
for global response (brain 
metastasis per mRECIST v1.1 


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Table 1.
Primary and Select Secondary Objectives and Endpoints
Objectives
Endpoints
and extracranial per RECIST 
v1.1)

DOR
o
for brain metastasis response 
per mRECIST v1.1 criteria
o
for extracranial response per 
RECIST v1.1
o
for global response (brain 
metastasis per mRECIST v1.1 
and extracranial per RECIST 
v1.1)

PFS
o
for brain metastasis per 
mRECIST v1.1 
o
for global assessment (brain 
metastasis per mRECIST v1.1 
and extracranial disease per 
RECIST v1.1)

BMRR per mRECIST v1.1 for Safety 
Lead-in only

Evaluate the efficacy of encorafenib + 
binimetinib combination therapy as 
measured by OS in patients with 
BRAFV600-mutant melanoma who 
have asymptomatic brain metastasis

OS

Further evaluate the safety profile of 
encorafenib + binimetinib combination 
therapy in patients with BRAFV600-
mutant melanoma who have 
asymptomatic brain metastasis

Incidence and severity of AEs graded 
according to the NCI CTCAE version 
4.03 and changes in clinical laboratory 
parameters, vital signs and ECGs

Characterize the PK of encorafenib and 
its metabolite LHY746, and binimetinib 
and its metabolite AR00426032 

Plasma concentration-time profiles and 
PK parameter estimates for encorafenib 
its metabolite LHY746, and binimetinib 
and its metabolite AR00426032
Overall Design:
Table 2 presents the key study design elements.


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Table 2.
Key Study Design Elements
Study Phase
2
Type of Design
This is a multicenter, randomized, open-label Phase 2 study to assess the 
safety, efficacy and PK of 2 different dosing regimens of encorafenib + 
binimetinib combination therapy in patients with BRAFV600-mutant 
melanoma with asymptomatic brain metastasis. 
The first 9 evaluable patients in the high-dose treatment will constitute 
the high-dose Safety Lead-in cohort. Evaluable patients for the Safety 
Lead-in cohort must have either: 

experienced a DLT or

received at least 75% of planned cumulative dose of both study 
drugs during Cycle 1.
If the high-dose treatment is determined to be safe, approximately 100 
eligible patients will be randomized 1:1 (50 in each arm) to receive either 
the standard-dose (Arm A) or the high-dose (Arm B) encorafenib + 
binimetinib combination. Randomization will be stratified by baseline 
tumor burden in the brain (1 to 2 brain lesions vs. ≥3 brain lesions at 
baseline assessment) and by prior local therapy [e.g., stereotactic 
radiosurgery (SRS) or stereotactic radiotherapy (SRT), (yes vs. no)]. 
If the high-dose treatment is determined not to be safe in the Safety Lead-
in, no patients will be enrolled into Arm B  and  up to 100 eligible 
patients will be enrolled into 2 cohorts in the standard-dose Arm A. 
Cohort 1: Up to 50 patients with BRAFV600 cutaneous melanoma with 
metastases to the brain confirmed by MRI, asymptomatic, and with prior 
local therapy (e.g., SRS or SRT). Cohort 2:  Up to 50 patients with 
BRAFV600 cutaneous melanoma with metastases to the brain confirmed 
by MRI, asymptomatic, without prior local therapy (e.g., SRS or SRT). 
Phase 2 enrollment will close when either Cohort 1 or 2 reaches 50 
patients.
The Sponsor, in consultation with the Steering Committee, will perform a 
comprehensive evaluation of safety, efficacy and PK data in the Safety 
Lead-in, as well as periodic safety evaluations during the conduct of the 
study.
Primary Purpose
Combination treatment with encorafenib + binimetinib using either a 
standard- or high-dose regimen is being evaluated for use in patients with 
BRAFV600-mutant melanoma brain metastasis. 
Intervention Model
Parallel: Patients are randomized to standard- or high-dose treatment 
arms unless the high-dose treatment arm is found intolerable during the 
Safety Lead-in.
Clinical Indication
Patients with BRAFV600-mutant melanoma brain metastasis.


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Table 2.
Key Study Design Elements
Population
Adult patients ≥18 years with asymptomatic BRAFV600-mutant 
melanoma brain metastasis. Patients must have at least 1 contrast-
enhancing metastatic brain lesion ≥0.5 cm and ≤4 cm, defined by MRI.
Patients may have received prior immunotherapy and may have received 
BRAF or MEK inhibitors in the adjuvant setting provided that the 
treatment ended ≥6 months prior to enrollment. Patients treated with 
BRAF or MEK inhibitors in the metastatic setting are excluded.
Patients must have presence of a BRAFV600 mutation in tumor tissue 
previously determined by a local PCR or NGS-based laboratory assay at 
any time prior to Screening or by a central laboratory during Screening. 
Patients are required to submit archival or fresh tissue and a blood sample 
prior to enrollment. Tissue samples will be used to confirm BRAFV600-
mutation status by central laboratory within 30 days of enrollment.
Number of Patients
Approximately 110.
Study Centers
Up to 75 centers in the US, Europe, Australia, New Zealand and other 
regions.
Treatment Regimens
Patients in the standard-dose treatment arm will receive encorafenib 
450 mg orally QD and binimetinib 45 mg orally BID in 28-day cycles. 
Patients who are able to tolerate the standard dose during the first 4 
weeks of treatment (Cycle 1) should be dose-escalated to 600 mg 
encorafenib QD plus 45 mg binimetinib BID provided they meet 
protocol-defined criteria.
Patients in the Safety Lead-in and the high-dose treatment arm will 
receive encorafenib 300 mg orally BID and binimetinib 45 mg orally BID 
in 28-day cycles. 
Estimated Duration 
of Study 
Participation
Up to 28 days for screening; continuous treatment in consecutive 28-day 
cycles provided the patient is receiving benefit and has not met criteria 
for treatment withdrawal; and follow-up for safety, disease assessments 
and survival. End of study will be defined as 2 years after treatment 
initiation of the last enrolled patient or the time when all patients have 
died, withdrawn consent or have been lost to follow up, whichever occurs 
first. 


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1.2. Schema
Figure 1.
Study Schema




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Table 3.
Schedule of Activities
Procedure/Assessment 
(± 3-day window for 
all Treatment Period 
visits except for C1D1 
[no window])
Screening
Treatment Period
Post-treatment Period
Notes/Protocol Section
Cycle 1
Cycle 2
Subsequent Cycles
EOT
30-Day 
Follow up
Surviva
l Follow 
up
Evaluation/Window
Day -28 
to -1
Day 1
Day 15
Day 1
Day 1
Day 15
± 7D
± 7D
Q12W
± 7D
HBV and HCV 
serology testing and 
HIV where applicable
X
See Section 7.3.10 and Table 11
LH, FSH and/or 
estradiol 
X
See Appendix 1
Dermatologic 
examination
X
X
X
X
X
Performed Q8W after C3D1. See 
Section 7.3.4
Physical exam
X
X
X
X
X
Height to be measured at Screening 
only; see Section 7.3.3
Vital signs
X
X
X
X
X
X
X
See Section 7.3.5
ECOG / Karnofsky 
status
X
X
X
X
X
See Section 7.2.5
Full ophthalmic 
examination
X
Only if clinically indicated
See Section 7.3.12
Triplicate 12-Lead 
ECG
X
X
Triplicate 12-lead ECGs performed 
predose on C1D1. See Section 7.3.6
and Table 10 for timing of ECG 
collection.
Single 12-Lead ECG
X
X
X
X
See Section 7.3.6 and Table 10 for 
timing of ECG collection
ECHO/MUGA
X
X
Every 12 
weeks
X
X
ECHO/MUGA scans will be performed 
on C2D1, then every 12 weeks.
ECHO/MUGA scans should be every 
24 weeks (or more frequently if clinical 
indicated) for patients who have been 
on treatment for ≥24 months without 
decreases of > 10% in LVEF compared 


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Table 3.
Schedule of Activities
Procedure/Assessment 
(± 3-day window for 
all Treatment Period 
visits except for C1D1 
[no window])
Screening
Treatment Period
Post-treatment Period
Notes/Protocol Section
Cycle 1
Cycle 2
Subsequent Cycles
EOT
30-Day 
Follow up
Surviva
l Follow 
up
Evaluation/Window
Day -28 
to -1
Day 1
Day 15
Day 1
Day 1
Day 15
± 7D
± 7D
Q12W
± 7D
to baseline and LVEF < LLN at any 
time while on study. 
See Section 7.3.11
MRI of brain (and 
spinal cord at 
Screening only). 
Contrast-enhanced CT 
or MRI of chest, 
abdomen and pelvis 
Brain metastasis 
target and non-target 
lesion assessment 
X
X
At Cycle 2 Day 1, Cycle 3 Day 1 and then every 8 weeks 
through Cycle 11.
After Cycle 11, scans occur every 12 weeks, unless 
response confirmation. Complete response/partial response 
confirmation assessments must take place at least 4 weeks 
after the initial response.
EOT scan NOT required if scan was 
done within 8 weeks of treatment 
discontinuation and progressive disease 
has been documented.
See Section 7.2.1
Extracranial target 
and non-target lesion 
assessment
X
X
At Cycle 2 Day 1, Cycle 3 Day 1 and then every 8 weeks 
through Cycle 11.
After Cycle 11, scans occur every 12 weeks, unless 
response confirmation. Complete response/partial response 
confirmation assessments must take place at least 4 weeks 
after the initial response.
EOT scan NOT required if scan was 
done within 8 weeks of treatment 
discontinuation and progressive disease 
has been documented.
See Section 7.2.1
Dispense encorafenib 
+ binimetinib (with 
dosing diary)
X
X
X
See Section 6.1 and 6.2
Administer 
encorafenib + 
binimetinib
X
Administer daily in 28-day cycles. See 
Section 6.1
Review dosing diary. 
Assess encorafenib 
X
X
X
X
X
See Section 6.4


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Table 3.
Schedule of Activities
Procedure/Assessment 
(± 3-day window for 
all Treatment Period 
visits except for C1D1 
[no window])
Screening
Treatment Period
Post-treatment Period
Notes/Protocol Section
Cycle 1
Cycle 2
Subsequent Cycles
EOT
30-Day 
Follow up
Surviva
l Follow 
up
Evaluation/Window
Day -28 
to -1
Day 1
Day 15
Day 1
Day 1
Day 15
± 7D
± 7D
Q12W
± 7D
and binimetinib 
compliance
Prior/concomitant 
medication
X
Assess continuously
See Section 6.5
Adverse event 
assessment
X
Assess continuously
See Section 7.4
Document 
subsequent 
anticancer therapies
X
X
See Section 7.2.4.2 and 7.2.4.3
Survival status
X
X
See Section 7.2.4.3
Hematology
X
X
X
X
X
X
X
See Section 7.3.7 and Table 11
Chemistry including 
troponin
X
X
X
X
X
X
X
See Section 7.3.7 and Table 11
Coagulation
X
Patients on anticoagulation treatment should have 
parameters monitored throughout the study as 
clinically indicated 
See Section 7.3.7 and Table 11
Serum pregnancy test
X
X
Serum pregnancy test within 24 hours 
prior to Day 1. 
See Section 7.3.8
Urine pregnancy test
X
X
X
See Section 7.3.8
Renal functioning 
monitoring
X
X
X
X
X
X
See Section 7.3.9
Urinalysis
X
Only if clinically indicated
X
See Section 7.3.7 and Table 11
PK blood sample
X
X
X
X
PK blood samples will be collected 
through Cycle 3 only. See 
Section 7.7.1,  Table 12 and Table 13


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2. INTRODUCTION
2.1. Background
2.1.1. Overview of Melanoma Brain Metastasis
Metastatic melanoma has a high risk of spreading to the central nervous system (Cohen et al,
2016, Sampson et al, 1998). The development of brain metastases in patients with melanoma 
has an observed incidence of up to 43% and 75% in clinical and autopsy studies, respectively 
(Long and Margolin 2013, Sampson et al. 1998). Intracranial melanoma accounts for up to 
54% of deaths in patients with melanoma (Budman et al, 1978, Davies et al, 2011). Multiple 
brain metastases are more common than oligometastasis. Contrast-enhanced MRI is the 
standard diagnostic modality, as CT imaging is less specific. Therefore, CT imaging requires 
MRI confirmation, particularly for a single metastasis (Usuki et al, 2016).
The most frequent genetic alteration in melanoma is the BRAFV600 mutation, which occurs 
in up to 50% of cases. BRAF mutations drive constitutive MAPK pathway activation and in 
turn proliferation with enhanced cellular survival. It is known that BRAF-mutated melanoma 
can be inhibited clinically by BRAF and MEK inhibitors (Dummer et al, 2018a).
2.1.2. Local Treatment for BRAF-mutant Melanoma Brain Metastasis
Treatment options for patients with melanoma brain metastasis are evolving, with adoption 
recently of targeted and immunotherapies for metastatic melanoma including BRAF-mutant 
disease. In past decades surgery, whole brain radiation therapy and stereotactic radiosurgery 
were the accepted standard of care for the management of melanoma brain metastasis. 
Currently stereotactic radiosurgery is an accepted alternative to resection followed by 
radiation therapy for a limited number of brain metastases, up to 3 lesions and 4 cm or less in 
size (Andrews et al. 2004, Kondziolka et al, 1999, Kondziolka et al, 2005, Sanghavi et al,
2001, Shaw et al, 2000, Sneed et al, 2002). Local therapy modalities offer control of a limited 
number of melanoma brain lesions, but do not control spread of metastatic brain lesions 
beyond the locally controlled lesions or extracranial disease (Tawbi et al. 2018a, Yamamoto 
et al,2017). Chao et al, (2008) showed that new tumors developed in 45% of patients at 6 
months after whole brain radiotherapy, the local modality considered to control the 
progression of micrometastatic brain tumors. In a multi-institutional pooled analysis of 569 
patients with brain metastasis treated with stereotactic radiosurgery alone compared to 
stereotactic radiosurgery with whole brain radiotherapy, Sneed et al (2002) reported that 37% 
of the patients with brain metastases treated with stereotactic radiosurgery alone underwent 
salvage therapy at a median 5.7 months after treatment compared to 7% after a median 8 
months following whole brain radiation therapy. Research and debate continue regarding the 
optimal number of lesions appropriate for stereotactic radiotherapy, fractionation schedules 
and feasibility of retreatment with stereotactic radiotherapy (Grob et al, 2018).
Surgery and radiotherapy continue to have a role in the management of symptomatic and 
large melanoma brain metastasis. Current prospective clinical research evaluating targeted 
therapies and checkpoint inhibitors has demonstrated clinical activity that supports clinical 
investigation to optimize systemic treatment of melanoma patients with brain metastasis 
(Davies et al, 2017, Goyal et al, 2015, Tawbi et al, 2018b).


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2.1.3. Systemic Treatment for BRAF-mutant Melanoma Brain Metastasis
Early clinical results suggested a role for targeted agents in BRAF-mutated melanoma brain 
metastasis. In a Phase 1 dose-finding study, Falchook et al, (2012a) described outcomes 
when the BRAF inhibitor dabrafenib was administered to patients with previously untreated 
melanoma brain metastasis. Nine of 10 patients with treatment-naïve melanoma brain 
metastasis experienced a reduction in brain lesion size. In a Phase 1 dose-finding study of the 
MEK inhibitor trametinib, Falchook et al, (2012b) identified 1 CR and 6 PRs among 
16 BRAF-mutant patients with previous and locally treated brain metastases who had not 
received prior BRAF inhibitor treatment. In patients with BRAFV600E-mutant melanoma 
brain metastases having had no prior local therapy, patients receiving dabrafenib 
monotherapy had ORR of 39.2%, median PFS of 16.1 weeks, median OS of 33.1 weeks and 
6-month OS rate of 61% (Long et al, 2012).
In a retrospective chart review of patients from 3 institutions, 75.8% of 161 patients with 
unresectable stage IIIC or IV BRAF-mutant melanoma received the BRAF inhibitor 
vemurafenib (Gummadi et al, 2015). The incidence rate ratio of brain metastasis between 
patients treated with vemurafenib before the development of brain metastasis and those not 
treated with vemurafenib before the development of brain metastases was 0.51 (95% CI 0.30, 
0.86, p = 0.009). While there was no difference in OS among patients with brain metastases 
and BRAF-mutated melanoma regardless of treatment with vemurafenib, the authors suggest 
a modest protective effect of vemurafenib from development of brain metastases in patients 
with melanoma. McArthur et al, (2017) evaluated vemurafenib monotherapy in patients with 
melanoma brain metastasis. Median PFS in the brain was relatively short, 3.7 months for 
patients with no prior brain metastasis treatment and 4.0 months for patients with previously 
treated brain metastasis. Combination BRAF and MEK inhibition therapy was suggested as 
another option for evaluation in patients with melanoma brain metastasis. 
In the COMBI-MB study (Davies et al, 2017), the combination of dabrafenib plus trametinib 
resulted in a 58% intracranial response rate in 76 patients with BRAFV600E-mutant 
melanoma brain metastases naïve to prior local therapy. The median duration of response 
was 6.5 months with a response rate at 6 months of 63%. The most common SAEs were 
pyrexia and decreased ejection fraction. Grade 3 AEs were reported in 39%, Grade 4 AEs in 
5% and Grade 5 AEs in 1% of patients. Grade 3 pyrexia was reported in 3% of patients. The 
6.5-month duration of response fell short of that observed in patients with melanoma without 
brain metastasis. Extracranial responses observed in 55% in the same cohort lasted a median 
of 10.2 months. In the Phase 3 COMBI-d trial, patients with asymptomatic and untreated 
extracranial melanoma treated with dabrafenib plus trametinib demonstrated a 12-month 
duration of response (Long et al, 2017).
Recent clinical studies continue to report responses to treatment with BRAF, MEK and 
checkpoint (i.e., anti-CTLA-4, anti-PD-1, alone or combined) inhibitors in patients with 
melanoma brain metastasis (Ascierto et al. 2016, Davies et al. 2017, Larkin et al. 2015, Long 
et al. 2015, Robert et al. 2015a, Robert et al. 2015b). Long et al, (2018a) reported on a 
randomized Phase 2 study of nivolumab and ipilimumab or nivolumab alone in patients with 
asymptomatic brain metastases with no previous local brain therapy or immunotherapy. In 
patients who received nivolumab and ipilimumab, 46% (16 of 35 patients) had an intracranial 


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response at or after Week 12. The landmark intracranial 6-month PFS was 53%. Grade 3 to 4 
AEs were reported in 54% of patients.
Pembrolizumab was investigated in a Phase 2 single-institution study of intracranial response 
in patients with untreated or progressive melanoma brain metastasis (Goldberg et al, 2016). 
Goldberg et al. found that 22% of patients had a confirmed PR (4 of 18 patients) after 
pembrolizumab monotherapy. None of the 4 responders had BRAF-mutant melanoma.
The CheckMate 204 study evaluated nivolumab and ipilimumab in asymptomatic metastatic 
melanoma patients with at least 1 brain metastasis. In this single-arm Phase 2 study, 
94 patients with a minimum follow up of 6 months and a median follow up of 14.0 months 
demonstrated an intracranial clinical benefit (SD+PR+CR) of 57% (95% CI 47%, 68%) 
(Tawbi et al, 2018b). Thirty percent of patients had a PR and 26% had a CR. The intracranial 
clinical benefit for BRAF-mutated patients totaled 59.3% (95% CI 45.0, 72.4) (32 of 54 
patients with BRAF mutation). The 12-month landmark global PFS (intracranial and 
extracranial) was 56.6%. Safety results in CheckMate 204 were consistent with the safety 
profile of nivolumab and ipilimumab in patients without melanoma brain metastasis. Grade 3 
to 4 AEs were reported in 60% of patients; 27% of patients discontinued treatment because 
of a treatment-related AE. 
Despite recent clinical improvements for patients with BRAF-mutant melanoma brain 
metastasis, the brain continues as a prominent organ for metastatic progression after targeted 
or checkpoint therapy. Current melanoma treatments show efficacy for metastatic disease to 
the brain, but short durations of response and suboptimal safety profiles necessitate 
evaluation of a new regimen for BRAFV600 melanoma brain metastasis.
Encorafenib and binimetinib have received marketing approval in the US, EU and several 
other regions. Regulatory approval of encorafenib and binimetinib in combination was based 
on the Phase 3 COLUMBUS study (randomized, 2-part, open-label, multicenter, 
international clinical study) (Dummer et al, 2018a, Dummer et al, 2018b). COLUMBUS 
demonstrated that combination encorafenib + binimetinib has favorable efficacy and safety in 
patients with BRAF-mutant metastatic melanoma. The aim of the present study is to evaluate 
through a dedicated melanoma brain metastasis trial the combination of encorafenib and 
binimetinib at the standard and high-dose regimens for patients with BRAFV600-mutated 
disease. The high-dose treatment arm investigates whether a high-dose regimen may 
overcome potential limitations in brain penetration for patients with melanoma brain 
metastasis. A detailed justification for evaluating a higher dose is provided in Section 4.3.
2.2. Overview of Encorafenib and Binimetinib
2.2.1. Encorafenib
Encorafenib is a potent and selective ATP-competitive inhibitor of BRAFV600-mutant 
kinase. Encorafenib 450 mg orally QD in combination with binimetinib 45 mg orally BID 
have been approved by the US FDA, the EMA and by other health authorities for the 
treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or 
V600K mutation as detected by an FDA-approved test. Encorafenib is known to induce 
CYP3A4. Therefore, hormonal birth control agents are permissible only when combined with 


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other highly effective or acceptable methods (see Section 6.5.1.1, Section 5.3 and 
Appendix 1.
Detailed information regarding nonclinical studies and clinical pharmacokinetics of 
encorafenib are presented in the Investigator’s Brochure.
2.2.2. Binimetinib
Binimetinib is a potent and selective allosteric, ATP-uncompetitive inhibitor of MEK1/2. 
Binimetinib 45 mg orally QD in combination with encorafenib 450 mg orally QD have been 
approved by the US FDA, the EMA and by other health authorities for the treatment of 
patients with unresectable or metastatic melanoma with a BRAFV600E or V600K mutation 
as detected by an FDA-approved test. Detailed information regarding nonclinical studies and 
clinical pharmacokinetics of binimetinib are presented in the Investigator’s Brochure.
2.2.3. Clinical Safety of Combination Encorafenib and Binimetinib
The COLUMBUS trial is a two-part, randomized Phase 3 trial evaluating the efficacy and 
safety of the combination of encorafenib and binimetinib compared to vemurafenib and 
encorafenib monotherapy in patients with locally advanced, unresectable or metastatic 
melanoma with BRAFV600 mutation. COLUMBUS results demonstrated improved 
tolerability in the encorafenib 450 mg QD + binimetinib 45 mg BID arm compared with 
single-agent encorafenib 300 mg QD (Dummer et al 2018a, Dummer et al 2018b). This is 
consistent with a body of literature that suggests the combination of a MEK inhibitor and a 
BRAF inhibitor results in improved tolerability compared with either agent alone (Flaherty et 
al, 2012, Long et al, 2014, Robert et al, 2015a, Larkin et al, 2014, Ascierto et al, 2016). 
Among patients receiving encorafenib and binimetinib combination therapy in the 
COLUMBUS study, the most common adverse reactions (≥20%, all grades) were fatigue 
(43%), nausea (41%), diarrhea (36%), vomiting (30%), abdominal pain (28%), arthralgia 
(26%), myopathy (23%), hyperkeratosis (23%), rash (22%), headache (22%), constipation 
(22%), visual impairment (20%), serous retinopathy (20%). Most of these toxicities were 
generally reversible and manageable by supportive medical care, dose modifications or 
discontinuation. Other clinically important adverse reactions occurring in < 10% of patients 
were facial paresis, pancreatitis, panniculitis, drug hypersensitivity and colitis. The most 
common laboratory abnormalities (≥2%, Grade 3 or 4) were increased GGT (11%), 
increased ALT (6%), increased creatine phosphokinase (5%), increased fasting glucose (5%), 
increased creatinine (4%), anemia (4%), hyponatremia (4%), increased AST (3%), 
neutropenia (3%) and lymphopenia (2%). Detailed information regarding clinical safety is 
presented in the respective Investigator’s Brochures for encorafenib and binimetinib.
Important potential adverse effects associated with the administration of the combination of 
encorafenib and binimetinib established primarily from safety data from the COLUMBUS 
study and, where indicated, from other studies of the combination, include:

New primary malignancies: Based on its mechanism of action, encorafenib may 
promote malignancies associated with activation of RAS through mutation or other 
mechanisms. Cutaneous and non-cutaneous malignancies occurred in patients, 


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including cutaneous squamous carcinoma/keratoacanthoma (2.6%) and basal cell 
carcinoma (1.6%).

Left ventricular dysfunction: Symptomatic or asymptomatic decreases in ejection 
fraction occurred in 7% of patients, with Grade 3 left ventricular dysfunction 
occurring in 1.6% of patients. 

Hemorrhage: Hemorrhage occurred in 19% of patients, with events ≥Grade 3 
occurring in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or 
progressive brain metastases occurred in 1.6% of patients. The most frequent 
hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), 
hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).

Venous thromboembolism: Occurred in 6% of patients, including 3.1% of patients 
who developed pulmonary embolism.

Ocular toxicities: Serous retinopathy is a class effect of MEK inhibitors. It is 
generally asymptomatic or mildly symptomatic and reversible (Urner-Bloch et al,
2016). Serous retinopathy occurred in 20% of patients. Symptomatic serous 
retinopathy occurred in 8% of patients with no cases of blindness. The median time to 
onset of the first event of serous retinopathy (all grades) was 1.2 months. RVO is a 
known class-related adverse reaction of MEK inhibitors and may occur in patients 
treated with binimetinib in combination with encorafenib. In patients with BRAF
mutation-positive melanoma across multiple clinical trials, 0.1% of patients 
experienced RVO. Uveitis, including iritis and iridocyclitis, has been reported in 
patients treated with encorafenib in combination with binimetinib. In the 
COLUMBUS study, the incidence of uveitis among patients treated with encorafenib 
450 mg QD in combination with binimetinib 45 mg BID was 4.4%.

Pneumonitis/Interstitial Lung Disease: Pneumonitis occurred in 0.3% of patients 
with BRAF mutation-positive melanoma across multiple clinical trials.

Hepatotoxicity: The incidence of Grade 3 or 4 increases in liver function laboratory 
tests was 6% for alanine aminotransferase (ALT), 2.6% for aspartate 
aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced 
Grade 3 or 4 serum bilirubin elevation.

CK Elevation/Rhabdomyolysis: Asymptomatic elevations of laboratory values of 
serum CK occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of 
patients with BRAF mutation-positive melanoma across multiple clinical trials.

QTc Prolongation: QT prolongation has been observed in patients treated with 
BRAF inhibitors. Encorafenib is associated with dose-dependent QTc interval 
prolongation in some patients. In the COLUMBUS study, an increase in QTcF to > 
500 ms was measured in 0.5% of patients.

Embryo-Fetal Toxicity: Encorafenib or binimetinib can cause fetal harm when 
administered to pregnant women.


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2.2.4. Clinical Safety of Encorafenib as a Single Agent in the COLUMBUS Study
The maximum well-tolerated dose of encorafenib when given as a single agent is 300 mg 
daily. Encorafenib 300 mg daily as a single agent is associated with an increased risk of 
certain AEs compared to when used in combination with binimetinib. For example, Grade 3 
or 4 dermatologic reactions in the COLUMBUS study occurred in 21% of patients treated 
with single-agent encorafenib compared to 2% of patients treated with encorafenib in 
combination with binimetinib. Among patients receiving single-agent encorafenib 300 mg 
QD across multiple clinical trials including COLUMBUS, the most common AEs (≥20%, all 
grades) were alopecia (50%), palmar-plantar erythrodysesthesia syndrome (48%), arthralgia 
(43%), hyperkeratosis (42%), nausea (35%), dry skin (29%), fatigue (28%), myalgia (28%), 
headache (27%), vomiting (25%), rash (23%) and palmoplantar keratoderma (22%).
Detailed information regarding clinical safety of encorafenib is presented in the encorafenib 
Investigator’s Brochure.
2.2.5. Clinical Safety of Encorafenib 600 mg QD in the CMEK162X2110 Study
Clinical Study CMEK162X2110 was a Phase 1b/2 multicenter, open-label, dose-finding, 
dose-escalation study. In Phase 1b, the primary objective was to estimate the MTD(s) and/or 
RP2D(s) of encorafenib + binimetinib (dual combination) and of encorafenib + binimetinib + 
ribociclib (triple combination) in patients with BRAF V600-dependent advanced solid 
tumors. In Phase 2, the primary objective of the study was to assess the clinical efficacy of 
the dual combination and the triple combination at each MTD/RP2D in the selective Phase 2 
populations.
A total of 47 patients treated with dual combination therapy were enrolled in the Phase 1b 
study, with only 1 patient (2.3%) across all cohorts investigated experiencing a DLT 
occurring in a patient receiving 800 mg encorafenib and 45 mg binimetinib (nonserious AE 
of Grade 3 arthritis). The most frequently reported AEs for the 600 mg QD encorafenib plus 
45 mg binimetinib Phase 1b patients (n=8) were nausea in 5 patients (62.5%), diarrhea in 7 
patients (87.5%) fatigue, constipation, and abdominal pain in 3 patients (37.5%). The 
proportion of patients reporting each of these events was generally comparable across all 
Phase 1b dose cohorts, with a higher incidence of nausea and diarrhea reported in the higher 
encorafenib dose cohorts.
At the completion of the Phase 1b, dose escalation portion of the CMEK162X2110 study, 2 
separate RP2Ds, encorafenib 600 mg QD (n=8) and 450 mg QD (n= 13), both in combination 
with binimetinib 45 mg BID, were identified. 
A total of 79 patients were treated in Phase 2 with 64 patients receiving 600 mg QD as the 
starting encorafenib dose and 15 patients received 450 mg QD as the starting encorafenib 
dose. Early-onset renal insufficiency (Grade 3 creatinine increase) was observed in 3 
melanoma patients (2 with pre-existing conditions that could be associated with renal 
insufficiency) at the higher encorafenib dose level (600 mg QD), leading to a decision to no 
longer treat patients at this dose. All subsequent Phase 2 patients were started at 450 mg QD, 
and all ongoing patients on the higher encorafenib dose were given the option to reduce the 
dose to 450 mg QD in combination with their current binimetinib dose. Further evaluation of 


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renal failure/acute renal injury have been evaluated during ongoing aggregate safety reviews 
across clinical trials with encorafenib. Most cases of renal impairment/insufficiency/failure 
or chronic kidney injury were associated with pre-renal causes, such as dehydration with 
vomiting or diarrhea, and other pre-existing conditions or risk factors, such as diabetes and 
hypertension. Furthermore, the Sponsor had an expert nephrologist consultant review renal 
biopsy reports, which concluded that these events were likely not intrinsic drug-induced 
toxicity. 
All 79 Phase 2 patients experienced at least 1 adverse event of any grade. The most 
frequently reported adverse events (≥ 25% of patients) regardless of grade were diarrhea in 
41 patients (51.9%), nausea in 37 (46.8%), vomiting in 29 patients (36.7%), pyrexia in 26 
patients (32.9%), arthralgia in 24 patients (30.4%), fatigue in 24 patients, constipation in 20 
patients (25.3%), and AST increased in 20 patients (25.3%). Most of the AESIs were 
reported with a severity of Grade 1 or 2.
Detailed information regarding clinical safety of encorafenib 600 mg QD in combination 
with binimetinib 45 mg BID is presented in the encorafenib Investigator’s Brochure.
2.3. Study Rationale
Results from the COLUMBUS Phase 3 trial provide the clinical support and rationale to 
conduct a study in a subpopulation of BRAFV600 melanoma patients with asymptomatic 
brain metastases. The Phase 3 COLUMBUS study (randomized, 2-part, open-label, 
multicenter, international clinical study) demonstrated clinically meaningful results of 
encorafenib + binimetinib treatment in patients with metastatic BRAFV600-mutant 
melanoma. Median PFS was 14.9 months (95% CI 11,0, 20.2) with encorafenib + 
binimetinib and 7.3 months (95% CI 5.6, 8.2) with vemurafenib (hazard ratio 0.54 [95% CI 
0.41, 0.71]; two-sided p <0.0001) (Dummer et al, 2018a). The hazard ratio for PFS in the 
encorafenib + binimetinib group compared to the encorafenib monotherapy group was 0.77 
(95% CI 0.59, 1.00, 2-sided p = 0.050) (Dummer et al, 2018b), thus confirming that 
combined BRAF and MEK inhibition provides a superior response compared to 
BRAF-inhibitor monotherapy. Median OS was 33.6 months (95% CI 24.4, 39.2) with 
encorafenib + binimetinib and 16.9 months (95% CI 14.0, 24.5) with vemurafenib (hazard 
ratio 0.61 [95% CI 0.47, 0.79]; two-sided p < 0.0001). 
A dedicated trial comparing high- and standard-dose regimens of encorafenib and 
binimetinib will provide additional clinical evidence in the subset of advanced melanoma 
patients with metastasis to the brain. In addition, the study will evaluate whether a high-dose 
regimen may overcome potential limitations in brain penetration compared to the standard-
dose regimen.
2.4. Benefit/Risk Assessment
The primary risks of encorafenib + binimetinib treatment are well characterized and include 
known class effects of BRAF and MEK inhibitors. These include skin toxicities; eye 
toxicities including RVO, serous retinopathy and uveitis; hypertension; hepatic toxicity; LV 
dysfunction; hemorrhage; thromboembolism; and rhabdomyolysis. The combination of 
encorafenib + binimetinib has a lower frequency and severity of pyrexia and photosensitivity 


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reactions than dabrafenib + trametinib and vemurafenib + cobimetinib combinations, 
respectively. Observed toxicities of encorafenib + binimetinib combination are generally 
manageable by dose modification, temporary interruption of treatment or discontinuation in 
conjunction with established medical management.
Investigators selected to participate in this study are experienced in managing toxicities 
associated with combination BRAF and MEK inhibitor therapy. This, together with regular 
monitoring of LVEF, liver function, CK, renal function (Section 7.3.9) and appropriate 
patient counseling regarding potential toxicities, minimizes the potential risks associated with 
treatment with encorafenib + binimetinib. The level of risk compared to the potential benefit 
to metastatic melanoma patients is acceptable. The relatively low rate of treatment 
discontinuation for adverse reactions, 6% in the COLUMBUS study (Dummer et al, 2018a) 
and dose intensity achieved for both encorafenib and binimetinib demonstrate that the 
combination is well tolerated.
There is a risk that the high-dose regimen will not be tolerable. However, the study design, 
including a Safety Lead-in will mitigate that risk. Results may demonstrate an effective 
treatment alternative for patients with melanoma brain metastasis after first-line checkpoint 
inhibitor therapy.
3. OBJECTIVES AND ENDPOINTS
Table 4.
Objectives and Endpoints
Primary Objective
Primary Endpoint
Safety Lead-in

Evaluate the safety of a high-dose 
regimen of encorafenib + binimetinib 
combination therapy in patients with 
BRAFV600-mutant melanoma who 
have asymptomatic brain metastasis 
Safety Lead-in

Incidence of DLTs 

Incidence and severity of AEs graded 
according to the NCI CTCAE version 
4.03 and changes in clinical laboratory 
parameters, vital signs and ECGs

Incidence of dose interruptions, dose 
modifications and discontinuations due to 
AEs 
Phase 2
If the high-dose regimen is determined to 
be safe based on the results of the Safety 
Lead-in phase, then

Evaluate the antitumor activity in 
brain metastases of the standard and 
high dose regimens of encorafenib + 
binimetinib combination therapy in 
patients with BRAFV600-mutant 
Phase 2

BMRR per mRECIST v1.1


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Table 4.
Objectives and Endpoints
melanoma who have asymptomatic 
brain metastasis
If the high-dose regimen is determined 
not to be safe based on the results of the 
Safety Lead-in phase, then

Evaluate the antitumor activity in 
brain metastases of the standard 
dosing regimen of encorafenib + 
binimetinib combination in patients 
with BRAFV600-mutant melanoma 
who have asymptomatic brain 
metastasis
Secondary Objectives
Secondary Endpoints

Further evaluate the antitumor activity 
of encorafenib + binimetinib 
combination therapy in patients with 
BRAFV600-mutant melanoma who 
have asymptomatic brain metastasis

Extracranial response rate per RECIST 
v1.1

Global response rate (brain metastasis 
response per mRECIST v1.1 and 
extracranial response per RECIST v1.1)

DCR
o
for brain metastasis response per 
mRECIST v1.1
o
for extracranial response per RECIST 
v1.1
o
for global response (brain metastasis 
per mRECIST v1.1 and extracranial 
per RECIST v1.1)

DOR
o
for brain metastasis response per 
mRECIST v1.1
o
for extracranial response per 
RECIST v1.1
o
for global response (brain 
metastasis per mRECIST v1.1 
and extracranial per RECIST 
v1.1)

PFS
o
for brain metastasis per 
mRECIST v1.1
o
for global assessment (brain 
metastasis per mRECIST v1.1 


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Table 4.
Objectives and Endpoints
and extracranial disease per 
RECIST v1.1)
•
BMRR per mRECIST v1.1 for Safety 
Lead-in only
•
Evaluate the efficacy of encorafenib + 
binimetinib combination therapy as 
measured by OS in patients with 
BRAFV600-mutant melanoma who 
have asymptomatic brain metastasis
•
OS
•
Further evaluate the safety profile of 
encorafenib + binimetinib 
combination therapy in patients with 
BRAFV600-mutant melanoma who 
have asymptomatic brain metastasis
•
Incidence and severity of AEs graded 
according to the NCI CTCAE version 
4.03 and changes in clinical laboratory 
parameters, vital signs and ECGs
•
Characterize the PK of encorafenib 
and its metabolite LHY746, and 
binimetinib and its metabolite 
AR00426032 
•
Plasma concentration-time profiles and 
PK parameter estimates for encorafenib 
and its metabolite LHY746, and 
binimetinib and its metabolite 
AR00426032
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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4. STUDY DESIGN
4.1. Overall Design
This is a multicenter, randomized open-label Phase 2 study to assess the safety, efficacy and 
PK of 2 dosing regimens of encorafenib + binimetinib combination therapy in patients with 
BRAFV600-mutant melanoma with asymptomatic brain metastasis. Approximately 
110 eligible patients will be enrolled, including 9 patients in a single-arm Safety Lead-in.
After a Screening Period, treatment will be administered in 28-day cycles and will continue 
until disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent 
anticancer therapy, death. Once the patient discontinues study treatment, the Treatment 
Period will end, and the patient will enter the Follow-up Period. The 2 doses of encorafenib + 
binimetinib combination treatment to be evaluated are summarized in Table 5.
The first 9 evaluable patients in the high-dose treatment will constitute the high-dose Safety 
Lead-in cohort. Evaluable patients for the Safety Lead-in cohort must have experienced:

either a DLT (Table 7) or 

received at least 75% of the planned cumulative dose of both study drugs during 
Cycle 1. 
If the high-dose treatment is found safe during the Safety Lead-in, based on predefined 
evaluation criteria (Section 6.6), eligible patients will be randomized (1:1; approximately 50 
patients in each treatment arm) to the standard-dose (Arm A) or high-dose (Arm B) treatment 
arm stratified by:

baseline number of brain metastases (1 to 2 brain lesions vs. ≥3 brain lesions at 
baseline assessment) and 

history of prior local therapy [e.g., SRS or SRT (yes vs. no)].
Table 5.
Planned Treatment Arms
Treatment Arm
Encorafenib Dose
Binimetinib Dose
A
(standard-dose)1
450 mg QD
45 mg BID
B
(high-dose)
300 mg BID
45 mg BID
1. The standard dose arm (Arm A) includes patients who have intra-patient dose escalation (see 
Section 6.7.2).
If the high-dose treatment is determined not to be safe in the Safety Lead-in, no patients will 
be enrolled into Arm B, and up to 100 patients will be enrolled into 2 cohorts in the standard-
dose Arm A:

Cohort 1: Up to 50 patients with BRAFV600 cutaneous melanoma with metastases to 
the brain confirmed by MRI, asymptomatic, and with prior local therapy (e.g., SRS or 
SRT). 


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
Cohort 2: Up to 50 patients with BRAFV600 cutaneous melanoma with metastases 
to the brain confirmed by MRI, asymptomatic, without prior local therapy (e.g., SRS 
or SRT). Phase 2 enrollment will close when either Cohort 1 or 2 reaches 
approximately 50 patients.
Patients who are able to tolerate the standard dose of encorafenib (450 mg QD) plus 
binimetinib (45 mg BID) during the first 4 weeks of treatment (Cycle 1) should be dose-
escalated to 600 mg encorafenib QD plus 45 mg binimetinib BID provided they meet 
protocol-defined criteria (see Section 6.7.2). 
As described in Section 6.10, patients who remain on treatment at the end of the study and 
who may, in the opinion of the Investigator, derive benefit from continued treatment with 
encorafenib + binimetinib may be provided the opportunity to continue treatment in 
accordance with local regulations.
4.2. Discussion of Study Design
This Phase 2 trial uses accepted tumor assessment endpoints with a primary endpoint of 
response, BMRR. Predefined, standardized and generally accepted criteria for this patient 
population are used to ascertain responses, specifically RECIST v1.1 and mRECIST v1.1. 
Response rate is deemed a direct measure of drug antitumor activity that can be evaluated in 
a single-arm trial (US Department of Health and Human Services 2007). 
The study design incorporates a Safety Lead-in to ensure an appropriate safety evaluation of 
a previously untested dosing regimen. If the high-dose regimen is determined to be safe 
based on the Safety Lead-in results, the stratified randomized study design provides an 
unbiased approach to evaluate the efficacy and safety of 2 dosing regimens. If the high-dose 
regimen is determined not to be safe based on the Safety Lead-in results, the 2 cohorts in the 
standard-dose treatment arm will allow the evaluation of the efficacy of standard-dose 
regimen in those patients with prior local therapy and those without prior local therapy in 
order to better understand the impact, if any, of prior local therapy on objective response to 
subsequent systemic therapy with encorafenib and binimetinib. 
Patients who are able to tolerate the standard dose of encorafenib (450 mg QD) plus 
binimetinib (45 mg BID) during the first 4 weeks of treatment (Cycle 1) should be dose-
escalated to 600 mg encorafenib QD plus 45 mg binimetinib BID provided they meet 
protocol-defined criteria (see Section 6.7.2). This update in protocol amendment version 3.0 
provides additional data to evaluate the safety, tolerability and efficacy of encorafenib + 
binimetinib combination therapy with dose-escalation to encorafenib 600 mg QD.
4.3. Justification for Dose
This study evaluates the combination of encorafenib and binimetinib using 2 regimens:

A standard-dose treatment arm (encorafenib 450 mg QD + binimetinib 45 mg BID)

A high-dose treatment arm (encorafenib 300 mg BID + binimetinib 45 mg BID)


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The standard-dose treatment employs a regimen for binimetinib and encorafenib identical to 
that used in the COLUMBUS study, which demonstrated clinically meaningful antineoplastic 
efficacy in patients with BRAF-mutant metastatic melanoma. Patients who tolerate the first 
cycle (4 weeks) of standard-dose treatment (see Section 6.7.2), should be dose escalated to 
receive encorafenib 600 mg QD, a dose that was previously shown to be safe and efficacious 
in Clinical Study CMEK162X2110 (see Section 2.2.5).
Encorafenib is a P-gp substrate and an inhibitor of BCRP, while binimetinib is a P-gp and 
BCRP substrate. Due to the function of the blood-brain barrier, the penetration of a drug into 
the brain depends on its intrinsic membrane permeability and its susceptibility to active 
efflux (Di et al. 2013). Although encorafenib and binimetinib have high intrinsic membrane 
permeability, efflux transporters may result in reduced brain concentrations for both. Animal 
models have limited utility in predicting the effect of efflux transporter proteins on human 
brain concentrations (Di et al 2013, Syvanen et al, 2009, Chu et al, 2013). 
The BBB may be compromised in patients with brain metastases (Cohen et al, 2016). The 
compromised blood brain barrier may at least in part explain the activity of other drugs in 
melanoma brain metastases. For example, dabrafenib and trametinib are efflux transporter 
substrates thought to have limited brain penetration based on nonclinical data (Mittapalli et 
al, 2013, Vaidhyanathan et al, 2014). Yet the combination had clinical activity in the 
COMBI-MB study (Davies et al, 2017). The role of the potentially compromised BBB in 
treating patients with brain metastases is not well understood, and thus evaluating a high-
dose regimen when feasible is seen as a potentially useful strategy in these patients.
The high-dose treatment arm investigates whether an alternate regimen may overcome 
potential limitations in brain penetration for patients with melanoma brain metastasis 
compared to the standard-dose treatment. The following sections describe the rationale for 
the high-dose regimen.
4.3.1. Binimetinib Regimen
Binimetinib monotherapy has been evaluated at 45 mg BID and 60 mg BID (clinical 
studies ARRAY-162-111 and CMEK162X2201). An observed incidence of reversible retinal 
events during dose expansion at 60 mg BID led to binimetinib dose reduction to 45 mg BID. 
A BID dosing regimen of 45 mg was used in the Phase 3 COLUMBUS study in 
BRAFV600-mutant melanoma (Dummer et al, 2018a, Dummer et al, 2018b). Options for 
increasing binimetinib dose are limited by transient ocular findings; therefore, the high-dose 
regimen for the current study explores only high-dose encorafenib in combination with the 
standard dose of binimetinib.
4.3.2. High-dose Encorafenib
The goals of including a high-dose regimen of encorafenib is this study are 2-fold: (1) to 
increase the total daily dose to offset the potential decrease in exposure in the brain due to the 
BBB and (2) to increase continuous target coverage throughout each day by increasing the 
dosing frequency.


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Compared to 450 mg QD, encorafenib at 300 mg BID is expected to increase the daily AUC 
by 33% and the trough concentration by 700%. The Cmax is expected to decrease by 32%. 
Higher daily encorafenib doses will increase exposure (i.e., AUC) and, in turn, result in 
higher brain exposure. The EC50 values for suppression of pMEK and pERK in A375 human 
melanoma cells expressing BRAFV600 are 2 nM and 3 nM, respectively. At a 450 mg QD 
encorafenib dose, the unbound steady-state Cmax is approximately 850 nM, which is ~280- to 
430-fold higher than these EC50 values. At a 300 mg BID encorafenib dose, the unbound 
steady-state Cmax is approximately ~190- to 290-fold higher than these EC50 values. 
Therefore, it is likely that a 32% reduction in Cmax will not be detrimental and may be offset 
by increases in AUC and trough concentrations.
Encorafenib BID regimen may have additional advantages for BRAFV600 coverage. The in 
vitro rate of dissociation of encorafenib from the target protein kinase, BRAFV600, has been 
observed to be slower than that of the BRAFV600 inhibitors dabrafenib and vemurafenib
(Delord et al, 2017). The relationship between the in vitro and in vivo kinetics and target 
inhibition in tumors has not been established. Once daily dosing is efficacious in peripheral 
BRAFV600 mutant melanomas (Dummer et al 2018a, Dummer et al 2018b). However, 
encorafenib concentrations in the brain may not provide adequate target inhibition during an 
entire 24-hour dosing cycle. With a 300 mg BID encorafenib regimen, an increased AUC and 
trough concentration may increase target inhibition in the brain. 
There is limited clinical experience with higher dose BID encorafenib regimen. Dose-ranging 
Study CMEK162X2110 evaluated regimens up to encorafenib 800 mg QD + binimetinib 45 
mg BID (see Section 2.2.5). 
Due to the potential for increased toxicity associated with the high-dose BID regimen, the 
study design includes a Safety Lead-in to assess tolerability based on predefined evaluation 
criteria (Section 6.6). Specific guidance related to renal safety monitoring is provided in 
Section 6.7.3.
4.4. End of Study Definition
End of study will be defined as 2 years after treatment initiation of the last enrolled patient or 
the point at which all patients have died or withdrawn consent or have been lost to follow up, 
whichever occurs first. At the end of the study, access to study treatment will be provided in 
accordance with applicable regulations and requirements to all patients who are continuing to 
benefit from study treatment (see Section 6.10).
4.5. Study Termination
The Investigator retains the right to terminate conduct of the study at any time, according to 
the terms specified in the clinical trial agreement. The Investigator is required to notify the 
IRB/IEC in writing of the study’s completion or early termination, send a copy of the 
notification to the Sponsor or Sponsor’s designee and retain a copy for the site study 
regulatory file.
The Sponsor will assess the benefits and risks associated with the study on a continuous basis 
based on information from the study, as well as from routine pharmacovigilance activities for 


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encorafenib and binimetinib, and may terminate the study electively if the balance of risks 
and benefits no longer supports continuation of the study, if required by regulatory decision 
or for other reasons (e.g., poor recruitment, changing scientific or clinical landscape). If the 
study is terminated prematurely, the Sponsor will notify the Investigators, the IRB/IEC and 
regulatory bodies of the decision and reason for termination of the study.
5. STUDY POPULATION
Patients must fulfill all eligibility criteria to be eligible for enrollment in the study. Questions 
regarding patient eligibility should be addressed to the Sponsor prior to enrollment.
Protocol deviations to recruitment and enrollment criteria are not permitted as they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability and/or 
patient safety.
5.1. Inclusion Criteria
Patients must meet all the following criteria to be eligible for enrollment in the study:
1. Able to provide written informed consent. Adult patients under guardianship may 
participate if permitted by local regulations with the consent of their legally 
authorized guardian. All local regulations concerning patients under guardianship 
must be followed.
2. Age ≥ 18 years at the time of informed consent. 
3. Histologically confirmed diagnosis of cutaneous melanoma with metastases to the 
brain.
4. Presence of BRAFV600 mutation in tumor tissue previously determined by a local 
PCR or NGS-based assay at any time prior to Screening or by a central laboratory 
during Screening. 
5. Patients are required to submit archival or fresh tumor tissue and a blood sample 
prior to enrollment. Tissue samples will be used to determine BRAFV600-mutation 
status by central laboratory. 
6. Must have at least 1 parenchymal brain lesion ≥0.5 cm and ≤4 cm, defined as an 
MRI contrast-enhancing lesion that may be accurately measured in at least 
1 dimension. 
Note: Measurable intracranial lesions that have been previously irradiated and have 
not been shown to be progressing following irradiation should not be considered as 
target lesions.


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7. Patients may have received the following prior therapies:
a.
Safety Lead-in, Phase 2 Randomized , Phase 2 Arm A Cohort 1: May have 
received prior local therapy for brain metastases including but not restricted to 
brain surgery, whole brain radiotherapy (WBRT), stereotactic radiotherapy or 
stereotactic radiosurgery (e.g. gamma knife, linear-accelerated-based 
radiosurgery, charged particles, and CyberKnife). Multiple local (brain) 
therapies or combinations of local therapies are allowed. For patients 
receiving local therapy to all brain lesions (including WBRT), progression of 
pre-existing lesions based on RECIST 1.1 (> 20% increase in longest diameter 
on baseline scan) or new measurable lesions are required. For patients 
receiving local therapy for some but not all lesions, disease progression based 
on RECIST 1.1 is not required as long as there are remaining brain lesions 
that are measurable and not previously treated. 
b. Phase 2 Arm A Cohort 2: Received no prior local therapy (e.g., brain 
surgery, craniotomy, SRS or SRT) for brain metastases.
c.
All patients (Safety Lead-In and Phase 2): May have received prior 
immunotherapy. 
d. All patients (Safety Lead-In and Phase 2): If receiving concomitant 
corticosteroids must be on a stable or decreasing dose (up to a total daily dose 
of 4 mg of dexamethasone or equivalent) for at least 2 weeks prior to first 
dose of study treatment.
8. An ECOG PS of 0 or 1 and Karnofsky score ≥ 80 (see Section 7.2.5). 
9. Adequate bone marrow, organ function and laboratory parameters:
a.
ANC ≥ 1.5 × 109/L;
b. Hemoglobin ≥ 9 g/dL with or without transfusions;
c.
Platelets ≥ 100 × 109/L; 
d. AST and ALT ≤ 2.5 × ULN; in patients with liver metastases ≤ 5 × ULN;
e.
Total bilirubin ≤ 1.5 × ULN;
Note: Patients with documented Gilbert syndrome or hyperbilirubinemia due 
to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following 
discussion and agreement with the Sponsor Medical Monitor.


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f.
Serum creatinine ≤ 1.5 × ULN; OR calculated creatinine clearance 
> 50 mL/min by Cockcroft-Gault formula; OR estimated glomerular filtration 
rate > 50 mL/min/1.73m2.
10. Female patients of childbearing potential, as described in Appendix 1, must have a 
negative serum β-HCG test result.
11. Female patients of childbearing potential must agree to protocol-approved methods 
of contraception, as described in Appendix 1, and to not donate ova from Screening 
until 30 days after the last dose of study drug.  
12. Male patients must agree to use methods of contraception that are highly effective 
or acceptable, as described in Appendix 1, and to not donate sperm from Screening 
until 90 days after the last dose of study drug. 
13. The patient is deemed by the Investigator to have the initiative and means to 
comply with scheduled visits, treatment plan and study procedures.
5.2. Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for enrollment in the study.
1. Patients with symptomatic brain metastasis (e.g., have neurologic symptoms related 
to brain metastases). 
2. Prophylactic or preventive anti-epileptic therapy.
Note: Anti-epileptic therapy indicated in order to prevent neurologic symptoms 
caused by a preexisting condition and not related to brain metastasis is allowed.
3. Known hypersensitivity or contraindication to any component of study treatment or 
their excipients.
4. Inability to swallow and retain study treatment.
5. Uveal or mucosal melanoma.
6. History of or current leptomeningeal metastases.
7. Treatment with SRS or craniotomy within 14 days prior to start of study treatment, 
or treatment with whole-brain radiation within 28 days prior to study treatment. 
Patients who received local therapy should have complete recovery with no 
neurological sequelae.


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8. Either of the following:
a.
Radiation therapy to non-brain visceral metastasis within 2 weeks prior to 
start of study treatment;
b. Continuous or intermittent small-molecule therapeutics or investigational 
agents within 5 half-lives of the agent (or within 4 weeks prior to start of 
study treatment, when half-life is unknown).
9. Patients treated in the adjuvant setting with BRAF or MEK inhibitor(s) < 6 months 
prior to enrollment. Patients who received BRAF or MEK inhibitors in the 
metastatic setting are excluded.
10. Is currently participating in a study and receiving an investigational agent; has 
received an investigational agent or used an investigational device within 14 days 
prior to start of study treatment.
11. Patients who have undergone major surgery (e.g., inpatient procedure with regional 
or general anesthesia) ≤6 weeks prior to start of study treatment. For minor 
surgical procedures ≤ 6 weeks prior to start of study treatment, consult the Sponsor 
Medical Monitor.
12. Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before 
starting study treatment.
Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such 
as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are 
exceptions and patients with these may enroll. 
13. Impaired cardiovascular function or clinically significant cardiovascular disease 
including, but not limited to, the following: 
a.
History of acute coronary syndromes (including myocardial infarction, 
unstable angina, coronary artery bypass grafting, coronary angioplasty or 
stenting) < 6 months prior to Screening;
b. Congestive heart failure requiring treatment (New York Heart Association 
Grade ≥2); 
c.
An LVEF < 50% as determined by MUGA or ECHO; 
d. Uncontrolled hypertension defined as persistent systolic blood pressure 
≥150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current 
therapy;


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e.
History or presence of clinically significant cardiac arrhythmias (including 
resting bradycardia, uncontrolled atrial fibrillation or uncontrolled 
paroxysmal supraventricular tachycardia);
f.
Triplicate average baseline QTcF interval ≥ 480 msec.
14. Impairment of gastrointestinal function or disease which may significantly alter the 
absorption of study treatment (e.g., active ulcerative disease; uncontrolled nausea, 
vomiting or diarrhea; malabsorption syndrome; small bowel resection). 
15. Concurrent neuromuscular disorder that is associated with elevated CK 
(e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, 
spinal muscular atrophy). 
16. Known history of acute or chronic pancreatitis.
17. 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); history of retinal degenerative disease. 
18. Use of herbal supplements, medications or foods that are moderate or strong 
inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 ≤1 week prior to the start 
of study treatment.
19. History of a thromboembolic event < 12 weeks prior to starting study treatment. 
Examples of thromboembolic events include transient ischemia attack, 
cerebrovascular accident, deep vein thrombosis or pulmonary embolism. Catheter-
related venous thrombosis is not considered a thromboembolic event for this trial 
even if < 12 weeks prior to starting study treatment. 
20. Concurrent or previous other malignancy within 2 years of study entry, except 
curatively treated basal or squamous cell skin cancer, prostate intraepithelial 
neoplasm, carcinoma in-situ of the cervix, Bowen’s disease and ≤ 6 Gleason 
prostate cancer. Patients with a history of other curatively treated cancers must be 
reviewed by the Sponsor prior to entering the study.
21. Active infection requiring systemic therapy. 
22. Known history of positive test for HIV or known AIDS. Testing for HIV must be 
performed at sites where mandated locally. 


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23. Evidence of HBV or HCV infection.
Note: Patients with laboratory evidence of cleared HBV or HCV infection may be 
enrolled.
Note: Patients with no prior history of HBV infection who have been vaccinated 
against HBV and who have a positive antibody against hepatitis B surface antigen 
as the only evidence of prior exposure may enroll. 
24. Pregnancy or breastfeeding or patients who plan to become pregnant during the 
duration of the study. 
25. Other severe, acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
treatment 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. 
5.3. Lifestyle Considerations
Please refer to Appendix 1 for guidance on contraceptive use.
5.3.1. Meals and Dietary Restrictions
Patients must avoid consumption of grapefruit, pomegranates, star fruits, Seville oranges or 
products containing the juice of each during the entire study, preferably 7 days before first 
dose of study drugs, due to potential CYP3A4 interaction with encorafenib. Orange juice is 
allowed.
5.3.2. Activity
Strenuous physical activities, such as competitive sports, may result in significant increases 
in CK levels while on binimetinib treatment. Patients should be cautioned to avoid new 
strenuous exercise after first dose of study treatment.
5.4. Screen Failures
Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently enrolled or randomized into the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria and any SAE.
Tests with results that fail eligibility requirements may be repeated during Screening if the 
Investigator believes the result to be in error. Additionally, a patient who fails Screening may 
repeat the Screening process 1 time if the Investigator believes that there has been a change 
in eligibility status. 


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6. STUDY TREATMENT
Study treatment is defined as any investigational drugs intended to be administered to a study 
patient according to the protocol. 
6.1. Study Treatments Administered
In patients who receive the standard dose, encorafenib 450 mg will be administered PO QD 
in continuous 28-day cycles. Patients receiving the standard dose of encorafenib will be 
instructed to take encorafenib daily in the morning at approximately the same time every day. 
In patients who receive the high dose, encorafenib 300 mg will be administered PO BID in 
continuous 28-day cycles. Patients receiving the high dose of encorafenib will be instructed 
to take encorafenib 12 ± 2 hours apart in the morning and in the evening at approximately the 
same times every day. On clinic visit days, dosing times may need to be adjusted to 
accommodate predose study assessments.
Binimetinib 45 mg will be administered PO BID in continuous 28-day cycles. Patients will 
be instructed to take binimetinib 12 ± 2 hours apart in the morning and in the evening at 
approximately the same times every day. On clinic visit days, dosing times may need to be 
adjusted to accommodate predose study assessments.
Encorafenib and binimetinib should be taken together, if applicable, and without regard to 
food. Patients will be instructed to swallow the capsules/tablets whole with a large glass of 
water and not to chew or crush them. Detailed information regarding the study treatment can 
be found in Table 6. 

Encorafenib QD Dosing: Patients will be instructed to take encorafenib capsules daily 
with a large glass of water 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.

Encorafenib BID Dosing (high-dose arm): Patients will be instructed to take 
encorafenib capsules 12 ± 2 hours apart with a large glass of water in the morning and 
in the evening at approximately the same times every day. Doses of encorafenib 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.

Binimetinib BID Dosing (standard-dose and high-dose arms): Patients will be 
instructed to take binimetinib tablets 12 ± 2 hours apart with a large glass of water 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.
Both study drugs (encorafenib and binimetinib) will be taken together in the morning. In the 
standard-dose treatment arm, only the BID administered drug (binimetinib) will be taken in 
the evening. In the high-dose treatment arm, encorafenib and binimetinib will be taken 
together in the evening. Dosing on days when PK blood draws are performed is described in 
Section 7.7.1.


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If a patient vomits at any time after dosing, the dose of study drug should not be re-
administered.
Patients will receive a diary to document self-administered dosing of encorafenib and 
binimetinib in each cycle to include the dose of study drug taken, the date of dosing, if any 
doses were missed and the reason for the missed dose. 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.
Detailed information on study drug preparation, handling, storage and accountability will be 
provided in the Pharmacy Manual.
Table 6.
Study Treatments
Study Treatment Name
Encorafenib
Binimetinib
Type 
Drug
Drug
Dose Formulation
Capsule
Tablet
Unit Dose Strength
75 mg
15 mg
Dosage Levels
450 mg QD
(standard-dose arm)
or
300 mg BID
(high-dose arm)
45 mg BID
Route of Administration
Oral
Oral
Sourcing
Encorafenib will be provided 
centrally by the Sponsor or designee.
Binimetinib will be provided 
centrally by the Sponsor or designee.
Packaging and Labeling
Encorafenib will be provided in high-
density polyethylene bottles. Each 
bottle will be labeled per local 
regulatory requirements.
Binimetinib will be provided in high-
density polyethylene bottles. Each 
bottle will be labeled per local 
regulatory requirements.
Former Names or Aliases
LGX818
ONO-7702
ARRAY-438162
MEK162
ONO-7703
6.2. Preparation/Handling/Storage/Accountability
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are reported and 
resolved before use of the study drug.
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatment must be stored in a secure, 
environmentally controlled and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff.
The Investigator (or designee), is responsible for study drug accountability, reconciliation 
and record maintenance (i.e., receipt, reconciliation and final disposition records). Inventory 
and accountability records must be maintained and readily available for inspection by the 


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study monitor and are open to inspection at any time by applicable regulatory authorities. 
The Investigator or designee must maintain records that document:

Delivery of study drugs to the site.

Inventory of study drugs at the site.

Patient use of study drugs including capsule/tablet counts from each supply 
dispensed.

Return of study drugs to the Investigator or designee by the patient.
The study treatment must be used only in accordance with the protocol. The Investigator will 
also maintain records adequately documenting that the patient was provided with the 
specified study drug. These records should include dates, quantities and any available batch 
or serial numbers or unique code numbers assigned to the study drug and study patients.
Completed accountability records will be archived by the site. The Investigator or designee 
will be expected to collect and retain all used, unused and partially used containers of study 
drug until verified by the study monitor (unless otherwise agreed to by the Sponsor). At the 
conclusion of the study, the Investigator or designee will oversee shipment of any remaining 
study drug back to the Sponsor or its designee, or for the destruction of study drug according 
to institutional standard operating procedures.
Detailed information on study drug preparation, handling, storage and accountability will be 
provided in the Pharmacy Manual.
6.3. Randomization
This is an open-label study; however, the study treatment to be taken by a patient will be 
assigned using an IWRS. The site will contact the IWRS to enroll a patient and receive study 
drug assignment. The site will also contact the IWRS to order additional study drug supplies 
and discontinue patients from study treatment. The site will record the treatment assignment 
on the applicable eCRF, if required. Full details will be provided in the IWRS or Study 
Manual.
If the high-dose treatment is determined to be safe in the Safety Lead-in, a patient 
randomization list will be produced by the IWRS provider using a validated system that 
automates the random assignment of patient numbers. A 1:1 randomization into both 
treatment arms will be initiated and will be stratified by baseline tumor burden and history of 
prior local therapy (Section 4.1).
If the high-dose treatment is determined not to be safe in the Safety Lead-in, no patients will 
be enrolled into the high-dose (Arm B), and patients will be enrolled at the standard-dose 
(Arm A) in 2 cohorts; patients who have received prior local therapy (e.g., SRS, SRT) for 
brain metastasis (Cohort 1) and patients who had no prior local therapy for brain metastasis 
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6.3.1. Patient Numbering
Each patient is identified in the study by a Patient Number (Patient No.) that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the study. The Patient No. consists of the 
4 digits Center Number (as assigned by the Sponsor or designee to the investigative site) with 
a sequential patient number suffixed to it (the last 4 digits of the Patient ID), so that each 
patient is numbered uniquely across the entire database. Upon signing the screening informed 
consent form, the patient is assigned to the next sequential Patient No. available to the 
Investigator through IWRS. Once assigned, the Patient No. must not be reused for any other 
patient and the Patient No. for that individual must not be changed, even if the patient is 
re-screened. If the patient fails to be randomized or start treatment for any reason, the reason 
will be entered into the eCRF. Refer to Section 5.4 for further information on data collected 
for screen failures. IWRS must be notified within 2 days that the patient was not randomized.
6.4. Study Treatment Compliance
Compliance with all study-related treatments will be emphasized to the patient by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study. 
Patient compliance with study treatment will be assessed at each visit. Compliance will be 
assessed by an accounting of returned study drug, patient interviews and a review of patient 
diary entries. Patients will be instructed to bring all study drugs with them to the study visits 
in order for site personnel to assess study drug accountability. Deviation(s) from the 
prescribed dosage regimen will be recorded in the eCRF.
In the case of overdosage of encorafenib or binimetinib, see Section 7.6. There is no known 
antidote for overdosage of encorafenib or binimetinib. Supportive care should be instituted.
6.5. Concomitant Therapy
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines and/or herbal supplements) must be recorded in the eCRF. 
Details regarding all prior anticancer treatment will also be recorded in the eCRF.
Any medication received within 28 days before the first dose of study treatment and within 
30 days after the last dose of study treatment, or until the patient begins a new anticancer 
therapy, whichever occurs first, will be recorded in the eCRF. Any addition, deletion or 
change in the dose of these medications will also be recorded. Details of prior antineoplastic 
treatments including number of prior metastatic regimens will also be recorded. Unless 
specifically prohibited, concomitant medications may be administered at the Investigator’s 
discretion to manage the patient’s medical condition and to conform to standard practice 
during the Treatment Period.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Reason for use.

Dates of administration including start and end dates.


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
Dosage information (using generic drug names when possible), including dose and 
frequency.
The Sponsor Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.1. Permitted Concomitant Therapy Requiring Caution and/or Action
6.5.1.1. 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 and induced CYP2B6, CYP2C9 and CYP3A4 in 
human primary hepatocytes. Permitted medications to be used with caution in this study 
include those that are sensitive substrates of CYP2B6, CYP2C9, CYP3A4 and UGT1A1 or 
those substrates that have a narrow therapeutic index.
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 for females of childbearing potential during participation in 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 as being metabolized by CYP3A4 and to a lesser extent by 
CYP2C19 in vitro. Concomitant use of moderate CYP3A4 inhibitors should be avoided. If 
use of a moderate CYP3A4 inhibitor is unavoidable, short-term use (30 days) following 
discussion with the Sponsor may be permitted with an accompanying dose reduction to one-
half of the encorafenib dose prior to use of the moderate CYP3A4 inhibitor (i.e., for the 
standard-dose treatment arm, 225 mg encorafenib QD, and for the high-dose treatment arm, 
150 mg encorafenib BID). After the inhibitor has been discontinued for 3 to 5 elimination 
half-lives, resume the encorafenib dose that was taken prior to initiating the CYP3A4 
inhibitor. 
In vitro, binimetinib has been identified to be primarily metabolized by glucuronidation. 
Strong inducers of UGT1A1 should be taken with caution when co-administered with 
binimetinib.
For tabulated CYP substrates, inhibitors and inducers to be used with caution or avoided, 
please consult the FDA website: Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers.
6.5.1.2. Transporter Substrates and Inhibitors
In vitro data showed that encorafenib is a substrate of the transporter P-gp. Thus, drugs that 
are known to inhibit or induce P-gp should be used with caution. Encorafenib is also a potent 
inhibitor of the renal transporters OAT1, OAT3 and OCT2, and the hepatic transporters 
OATP1B1 and OATP1B3. The co-administration of drugs that are known to be sensitive or 
narrow therapeutic index substrates of OAT1, OAT3, OCT2, OATP1B1 or OATP1B3 should 
be used with caution.


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Binimetinib has also been shown to be a substrate of P-gp and BCRP. It is advised that 
inhibitors and inducers of P-gp and BCRP transporters should be taken with caution when 
co-administered with binimetinib. 
For tabulated transporter substrates, inhibitors and inducers to be used with caution, please 
consult the FDA website: Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers.
6.5.1.3. Drugs with a Known Conditional or Possible Risk to Prolong QT Interval 
and/or Induce Torsade de Pointes
Investigators should use caution when administering encorafenib with concomitant 
medications with a known, conditional or possible risk to prolong the QT interval and/or 
induce torsade de pointes. Patients receiving such medications must be carefully monitored 
for potentiating of toxicity due to any individual concomitant medication and may require 
dose titration of the concomitant medication. See the CredibleMeds® website: Combined 
List of Drugs That Prolong QT and/or cause Torsades de Pointes (TDP). 
6.5.2. Prohibited Concomitant Therapy
Medications specified below are not allowed during the study. If there is a clinical indication 
for one of these medications specifically prohibited during the study, discontinuation from 
the study treatment may be required. Patients may receive other medications that the 
Investigator deems to be medically necessary. The Investigator should discuss any questions 
regarding medications with the Sponsor. The final decision on any supportive therapy rests 
with the Investigator and/or the patient’s primary physician. The decision to continue the 
patient in the study requires mutual agreement of the Investigator, the Sponsor and the 
patient.
The following therapies are prohibited during the Screening and Treatment Periods of this 
study (unless otherwise noted). 

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 treatment.

Investigational drugs and devices.

Radiation therapy (not including palliative radiotherapy at focal sites that covers 
≤10% of the bone marrow reserve).
Note: Palliative radiation therapy to target lesions is prohibited. Administration of 
palliative radiation therapy will be considered clinical progression for the purposes of 
determining PFS.

Concomitant strong systemic CYP3A4 inhibitors, which could significantly increase 
the exposure of encorafenib. 

Concomitant moderate or strong systemic CYP3A4 inducers, which could 
significantly decrease the exposure of encorafenib.
No therapies are prohibited during the post-treatment Follow-up Period.


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6.6. High-dose Safety Assessment
After 9 evaluable patients in the Safety Lead-in have completed one 28-day cycle of 
treatment, safety assessments will be conducted. All toxicities will be assessed for severity 
by the Investigator using CTCAE v4.03. Evaluable patients for the Safety Lead-in cohort 
must have either:

experienced a DLT (Table 7) or 

received at least 75% of the planned cumulative dose of both study drugs during 
Cycle 1.
The Sponsor and participating Investigators will perform ongoing reviews of patient safety 
data through regular teleconferences approximately weekly during the Safety Lead-in.  Once 
9 evaluable patients are available for assessment, the Sponsor will convene a joint 
teleconference with participating Investigators. If the high-dose treatment is found safe based 
on 9 evaluable patients, subsequent patients will be randomized 1:1 to receive either the 
standard or high-dose treatment. If the high-dose treatment is determined not to be safe, 
enrollment will proceed with the standard-dose treatment as outlined in Section 4.1. The 
high-dose treatment will be considered safe if the rate of DLTs (Table 7) observed in the first 
cycle of treatment in the Safety Lead-in is < 33%. 


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Table 7.
Criteria for Defining Dose-limiting Toxicities
DLT Definition
A DLT is defined as any AE or laboratory abnormality that is not explained by underlying disease, disease 
progression, intercurrent illness, or concomitant therapies that either meets the criteria described below or results in 
the inability to tolerate at least 75% of the planned dose of binimetinib or encorafenib during Cycle 1.
Specific DLT Criteria
Cardiac disorders

Absolute decrease of LVEF > 10% compared to baseline and the LVEF is below the institution’s LLN 

LV systolic dysfunction Grade ≥ 3 

Other cardiac disorders Grade ≥ 3
Vascular disorders

Grade 3 hypertension for > 14 consecutive days 

Grade 4 hypertension
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
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 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: 
a.
Lymphocyte count decreased (lymphopenia) Grade ≥ 3 unless clinically significant
Renal dysfunction

Calculated GFR decrease of 50% from baseline

Proteinuria 24-hour urine protein > 2 g/24 hours
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.
QTcF must be prolonged on 2 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 
reviewable toxicities upon review and agreement by the Investigator and Sponsor Medical Monitor.


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6.6.1. Management and Follow up of Reviewable Toxicities
Patients who experience a reviewable toxicity will receive appropriate treatment and 
supportive care as necessary and will be monitored closely until resolution of the toxicity to 
baseline or the event appears to have stabilized for a minimum of 2 weeks (14 days). During 
follow up, patients should be seen as often as medically indicated to assure safety.
6.6.2. Procedure for High-dose Safety Review 
The Sponsor and Investigators will perform a safety review of the high-dose treatment arm 
after there are 9 evaluable patients in the Safety Lead-in. An evaluable patient is defined in 
Section 6.6. The Sponsor and participating Investigators will also perform an ongoing weekly 
review of safety data to assess tolerability and safety during the Safety Lead-in. A Steering 
Committee will be consulted throughout the study on topics including ongoing individual 
toxicities and AEs (Section 9.6.1). 
Routine safety monitoring is described from Section 7.3 through Section 7.6. 
6.7. Dose Modification
6.7.1. General Procedures for Dose Modification
Treatment with encorafenib and binimetinib may be delayed, allowing for resolution of 
toxicity. Patients may resume treatment if no medical condition or other circumstance exists 
that, in the opinion of the Investigator, would make the patient unsuitable for further 
participation in the study. Patients should resume study treatment within 2 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The Investigator should 
contact the Sponsor Medical Monitor to discuss the case of any patient whose treatment has 
been delayed for more than 2 weeks (14 days) before restarting study treatment.
Instructions for dose modifications and interruptions are outlined in Appendix 2
(encorafenib) and Appendix 3 (binimetinib). Individual decisions regarding dose 
interruptions and modifications should be made using appropriate clinical judgment in 
consultation with the Sponsor Medical Monitor, considering relatedness of the AE to the 
study treatment and the patient’s underlying condition. Adverse events that have a clear 
alternative explanation, or transient (≤72 hours) abnormal laboratory values without 
associated clinically significant signs or symptoms may be exempt from dose-reduction rules 
as clinically appropriate. Dose interruptions are permitted in the case of medical or surgical 
events or logistical reasons not related to study treatment (e.g., elective surgery, unrelated 
medical events, patient vacation, holidays). The reason for interruption will be documented 
in the patient’s study record. All dose modifications are based on the worst preceding 
toxicity. 
Doses of encorafenib and binimetinib may be independently delayed and reduced for toxicity 
management as outlined in Table 8. The Investigator should refer to and follow the labeled 
guidance (if applicable) and/or institutional guidelines for the management of toxicities 
relating to encorafenib and binimetinib. Detailed guidelines can also be found in Appendix 2
and Appendix 3.


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When the AE that resulted in a dose reduction improves to and remains stable to the patient’s 
baseline for a minimum of 14 days, the dose can be re-escalated up to the starting dose level 
(450 mg encorafenib QD plus 45 mg binimetinib BID) 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; 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; 

No dose re-escalation of binimetinib or encorafenib is allowed after a dose reduction 
due to ocular toxicity ≥ Grade 2.

Patients who are receiving 600 mg encorafenib QD plus 45 mg binimetinib BID who 
require a dose reduction are not permitted to re-escalate (see Section 6.7.2).
Table 8.
Dose Reductions for Encorafenib and Binimetinib
Level
Dose
Dose Reduction for Encorafenib in the High-dose Combination Arm
0 (starting dose)
300 mg BID
-1
225 mg BID
-2
150 mg BID
-3
75 mg BIDa
Dose Reduction for Encorafenib in the Standard-dose Combination Arm
0 (starting dose)
450 mg QD
-1
300 mg QD
-2
225 mg QDb
Dose Reduction for Single-agent Encorafenibc
-1
300 mg QD
-2
225 mg QDb
Dose Reduction for Binimetinib (both arms)
0
45 mg BID
-1
30 mg BIDd


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Table 8.
Dose Reductions for Encorafenib and Binimetinib
Level
Dose
NOTE: Dose reduction is based on the highest AE grade.
a.
Dose reduction below 75 mg BID is not allowed.
b.
Dose reduction below 225 QD is not allowed.
c.
Single-agent encorafenib dose reduction applies to patients who have permanently discontinued binimetinib.
d.
Dose reduction below 30 mg BID is not allowed.
If a patient misses > 28 consecutive days of dosing with combination treatment (both 
encorafenib and binimetinib), study treatment will be discontinued unless, in the opinion of 
the Investigator, the patient will derive clinical benefit from continued treatment. The 
Investigator will discuss this decision with the Sponsor Medical Monitor. If a patient 
permanently discontinues binimetinib (i.e., no dose for > 28 days), the patient may continue 
single-agent encorafenib if, in the opinion of the Investigator, the patient is deriving clinical 
benefit. Doses of single-agent encorafenib are decreased to a maximum of 300 mg QD when 
binimetinib is permanently discontinued. 
If a patient permanently discontinues treatment with encorafenib, he or she must 
discontinue treatment with binimetinib. 
6.7.2. Intra-Patient Dose Escalation of Encorafenib
During the Phase 2 part of the study, all patients will begin treatment with standard doses of 
encorafenib (450 mg QD) plus binimetinib (45 mg BID).  Patients who are able to tolerate 
the standard dose of encorafenib (450 mg QD) plus binimetinib (45 mg BID) during the first 
4 weeks of treatment (Cycle 1) should be dose-escalated to 600 mg encorafenib QD plus 45 
mg binimetinib BID provided the following criteria are met:

Must not have experienced a clinically meaningful treatment-related adverse event of 
CTCAE ≥ Grade 2 that based on investigator assessment prohibits escalation.

Requires no dose reductions during the first 4 weeks (Cycle 1; guidelines for dose 
reductions are detailed in Appendix 2 for encorafenib and Appendix 3 for 
binimetinib). However, a single dose interruption of up to 4 days is permitted during 
Cycle 1. To ensure steady state exposures of encorafenib + binimetinib in patients 
undergoing intra-patient dose escalation, 7 days of consecutive dosing at the starting 
doses (450 mg QD encorafenib + 45 mg BID binimetinib) are required prior to the 
intra-patient escalation (600 mg QD encorafenib + 45 mg BID binimetinib). 
Therefore, intra-patient dose escalation should occur on Cycle 2 Day 1 (+ 7 days).
Investigators must confirm patients meet all criteria to qualify for dose escalation.  Patients 
who cannot tolerate 600 mg QD encorafenib plus 45 mg BID binimetinib will be dose 
reduced to 450 mg QD encorafenib plus 45 mg BID binimetinib. Re-escalation up to 600 mg 
QD will not be permitted.  Additional dose delays or reductions will be permitted for toxicity 
management as outlined in Table 8.


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6.7.3. Renal Changes in Dose Modification
Encorafenib dose reduction will be considered when either of the following criteria are met:

ACR increase from baseline > 50%.

Baseline absolute serum creatinine value increases by ≥2 grades on more than 
1 occasion. If this occurs, obtain a second serum creatinine measurement within 
1 week.
If either of the above criteria are met, a 24-hour urine collection will be assessed for protein 
and creatinine and serum creatinine will be repeated.
All dosing with study treatment will pause if any of the following criteria are met:

Calculated GFR decrease of ≥50% from baseline.

Creatinine clearance decrease of ≥50% from baseline.

24-hour urine protein of > 2 g/24 hours.
If any of the criteria for pausing study treatment are met, the site is directed to obtain a renal 
consult and to discuss whether the patients should continue study treatment with the Sponsor 
Medical Monitor.
6.8. Criteria for Permanent Discontinuation of Study Treatment
A patient may choose to withdraw from the study treatment at any time or be withdrawn 
from the study treatment by the Investigator or Sponsor if the patient does not comply with 
study requirements. If a patient is withdrawn from study treatment, reasonable efforts will be 
made to determine the reason for withdrawal, and this information will be recorded in the 
eCRF.
Patients meeting any of the following criteria should discontinue study treatment:

Withdrawal of consent/assent (no further participation and thus no further protected 
health information may be collected).
Note: Patients may choose to discontinue study treatment and remain in the study to 
be followed for progression and survival. Patients who indicate they wish to withdraw 
consent should be carefully assessed regarding their intention with respect to further 
follow-up assessments on study. Consent withdrawn means that the patient has 
explicitly indicated that he or she no longer wants to be followed; in this case no 
further data, except data in the public domain, may be solicited from or collected on 
the patient. 

Unacceptable AEs or failure to tolerate study treatment as defined as:
o
Grade 4 or life-threatening AE;
o
Toxicity requiring more than the allowed number of dose reductions for 
encorafenib and binimetinib as described in Table 8;


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o
Occurrence of an AE that is related to study treatment and in the judgment of 
the Investigator compromises the patient’s ability to continue study-specific 
procedures, or is considered to not be in the patient’s best interest; 

Missing > 28 consecutive days of dosing with treatment, unless, in the opinion of the 
Investigator and in consultation with the Sponsor Medical Monitor, the patient will 
derive clinical benefit from continued treatment. 

Clinical progression, as determined by the Investigator in the absence of radiographic 
progression as defined by RECIST v1.1.

Disease progression per both mRECIST v1.1 for brain metastasis and RECIST v1.1 
for extracranial disease. If there is progression in either brain metastasis or 
extracranial disease (not both compartments), the patient may continue treatment if, 
in the opinion of the Investigator, the patient is deriving clinical benefit. 

Patient becomes pregnant or begins breastfeeding.

Significant protocol deviation that, in the opinion of the Investigator or Sponsor, 
renders the patient unsuitable for further study treatment administration.

Patient noncompliance with study procedures that, in the judgment of the Investigator 
or Sponsor, renders the patient unsuitable for further study participation. 

Lost to follow up.

Death.

Termination of the study by the Sponsor (described in Section 9.10).
Note that patients who discontinue study treatment may participate in treatment 
discontinuation assessments at the EOT visit, if applicable, as outlined in the SoA (Table 3). 
The date of the last dose of study treatment will be recorded in the eCRF. See the SoA for 
data to be collected at the time of treatment discontinuation and follow up.
Patients will have the option to stop receiving study treatment and continue in the Follow-up 
Period of the study for safety/efficacy assessments. If the patient discontinues study 
treatment and actively withdraws consent for collection of follow-up data (safety follow up 
and disease assessments), no additional data collection will occur. 
6.9. Patient Discontinuation/Withdrawal from the Study

A patient may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance or administrative reasons. This is expected to be uncommon.

See the SoA (Table 3) for data to be collected at the time of study discontinuation and 
follow up and for any further evaluations that need to be completed.

If the patient withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a patient withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records.


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6.10. Intervention After the End of the Study
At the end of the study, access to study treatment will be provided, in accordance with 
applicable regulations and requirements, to all patients who are continuing to benefit from 
study treatment. Where required by local regulations, this protocol may be amended to allow 
patients to continue treatment, and reconsent of ongoing patients will be required. 
The Sponsor will notify all applicable regulatory agencies in accordance with local 
requirements when the study has ended. In such cases, appropriate safety information will 
continue to be captured per protocol and submitted to the Sponsor. The information to be 
collected includes treatment-related AEs and SAEs, laboratory results of special interest, 
study treatment administration, patient status and date and reason(s) for study withdrawal.
6.11. Replacement of Patients
Patients may be replaced for any of the following reasons:

During the Safety Lead-in, any patient who receives < 75% of the planned cumulative 
dose of either encorafenib or binimetinib during Cycle 1 for any reason other than a 
DLT (e.g., not evaluable for a DLT [Table 7]) may be replaced to ensure a minimum 
number of evaluable patients.

Patients who do not meet the eligibility requirements of the study may be replaced.

Patients for whom the BRAFV600 mutation status is not confirmed by central 
laboratory may be replaced. This includes either an Indeterminate or a No Mutation 
BRAFV600 Detected result.
6.12. Lost to Follow up
A patient will be considered lost to follow up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a patient fails to return to the clinic for a required 
study visit:

The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in 
the study.

Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient. These contact attempts will be 
documented in the patient’s medical record.

Should the patient be unreachable, he/she will be considered to have withdrawn from 
the study and lost to follow up. 


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6.13. Withdrawal Consent
Patients who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a patient specifically withdraws consent for any further contact with 
him or her or persons previously authorized by the patient to provide this information. 
Patients should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible. The withdrawal of consent should be explained in detail 
in the medical records by the investigator, as to whether the withdrawal is only from further 
receipt of study treatment or also from study procedures and/or posttreatment study 
follow-up and entered on the appropriate CRF page. In the event that vital status (whether the 
patient is alive or dead) is being measured, publicly available information should be used to 
determine vital status only as appropriately directed in accordance with local law.
7. STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Table 3). Protocol waivers or 
exemptions are not allowed. Safety concerns should be discussed with the Sponsor Medical 
Monitor immediately upon occurrence or awareness to determine if the patient should 
continue or discontinue study treatment. Adherence to the study design requirements, 
including those specified in the SoA, is essential and required for study conduct.
7.1. Screening Procedures
Screening is the interval between signing the ICF and the day the patient is enrolled in the 
study (Cycle 1 Day 1). Screening may not exceed 28 days. Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the 
screening process.
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count, 
imaging study) and obtained before signing of the ICF may be used for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Table 3). If baseline scans from an institution other 
than the investigational site are used, the site must obtain copies of the radiographic scans 
prior to enrollment of the patient, or the scans must be repeated at the investigational site and 
submitted.
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. Tests with results that fail eligibility requirements may be repeated once during 
screening if the Investigator believes the results to be in error. For screening assessments that 
are repeated, the most recent available results before enrollment will be used to determine 
eligibility.
See Section 5.4 and Section 6.11 for information regarding screen failures and replacement 
of patients, respectively.


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7.1.1. Baseline Documentation of Intracranial Target and non-Target Lesions
All baseline lesion assessments must be performed 28 days prior to the first dose of study 
treatment. Refer to Appendix 5.
Note:

Cystic lesions thought to represent cystic metastases should not be selected as target 
lesions when other suitable target lesions are available.

Measurable intracranial lesions that have been previously irradiated and have 
not been shown to be progressing following irradiation should not be considered 
as target lesions.

Prior excision of a single melanoma brain metastasis is allowed and may be selected 
as a target lesion provided there is regrowth in the cavity. 
All other intracranial lesions should be identified as non-target and should also be recorded at 
baseline. Measurements of non-target lesions are not required, but the presence or absence of 
each should be noted throughout follow-up.
7.1.2. Baseline Documentation of Extracranial Target and non-Target Lesions
All baseline lesion assessments must be performed 28 days prior to the first dose of study 
treatment. Refer to Appendix 4. 
Note: Measurable extracranial lesions that have been previously irradiated and have 
not been shown to be progressing following irradiation should not be considered as 
target lesions.
All other lesions (or sites of disease, excluding the brain) should be identified as non-target 
and should also be recorded at baseline. Non-target lesions will be grouped by organ. 
Measurements of these lesions are not required, but the presence or absence of each should 
be noted throughout follow-up.
7.2. Efficacy Assessments
All data acquired for efficacy purposes (e.g., CT, MRI, X-ray, FDG-PET, pathology reports, 
caliper measurements and measurements of tumor markers) obtained at Screening and while 
on study, including off-schedule imaging studies, will be made available if requested by the 
Sponsor. 
7.2.1. Radiological Tumor Evaluation
Appropriate radiological scans of all suspected sites of disease are performed until disease 
progression using the same method and technique throughout the study. Target lesions 
should demonstrate the patient’s baseline tumor burden and should be selected based on their 
size (i.e., lesions with the longest diameter) and their suitability for accurate repeat 
assessment. See the SoA (Table 3) for the schedule of brain and extracranial assessments.
When possible, each center will have a designated radiologist responsible for the 
interpretation of scans and response evaluations for study patients. A single radiologist 
should perform all evaluations for an individual patient.


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Assessments will be performed until disease progression, withdrawal of consent, initiation of 
subsequent anticancer therapy, patient is lost to follow up, death or defined end of study 
(Section 4.4). 
The following will be performed:

Screening and on treatment gadolinium-enhanced MRI of the brain.

Screening and on treatment chest, abdomen and pelvis CT (or MRI) scans.

An MRI of spine is required at screening only. 

Skeletal lesions identified at baseline will 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 at any time if there is symptomatic 
evidence suggesting the possibility of disease progression based on clinical symptoms 
or physical examination.
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. 
Extracranial lesions will be assessed using RECIST v1.1 (Eisenhauer et al, 2009, 
Appendix 4); brain metastasis will be assessed per mRECIST v1.1 (Appendix 5) and per 
RANO-BM in an exploratory analysis (Lin et al, 2015). All CT scans will 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. Chest X-ray 
or ultrasound will not be used for tumor response assessments in this study.
Any extracranial lesions that have been subjected to loco-regional therapies (e.g., 
radiotherapy, ablation, etc.) will not be considered measurable unless they have clearly 
progressed since the therapy. Previously treated lesions that have not progressed will be 
considered non-measurable and assessed as non-target lesions. 
While FDG-PET scans are not required for this study, sites may perform extracranial 
imaging by PET-CT 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 
standards, FDG-PET may be used to document PD in accordance with RECIST v1.1. 
The initial Screening imaging should be performed within 28 days of the first dose of study 
treatment. Post-Screening assessments will be performed as described in the SoA (Table 3) 
(± 7 days). Imaging will not be delayed for delays in cycle start. Every effort must be 
made to assess each lesion that is measured at Screening by the same method throughout the 
study to enable consistent comparison. 


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Confirmation of brain, extracranial and global CR and PR is required. Confirmation 
assessments must be performed no less than 4 weeks after the criteria for response have 
initially been met and may be performed at the next scheduled assessment. If a confirmation 
assessment is performed prior to the next scheduled assessment, the next scheduled 
evaluation is still required (i.e., regularly scheduled study visit evaluations must occur at each 
scheduled time point regardless of unscheduled assessments). Partial response can be 
confirmed at an assessment later than the next assessment after the initial documentation of 
PR. If the criteria for a CR or PR are not confirmed, then SD can be considered the best 
response if it has been demonstrated for a minimum of 6 weeks.
7.2.2. Imaging Assessments for RECIST v1.1 and mRECIST v1.1
Details of response assessments are described in Appendix 4, Appendix 5 and Appendix 6.
Brain lesions will be assessed by mRECIST v1.1 criteria. Modification of RECIST v1.1 
allows up to 5 intracranial target lesions of 5 to 40 mm in diameter and includes target 
lesions measuring 5 to 10 mm in their longest diameter. Brain lesions will be measured only 
by gadolinium-enhanced MRI, with a scan-slice thickness of 1 mm for metastases with a 
longest diameter of 5 to 10 mm. 
7.2.3. Blinded Independent Central Review
All radiological assessments obtained for patients will be centrally collected by an imaging
vendor designated by the Sponsor and may be assessed centrally by a BICR in addition to the 
local (Investigator) assessment if deemed necessary.  
7.2.4. Post-treatment Follow up
All AEs suspected to be related to study treatment should be followed up weekly, or as 
clinically indicated, until resolution or stabilization. In addition, dermatologic screening for 
skin malignancies should be performed every 2 months until 6 months after the last dose of 
encorafenib.
7.2.4.1. 30-Day Safety Follow Up
All patients will return for a 30-Day Safety Follow-up Visit 30 ± 7 days after the last dose of 
study drug, or prior to starting 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. 
7.2.4.2. Disease Follow Up
Patients who discontinue study treatment for a reason other than disease progression will 
move into the disease status follow up and should be assessed every 8 weeks (± 7 days) by 


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radiological imaging to monitor disease status. Every effort should be made to collect 
information regarding disease status until:

The start of new anticancer therapy.

Disease progression.

Death.

The end of study.
7.2.4.3. Survival Follow up
Once a patient has received the last dose of study treatment, has confirmed disease 
progression or starts a new anticancer therapy, the patient moves into the Survival Follow-up 
Period and should be contacted by telephone, email or site visit to undergo the following 
assessments at least every 12 weeks (± 7 days) until withdrawal of consent, the patient is lost 
to follow up, death or defined end of the study, whichever occurs first:

Record new SAEs that are considered related to study drug.

Record all subsequent anticancer therapies.

Determine survival status.
7.2.5. Performance Status
Assessments of ECOG PS and Karnofsky Status will be conducted as shown in Table 9
(Oken et al, 1982) at the time points specified in the SoA (Table 3).
Table 9.
Performance Status Scoring
Karnofsky Status
Karnofsky 
Grade
ECOG Grade
ECOG Performance Status
Normal, no complaints
100
0
Fully active, able to carry on all pre-
disease performance without 
restriction
Able to carry on normal 
activities. Minor signs or 
symptoms of disease
90
1
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or sedentary 
nature, e.g., light house work, office 
work
Normal activity with effort
80
1
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or sedentary 
nature, e.g., light house work, office 
work
Care for self. Unable to carry on 
normal activity or to do active 
work
70
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
Requires occasional assistance, 
but able to care for most of his 
needs.
60
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


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Table 9.
Performance Status Scoring
Karnofsky Status
Karnofsky 
Grade
ECOG Grade
ECOG Performance Status
Requires considerable 
assistance and frequent medical 
care
50
3
Capable of only limited self-care; 
confined to bed or chair more than 
50% of waking hours
Disabled. Requires special care 
and assistance
40
3
Capable of only limited self-care; 
confined to bed or chair more than 
50% of waking hours
Severely disabled. 
Hospitalization indicated 
though death non-imminent
30
4
Completely disabled; cannot carry on 
any self-care; totally confined to bed 
or chair
Very sick. Hospitalization 
necessary. Active supportive 
treatment necessary
20
4
Completely disabled; cannot carry on 
any self-care; totally confined to bed 
or chair
Moribund
10
4
Completely disabled; cannot carry on 
any self-care; totally confined to bed 
or chair
Dead
0
5
Dead
7.2.6. BRAF Testing
Patients will be eligible for the study based on identification of a BRAFV600 mutation in 
tumor tissue as determined by a local laboratory PCR or NGS-based assay. Patients must 
have written documentation from a previous local laboratory pathology report of a 
BRAFV600 mutation.  
The investigator must confirm prior to enrollment that the patient has adequate tumor tissue 
available to determine BRAFV600 mutation status by a central laboratory. All patients are 
required to submit either an archived tumor tissue sample or a newly obtained core or 
excisional biopsy (fine needle aspiration is not adequate for either archival or new tissue 
samples).
For archival tumor tissue samples, whenever possible the sample sent for central testing 
should be from the same tumor block that was used for local testing. A minimum of 8-15 
unstained slides or 1 block of tissue should be submitted to the central laboratory. Further 
details regarding sample submission including instructions for sample processing and 
shipping will be provided in the Laboratory Manual. If a biopsy is taken, the biopsy should 
be taken from a non-target lesion. If the patient is enrolled based on local assay results, the 
BRAF mutation status must be evaluated by a 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 a central laboratory is not able to confirm presence of a BRAFV600 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 clinical benefit. In such instances, patients 


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must be informed that the BRAF mutation status is unconfirmed and must sign a separate 
ICF. Patients with discordant local and central results will be replaced.
Central laboratory BRAF mutation tests with a definitive result (positive or negative) may not 
be repeated to resolve a discordant result unless a biopsy sample from a different tumor 
lesion can be provided. Patients whose sample is determined inadequate or who have an 
indeterminate result on central testing may have samples resubmitted for testing. 
7.3. Safety Assessments
The Sponsor Medical Monitor, or designee, and the Sponsor’s Drug Safety and 
Pharmacovigilance 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. 
Planned time points for all safety assessments are provided in the SoA (Table 3).
7.3.1. Patient Demographics and Other Baseline Characteristics
Demographic data, medical, surgical and social history will be collected at Screening.
7.3.2. Disease Characteristics and Treatment History
A history of present illness (disease-specific medical history) will be collected at Screening. 
Details regarding the patient’s malignancy under study, including date of diagnosis, cancer 
stage at diagnosis, tumor histology and prior treatments will be recorded.
7.3.3. Physical Examinations
Physical examinations will be performed by trained medical personnel at the time points 
specified in the SoA (Table 3).
At Screening, the physical examination will 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 or 
symptoms, rectal, external genitalia, breast and pelvic examinations will be performed. 
Body weight will be measured as part of the physical examination at each visit. Height will 
be measured only at Screening. For subsequent visits, the physical examinations will be 
targeted as clinically indicated. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
All physical examinations occurring on dosing days must be performed prior to study drug 
administration. Any treatment-emergent abnormal findings will be recorded as AEs.
7.3.4. Dermatological Examinations
Dermatologic evaluations will be performed at the site by the Investigator to monitor for the 
possible development of keratoacanthoma and/or squamous cell carcinoma, as these have 


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been reported to occur with selective BRAF inhibitor treatment (Flaherty et al, 2010, Kefford 
et al, 2010, Robert et al, 2011). This assessment may be performed predose or postdose at the 
time points specified in Table 3. In addition, dermatologic screening for skin malignancies 
will be performed every 8 weeks until 6 months after the last dose of encorafenib. 
In case of occurrence of keratoacanthoma or squamous cell carcinoma, patients will undergo 
complete surgical excision of the skin lesion following institutional standards. Dermatologic 
evaluations should be performed by a dermatologist as clinically indicated.
7.3.5. Vital Signs
Vital sign measurements (to be taken before blood collection for laboratory tests) will be 
measured per institutional standards as part of the physical examination at the time points 
specified in SoA (Table 3). Vital sign assessments include the following:

Temperature, pulse rate, respiratory rate and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. Blood pressure and pulse measurements will be preceded by at least 5 
minutes of rest for the patient in a quiet setting without distractions (e.g., television, 
cell phones).
All vital sign measurements occurring on dosing days must be performed prior to study drug 
administration. Abnormal vital sign results identified after the first dose of study treatment 
constitute an AE if they are considered clinically meaningful, induce clinical signs or 
symptoms, require concomitant therapy or require changes in study treatment.
7.3.6. Electrocardiograms
A triplicate ECG (3 serial ECGs conducted within approximately 5 to 10 minutes total time) 
will be performed at Screening to determine eligibility and predose on Cycle 1 Day 1 to serve 
as baseline. A single ECG will be performed at all remaining time points specified in the 
SoA (Table 3). A detailed description of the timing of ECGs is provided in Table 10.
Prior to performing the 12-lead ECG, patients will rest in the supine position for at least 
5 minutes. When an ECG is to be performed at the same time point as a blood collection, the 
ECG is to be performed first. The ECG measurement at any time point will be used for AE 
grading and recommended dose modifications. 
Interpretation of the tracing will be made by a qualified physician and documented in the 
eCRF. QT interval values will be corrected using the QTcF formula. Clinically significant 
abnormalities present when the patient signed the screening informed consent/assent will be 
reported in the eCRF. New or worsened clinically significant findings occurring after the 
screening informed consent/assent must be recorded in the eCRF.
An abnormal ECG (e.g., ECG of > 500 ms or with a change in QTcF from baseline of 
≥60 ms) may be repeated if it cannot be interpreted by the Investigator. ECG tracings will be 


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made available if requested by the Sponsor for central assessment by an independent 
reviewer. 
Table 10.
Timing of ECGs
Visit
Any Time
Before Morning Dose of 
Study Treatment
2 Hours (± 15 min) After 
Morning Dose of Study 
Treatment
Triplicate ECGs
Screening
X
Cycle 1 Day 1
X
Single ECGs
Cycle 1 Day 1
X
Cycle 2 Day 1
X
X
Subsequent Cycles Day 1
X
X
EOT
X
7.3.7. Clinical Safety Laboratory Assessments
Blood and urine samples for the laboratory tests listed in Table 11 will be collected at the 
time points specified in the SoA (Table 3).
A certified laboratory local to the investigative site will be used for all clinical laboratory 
assessments for safety (i.e., blood chemistries, hematology, coagulation, serology, renal 
function, urinalysis), in accordance with the SoA (Table 3). The investigative site will enter 
the laboratory results into the eCRF. PK 
 assessments will be sent 
to a central laboratory in accordance with the SoA and the Laboratory Manual. Information 
regarding collection, processing and shipping of laboratory assessments is provided in the 
Laboratory Manual.
The Investigator must review the laboratory report and document this review. The laboratory 
reports must be filed with the source documents. Additional testing may be required by the 
Sponsor based on emerging safety data. Additional tests may also be performed if clinically 
indicated.
Screening laboratory assessments must be performed within 28 days of Cycle 1 Day 1. If 
performed more than 28 days before Cycle 1 Day 1, then the tests must be repeated, and 
eligibility confirmed, before study treatment administration on Cycle 1 Day 1. Laboratory 
assessments collected on Cycle 1 Day 1 must be performed before study treatment 
administration. After Cycle 1, predose laboratory procedures can be conducted up to 72 
hours before study treatment administration (within a 3-day study window), and results will 
be reviewed by the Investigator or qualified designee and found to be acceptable before study 
treatment is administered.
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the Investigator to be more severe than expected for 
the patient's condition. All laboratory tests with values considered significantly abnormal 
during participation in the study or within 30 days after the last dose of study intervention 
CCI


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should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator.
Electrolyte abnormalities including magnesium should be corrected and cardiac risk factors 
for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled.
Table 11.
Summary of Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Coagulation
Others
Hemoglobin
Hematocrit
RBC
Platelets
WBC
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Albumin
Alkaline phosphatase
ALT
Amylase
AST
Bicarbonate (CO2)
Total bilirubin
BUN or urea
Calcium
Chloride
CK (If total CK ≥ 3 × 
ULN, then measure 
isoenzymes, serum 
creatinine and myoglobin 
in blood or urine weekly)
Creatinine
Glucose
LDH
Lipase
Phosphate
Magnesium
Potassium
Total protein
Sodium
Troponin
Uric acid
Direct bilirubin (if total 
bilirubin values are 
abnormal)
Appearance
Color
Specific gravity
pH
Protein
Albumin
Creatinine
Glucose
Ketones
Blood
Nitrite
Leukocytes
PT 
INR
PTT or aPTT
At Screening only:
Hepatitis B surface 
antigen
Hepatitis B surface 
antigen antibody
Hepatitis B core antibody
Hepatitis C antibody
HIV, as applicable per 
local regulations
If applicable:
Females of childbearing 
potential require LH, FSH 
and/or estradiol, serum 
and urine pregnancy tests 
as described in the SoA 
(Table 3).
Pregnancy tests (serum or 
urine) should be repeated 
if required by local 
regulations or as clinically 
indicated.
7.3.8. Pregnancy Testing
A serum pregnancy test will be required for all women of childbearing potential (see
Appendix 1) as outlined in the SoA (Table 3). Urine pregnancy tests will be performed 
locally as outlined in the SoA, as medically indicated (e.g., in case of loss of menstrual cycle, 
when pregnancy is suspected), or per country-specific requirement (note that country-
required urine pregnancy testing will be outlined and communicated to investigational sites 


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under separate cover). All blood and urine collections for pregnancy tests occurring on 
dosing days must be performed prior to study drug administration, with a negative test result 
required prior to administration of study treatment.
If a urine pregnancy test is positive, the results will be confirmed with a serum pregnancy 
test. If the serum pregnancy test is negative after a urine test was positive, the Investigator 
will assess the potential benefit/risk to the patient and determine whether it is in the patient’s 
best interest to resume study treatment and continue participation in the study. Any female 
patient who becomes pregnant while participating in the study will be instructed to 
immediately discontinue study treatment. If pregnancy is confirmed by a serum pregnancy 
test, see Section 7.4.5.1 for reporting requirements.
Patients of nonchildbearing potential (see Appendix 1) do not require pregnancy tests.
7.3.9. Renal Function Monitoring
Renal function monitoring will be conducted to assess for renal dysfunction at the time points 
specified in SoA (Table 3).
See Section 6.7.3 for renal-function-related criteria for modifying or pausing dosing.
7.3.10. Serology
Hepatitis screening assessments will be performed at a local laboratory at the Screening visit 
to rule out hepatitis infection; required analytes are shown in Table 11. Generally, hepatitis 
tests will be performed early in the screening process due to the length of time needed to 
obtain the results. Additional tests may be performed if clinically indicated.
7.3.11. Echocardiogram/Multi-gated Acquisition
Cardiac ejection fraction will be assessed by transthoracic ECHO or MUGA at the time 
points specified in SoA (Table 3).
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 measurements by ECHO or MUGA.
7.3.12. Ophthalmic Examination
7.3.12.1. Testing at Screening and During the Treatment Period
Full ophthalmic examination will be performed by an ophthalmologist at Screening 
(Table 3), including best corrected visual acuity, slit lamp examination, intraocular pressure, 
dilated fundoscopy and OCT. Examination of the retina is required (especially to identify 
findings associated with RPED, serous detachment of the retina and RVO). Ophthalmic 
evaluation may be performed again during the treatment period as clinically indicated.


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7.3.12.2. Additional Testing
Patients with clinical suspicion of retinal abnormalities of any grade (e.g., RPED, serous 
detachment of the retina, RVO, photopsia, metamorphopsia, impairment of visual acuity)
must complete at least one of the following additional assessments:

For non-vascular abnormalities: OCT (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) must be sent to the investigational site and be maintained in the patient’s source 
document file. These images/results must be made available upon Sponsor request. 
7.4. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 7.
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the patient to discontinue the 
study treatment.
The patient will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow up 
information in an expedited fashion.
7.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving study treatment), through and including a minimum 
of 30 calendar days, except as indicated below, after the last administration of the study 
treatment. 
During the long-term follow-up period in this study for survival, only SAEs will be actively 
elicited and collected after completion of the active collection period described above. The 
SAEs identified during long-term follow-up will be reported to Pfizer Safety on the CT SAE 
Report Form only if considered reasonably related to the study treatment.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.


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If the patient withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a patient definitively discontinues or temporarily discontinues study treatment because of 
an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the 
CT SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the patient has concluded 
study participation.  However, if the investigator learns of any SAE, including a death, at any 
time after a patient has completed the study, and he/she considers the event to be reasonably 
related to the study treatment, the investigator must promptly report the SAE to Pfizer using 
the CT SAE Report Form.
7.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period as described in 
Section 7.4.1. are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 7.4. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.  Note that a switch to a commercially available version of the study treatment is 
considered as a new anticancer therapy for the purposes of SAE reporting.
7.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a patient during the active collection period, 
which begins after obtaining informed consent as described in Section 9.4, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the patient.
If a patient begins a new anticancer therapy, the recording period for nonserious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.  Note that a switch to a 
commercially available version of the study treatment is considered as a new anticancer 
therapy for the purposes of SAE reporting.
7.4.2. Methods of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 7.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open ended and 
nonleading verbal questioning of the patient is the preferred method to inquire about AE 
occurrences.


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7.4.3. Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
at subsequent visits/contacts.  For each event, the investigator must pursue and obtain 
adequate information until resolution, stabilization, the event is otherwise explained, or the 
patient is lost to follow-up.
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a patient death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 7.3.
7.4.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
treatment under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (e.g., summary or 
listing of SAEs) from the sponsor will review and then file it along with the Investigator 
Brochure for the study and will notify the IRB/EC, if appropriate according to local 
requirements.


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7.4.5. Exposure During Pregnancy or Breastfeeding and Occupational Exposure
Exposure to the study treatment under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
7.4.5.1. Exposure During Pregnancy
An EDP occurs if:

A female patient is found to be pregnant while receiving or after discontinuing 
study treatment. 

A male patient who is receiving or has discontinued study treatment exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study treatment due to environmental exposure.  Below are examples of 
environmental exposure during pregnancy:  

A female family member or healthcare provider reports that she is 
pregnant after having been exposed to the study treatment by ingestion.

A male family member or healthcare provider who has been exposed to 
the study treatment by ingestion then exposes his female partner prior to or 
around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred.  The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a patient or a patient’s partner, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred.  Details of the 
pregnancy will be collected after the start of study treatment and until 30 days 
after last dose.

If EDP occurs in the setting of environmental exposure, the investigator must 
report information to Pfizer Safety using the CT SAE Report Form and EDP 
Supplemental Form.  Since the exposure information does not pertain to the 
patient enrolled in the study, the information is not recorded on a CRF; however, 
a copy of the completed CT SAE Report Form is maintained in the investigator 
site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 


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follow-up to the initial EDP Supplemental Form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly [in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death]), the investigator should follow the procedures 
for reporting SAEs.  Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs.  In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to the study treatment. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the patient with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner.
7.4.5.2. Exposure during Breastfeeding
An exposure during breastfeeding occurs if: 

A female patient is found to be breastfeeding while receiving or after discontinuing 
study treatment.

A female is found to be breastfeeding while being exposed or having been exposed to 
study treatment (ie, environmental exposure).  An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study treatment by 
inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred.  The 
information must be reported using the CT SAE Report Form.  When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the patient enrolled in the study, so the information is not recorded on a CRF.  
However, a copy of the completed CT SAE Report Form is maintained in the investigator 
site file.


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An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (e.g., vitamins) is administered in accord with 
authorized use.  However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
7.4.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study treatment, which may or may not lead to the occurrence of an AE.  Such persons may 
include healthcare providers, family members, and other roles that are involved in the trial 
patient’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
patient enrolled in the study, the information is not recorded on a CRF; however, a copy of 
the completed CT SAE Report Form is maintained in the investigator site file.
7.4.6. Cardiovascular and Death Events
All cardiovascular events will be managed per the dose modification guidelines in 
Appendix 2 and Appendix 3. Additionally, cardiovascular events will be reported per AE and 
SAE reporting guidelines and ECG criteria, as detailed in Section 7.4 and Section 7.3.6,
respectively. AEs and SAEs that result in death will be reported per the reporting guidelines 
as outlined in Section 7.4.
7.4.7. Disease-Related event and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs
Not applicable
7.4.8. Adverse Events of Special Interest
See Section 2.2.3 Clinical Safety of Combination Encorafenib and Binimetinib for 
descriptions of AESIs.
7.4.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
7.4.9. Medical Device Deficiencies
Not applicable
7.4.10. Medication Errors 
Medication errors may result from the administration or consumption of the study treatment 
by the wrong patient, or at the wrong time, or at the wrong dosage strength.
Exposures to the study treatment under study may occur in clinical trial settings, such as 
medication errors.


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Safety Event
Recorded on the AE 
CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
Medication errors Only if associated with an 
AE or SAE
Only if associated with an SAE
Medication errors include:

Medication errors involving patient exposure to the study treatment;

Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the study patient. 
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
If applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of 
the CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
7.5. Product Complaints
The Sponsor collects product complaints on study drugs/treatments used in clinical studies to 
ensure the safety of study patients, monitor quality and facilitate process and product 
improvements.
All product complaints associated with material packaged, labeled and released by the 
Sponsor (or designee) will be reported to the Sponsor. All product complaints associated with 
other study material will be reported directly to the respective manufacturer.
The Investigator or his/her designee is responsible for reporting a complete description of the
product complaint via email or other written communication to the Sponsor contact or 
respective manufacturer within 1 business day of discovery. Any AE associated with a 
product complaint should be recorded as described in Section 7.4.4 and Section 7.4.5.
If the Investigator is asked to return the product for investigation, he/she will return a copy of 
the product complaint communication with the product.
7.6. Treatment of Overdose
There is no antidote known to over dosage either encorafenib or binimetinib. Supportive 
measures should be instituted.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor within 24 hours.


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2. Closely monitor the patient for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of study treatment (whichever 
is longer).  Closely monitor the patient for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor Medical Monitor based on the clinical evaluation of the 
patient.
7.7. Pharmacokinetic Assessments
7.7.1. Blood Sample Collection
Blood samples (~4 mL each) for plasma PK analysis of encorafenib, its metabolite 
(LHY746), binimetinib and the active metabolite of binimetinib (AR00426032) will be 
collected from all patients enrolled in the Safety Lead-in portion of the study as shown in 
Table 12. If the high-dose regimen is determined to be safe and patients are randomized to 
the high-dose and standard-dose treatments in the Phase 2 portion of the study, PK samples 
will also be collected from all Phase 2 patients as shown in Table 12. However, if the high-
dose regimen is determined not to be safe in the Safety Lead-in, PK samples will be collected 
from all Phase 2 patients as shown in Table 13 using a reduced sampling schedule.
In addition to PK samples stated above, blood samples for PK may be requested for patients 
experiencing unexpected or serious adverse events; with evidence of disease progression; or 
with other events where PK sampling is considered useful (upon agreement between 
investigator and Sponsor).  More than 1 PK sample per patient may be collected throughout 
the study; however, the total blood volume of additional PK samples collected per patient 
should not exceed 20 mL (ie, no more than 5, 4 mL samples).  
Study visits for PK sampling should be scheduled in the morning so that proper predose and 
postdose PK blood samples can be collected. On the PK visit days, the morning doses of 
encorafenib and binimetinib will be taken at the study site at approximately the same time, 
only after collecting the predose PK sample. Predose sampling information will include the 
date and exact time of the most recent previous dose of encorafenib and binimetinib (except 
Cycle 1 Day 1), including the dose amount taken. Postdose sampling information, only 
needed for days with postdose PK sampling (i.e., Cycle 1 Day 1 and Cycle 1 Day 15), will 
include the date and exact time of the morning dose, including the dose amount taken. Except 
for the Cycle 1 Day 1 PK samples, which have to be obtained on the scheduled day, other PK 
samples may be obtained 1 day from the scheduled date. 
If vomiting occurs within 4 hours following study drug administration on the day of PK 
sampling, no additional study treatment will be taken to replace the material that has been 
vomited and it is recommended that no more PK samples be taken after the emesis occurs. 
Vomiting that occurs on Cycle 1 Day 1 and Day 15 will be noted in the PK eCRF. Further 








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7.11. Unscheduled Visits
Unscheduled study visits may occur at any time if medically warranted. Any assessments 
performed at those visits will be recorded in the eCRF.
7.12. End of Treatment and/or Early Termination
When the patient permanently discontinues study treatment, whether the patient is 
terminating the study early or the patient has completed the study, the EOT evaluations must 
be conducted. If the EOT visit coincides with a regular study visit, the EOT evaluations will 
supersede those of the scheduled visit and the data will be entered in the EOT visit in the 
eCRF. The patient should be encouraged to return for the 30-Day Follow-up Visit.
8. STATISTICAL CONSIDERATIONS
A detailed SAP will be prepared by the Sponsor or designee. This plan may modify the 
statistical methods outlined in the protocol; however, any major modifications of the primary 
endpoint definition or analysis will also be described in a protocol amendment.
8.1. Statistical Hypotheses
The primary endpoint of the study is BMRR per mRECIST v1.1. The study is designed to 
test the null hypothesis of BMRR ≤ 30%, which is considered not clinically meaningful and 
insufficient to warrant further study. The alternative hypothesis is the true BMRR for this 
patient population is at least 50%. This hypothesis applies to both the high-dose treatment 
arm and the standard dose treatment arm and will be tested using an exact binomial test at a 
one-sided 5% significance level.
8.2. Sample Size Determination
Safety Lead-in
During the Safety Lead-in, the first 9 evaluable patients will be enrolled to receive the high-
dose encorafenib + binimetinib combination therapy. The high-dose treatment will be 
considered tolerable if the observed Cycle 1 DLT rate is < 33% (i.e., < 3 patients with DLTs 
out of 9 patients). Table 14 provides a comparison of the characteristics for this 
dose-escalation rule with 9 patients and the traditional 3 + 3 rules.
Table 14.
Characteristics of Safety Lead-in Criteria for Cycle 1 Dose-limiting 
Toxicity Rate
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


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If the Sponsor and Investigators determine that the high-dose treatment is safe in the 
9 evaluable patients, randomization will start for the Phase 2 portion of the study. Otherwise, 
no patients will be enrolled into the high-dose treatment Arm in Phase 2.
Phase 2
The sample size calculation of Phase 2 portion of the study is based on the primary endpoint 
of BMRR per mRECIST v1.1. The hypothesis to be tested and details of testing strategy are 
described in Section 8.1.
If the high-dose treatment is determined to be safe in the Safety Lead-in phase, 
approximately 100 eligible patients will be randomized in a 1:1 ratio, stratified by baseline 
tumor burden in the brain (1 to 2 brain lesions vs. ≥3 brain lesions at baseline assessment) 
and by prior local therapy (yes vs. no) to the standard-dose and the high-dose treatment arm 
(i.e., approximately 50 patients per treatment arm). No formal statistical comparison will be 
performed between the 2 treatment arms and the statistical analysis will be performed 
separately by treatment arm. 
If the high-dose treatment is determined not to be safe in the Safety Lead-in phase, no 
patients will be enrolled into the high-dose treatment arm. Up to 100 eligible patients will be 
enrolled into 2 cohorts in the standard-dose treatment arm. Phase 2 enrollment will close 
when either Cohort 1 or 2 reaches the enrollment of 50 patients. 

Cohort 1: Patients with locally confirmed BRAFV600 cutaneous melanoma with 
metastases to the brain confirmed by MRI, asymptomatic, and with prior local therapy 
(e.g., SRS or SRT). 

Cohort 2:  Patients with locally confirmed BRAFV600 cutaneous melanoma with 
metastases to the brain confirmed by MRI, asymptomatic, without prior local therapy 
(e.g., SRS or SRT). 
No formal statistical comparison will be conducted between the 2 cohorts. 
Assuming a true BMRR ≥ 50%, the null hypothesis of BMRR ≤ 30% will be rejected if at 
least 21 brain metastasis responses per mRECIST v1.1 are observed in a cohort of 50 
patients. With approximately 50 eligible patients, the study will provide approximately 90% 
power at a one-sided 5% significance level.
8.3. Analyses Sets
For purposes of analysis, the following analysis sets are defined in Table 15:




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8.4.1. Primary Analyses
Safety Lead-in
The number and proportion of patients in the Dose-determining Set experiencing DLTs during 
the first treatment cycle in the Safety Lead-in will be summarized. Safety and exposure data 
will be summarized as described in the SAP. 
Phase 2
The primary endpoint in the Phase 2 portion of the study is BMRR per mRECIST v1.1. It is 
defined as the proportion of patients who have achieved a best overall brain metastasis 
response of CR or PR according to mRECIST v1.1 per Investigator assessment. Details of 
best overall brain metastasis response are specified in Appendix 5.
Both confirmed and unconfirmed BMRR will be summarized, but the primary analysis will 
be based on confirmed responses. 
The primary analysis will take place after all patients in the Efficacy Set have had the 
opportunity for at least 2 post-baseline tumor assessments, and after all patients with an 
initial response have had an opportunity to be followed up for at least 6 months. 
The BMRR will be calculated with an exact two-sided 90% CI. In addition, the exact 
two-sided 95% CI of BMRR will also be calculated.  
8.4.2. Secondary Analyses
The secondary efficacy endpoints are listed in Table 4. 
8.4.2.1. Extracranial Response Rate
Extracranial response rate is defined as the proportion of patients with a best overall 
extracranial response of CR or PR according to RECIST v1.1 per Investigator assessment. 
Extracranial response rate will be calculated with an exact two-sided 95% CI. 
8.4.2.2. Global Response Rate
Global response rate is defined as the proportion of patients with a best overall response of 
CR or PR per Investigator assessment for brain metastasis and extracranial lesions according 
to mRECIST v1.1 and RECIST v1.1, respectively. Details of best overall response are 
specified in Appendix 6. 
ORR will be calculated with exact two-sided 95% CIs. 
8.4.2.3. Disease Control Rate
Disease control rate is defined as the proportion of patients with a best overall response of 
CR, PR or SD per Investigator assessment. 
DCR will be calculated for brain metastasis, extracranial and global response along with 
exact two-sided 95% CIs, respectively. 


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8.4.2.4. Duration of Response
Duration of response is defined as the time from the date of the first documented response to 
the first documented disease progression or death due to any cause, whichever occurs first. If 
a patient with a CR or PR has neither progressed nor died at the time of the analysis cutoff or 
at the start of any new anticancer therapy, the patient is censored at the date of last adequate 
tumor assessment. DOR will be calculated for patients who achieve a confirmed response 
(i.e., CR or PR) for brain metastasis, extracranial and global response, respectively. 
The survival distribution function for DOR will be estimated using the Kaplan-Meier 
method. In addition, the proportion of patients with a confirmed response for a duration of at 
least 6 months among all patients in the Efficacy Set will also be summarized. 
8.4.2.5. Progression-free Survival
Progression-free survival is defined as the time from the date of first dose of study drug to 
the time of the first documented progression or death, whichever occurs first. If a patient has 
not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer 
therapy, PFS is censored at the date of last adequate tumor assessment. 
The survival distribution function for PFS will be estimated using the Kaplan-Meier method. 
8.4.2.6. Overall Survival
Overall survival is defined as the time from the date of first dose of study drug to the date of 
death due to any cause. If a death has not been observed by the date of the analysis cutoff, 
OS will be censored at the date of last contact. 
The survival distribution function for OS will be estimated using the Kaplan-Meier method.
8.4.2.7. Brain Metastasis Response Rate for Safety Lead-in
Brain metastasis response rate per mRECIST v1.1 will also be calculated for 
Dose-determining Set patients in the Safety Lead-in portion of the study. An exact two-sided 
95% CI of BMRR will be reported. 
8.4.3. Safety Analyses 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. Adverse events will be coded using the MedDRA. 
Incidence tables will be presented for all AEs by maximum severity, SAEs, AEs assessed as 
related to study drug and AEs resulting in discontinuation of study drug. Listings of all safety 
data by treatment arm, patient and assessment date will be provided.
Clinical laboratory data will be analyzed using summary statistics. In addition, distributions 
of key laboratory parameters may be plotted over time; these values will also be classified 
into CTCAE toxicity grades and tabulated. 
Summaries of clinically notable vital sign measurements will be provided. Definitions of 
“clinically notable” will be provided in the SAP.




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9. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
9.1. Regulatory, Ethical, and Study Oversight Considerations
The study will be performed in accordance with the requirements of the applicable regulatory 
authorities in each country where this study is conducted and will also meet all of the 
requirements of ICH GCP guidance. In addition to IRB/IEC 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.
Amendments to the protocol will be submitted to all applicable regulatory authorities for 
approval prior to implementation. 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 
IRB/IEC must be sought and the Investigator will inform the Sponsor and the full IRB/IEC 
within 5 working days after the emergency occurred. All amendments that have an impact on 
patient’s risk or the study objectives or require revision of the informed consent document 
must receive approval from the IRB/IEC prior to implementation.
9.2. Investigator Responsibilities
The Investigator is the person responsible for the conduct of the study at the investigational 
site. A sub-Investigator is any member of the clinical study team designated and supervised 
by the Investigator to perform critical study-related procedures and/or to make important 
study-related decisions.
The protocol, protocol amendments, ICF, Investigator Brochure and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. Any amendments to the 
protocol will require IRB/IEC approval before implementation of changes made to the study 
design, except for changes necessary to eliminate an immediate hazard to study patients.
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies and procedures 
established by the IRB/IEC.

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures.

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable) and all other applicable local regulations.
Investigators must apply due diligence to avoid protocol deviations (with the exception of 
medical emergencies) 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 approved by the 


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Sponsor and by the IRB/IEC. The Investigator is responsible for enrolling patients who have 
met the specified eligibility criteria. All protocol deviations will be recorded.
The Investigator must retain records in accordance with all local, national and regulatory 
laws, but for the minimum period of at least 2 years after the last marketing application 
approval in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or, if not approved, 2 years after the termination of the study 
drug for investigation to ensure the availability of study documentation should it become 
necessary for the Sponsor or a regulatory authority to review.
The Investigator must not destroy any records associated with the study without receiving 
written approval from the Sponsor. The Investigator must notify the Sponsor or its designee 
in the event of accidental loss or destruction of any study records. If the Investigator leaves
the institution where the study was conducted, the Sponsor or its designee must be contacted 
to arrange alternative record storage options (if applicable).
All eCRF data entered by the site (including audit trail), as well as computer hardware and 
software (for accessing the data), will be maintained or made available at the site in 
compliance with applicable record retention regulations. The Sponsor will retain the original 
eCRF data and audit trail.
9.3. Financial Disclosure
Before study initiation, all clinical Investigators are required to abide by FDA Regulation 
Title 21 CFR Part 54 - Financial Disclosure by Clinical Investigators (i.e., “covered studies”) 
and are required to submit a completed Clinical Investigator Financial Disclosure form that 
sufficiently details any financial interests and arrangements that apply. For the purpose of 
this regulation, this applies to the Investigator and any sub-Investigator who is directly 
involved in the treatment of or evaluation of research patients, including the spouse and each 
dependent child of the Investigator or sub-Investigator. These requirements apply to both US 
and foreign clinical Investigators conducting covered clinical studies. Any new clinical 
Investigators added to the covered clinical study during its conduct must also submit a 
completed Investigator Financial Disclosure Form.
During the clinical study, any changes to the financial information previously reported by the 
Investigator or sub-Investigator must be reported to the Sponsor or designee. At the
conclusion of the clinical study, the Investigator and sub-Investigators will remain obligated 
to report to the Sponsor or designee any changes to the financial information previously 
reported, as well as any changes in their financial information for a period of 1 year after the 
completion of the clinical study.
9.4. Informed Consent Process
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. The Investigator 
or his/her representative will explain the nature of the study to the patient or his/her legally 
authorized representative and answer all questions regarding the study.


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Informed consent must be obtained before any study-related procedures are conducted, 
unless otherwise specified by the protocol. Informed consent must be obtained using the 
IRB/IEC-approved version in a language that is native and understandable to the patient. A 
template will be provided by the Sponsor its designee. The Sponsor or its designee must 
review and acknowledge the site-specific changes to the ICF template. The ICF must include 
a statement that the Sponsor or its designee and regulatory authorities have direct access to 
patient records.
The ICF must contain all required elements and describe the nature, scope and possible 
consequences of the study in a form understandable to the patient. The medical record must 
include a statement that written informed consent was obtained before the patient was 
enrolled in the study and the date the written consent was obtained. The authorized person 
obtaining the informed consent must also sign the ICF.
9.5. Data Protection
Patients will be assigned a unique identifier by the Sponsor. Patient records or datasets that 
are transferred to the Sponsor will contain the identifier only. Patient names or any 
information which would make the patient identifiable will not be transferred. If the patient’s 
name appears on any record or document, it will be obliterated on the copy of the document 
to be supplied to the Sponsor or its designee. Study findings stored on a computer will be 
stored in accordance with local data protection laws.
The Investigator will 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. The patient must be informed that his/her personal study-related data 
will be used by the Sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members and by inspectors from regulatory authorities.
The Investigator and the Sponsor or its designee must adhere to applicable data privacy laws 
and regulations. The Investigator and the Sponsor or its designee are responsible for ensuring 
that sensitive information is handled in accordance with local requirements (e.g., HIPAA). 
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) 
of protected information must be obtained.
9.6. Committees 
9.6.1. Steering Committee
A Steering Committee comprised of study Investigators and Sponsor representatives will be 
created. The Sponsor will consult with the Steering Committee about study design, eligibility 
criteria, quality, ongoing individual toxicities and AEs and writing study publications. 
Section 7.3 describes ongoing safety monitoring for this study. No Data Monitoring 
Committee will be formed, as this study evaluates 2 agents with a well characterized safety 


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profile in combination. (Section 2.2.3 describes 2 recommended Phase 2 doses of 
encorafenib, one of which is 600 mg QD.) The study does not recruit vulnerable patients 
such as children, pregnant women or the incarcerated. It is an open-label study that will 
undergo continuous data review and on-site monitoring. 
9.7. Dissemination of Clinical Study Data
Information concerning the study, patent applications, processes, scientific data or other 
pertinent information is confidential and remains the property of the Sponsor. By signing this 
protocol, the Investigator and his/her institution agree that the results of the study may be 
used by the Sponsor, for the purposes of national and/or international registration, publication 
and information for medical and pharmaceutical professions. Information regarding the study 
and study results will be published in accordance with applicable local and national 
regulations. If necessary, the authorities will be notified of the Investigator’s name, address, 
qualifications and extent of involvement.
It is understood by the 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. To allow 
the use of the information derived from this clinical study, the Investigator understands that 
he/she has an obligation to provide complete test results and all data obtained during this 
study to the Sponsor. Data analysis performed independently by an Investigator will be 
submitted to the Sponsor before publication or presentation. 
9.7.1. Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bonafide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
9.8. Data Quality Assurance

Data management will be performed in a validated EDC system. All patient data 
relating to the study will be recorded in an eCRF unless transmitted to the Sponsor or 
designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. The Investigator will be provided with access to an EDC system so 
that the eCRF can be completed for each patient.

The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. Following review and approval, the Investigator 


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will electronically sign and date the pages. This signature certifies that the 
Investigator has thoroughly reviewed and confirmed all data on the eCRF.

A PDF and/or electronic file of the eCRFs will be provided to the site after all data 
have been monitored and reconciled and will be archived at the site as required by 
any applicable local regulatory requirements.

The Investigator must permit study-related monitoring, audits, IRB/IEC review and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote or on-site 
monitoring) are provided in the Monitoring Plan and in accordance with the signed 
site agreement. 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.

The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations).

Qualified study monitors will perform ongoing source data verification to confirm 
that data entered into the eCRF by authorized site personnel are accurate, complete 
and verifiable from source documents; that the safety and rights of patients are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP and all applicable 
regulatory requirements. Every effort will be made to maintain the anonymity and 
confidentiality of patients during this study.

Qualified representatives of the Sponsor or its designee may audit the clinical study 
site and study data to evaluate compliance with the protocol, applicable local clinical 
study regulations and overall study conduct. The Investigator must allow the auditors 
to review original source documents and study documentation for all patients.

Regulatory authorities may conduct an inspection of the study and the site at any time 
during the study. The Investigator and site staff are expected to cooperate with the 
inspectors and allow access to all source documents supporting the eCRFs and other 
study-related documents. The Investigator must immediately notify the Sponsor when 
contacted by any regulatory authority for the purposes of conducting an inspection.

Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for at least 2 years after study completion 
unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of 


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the Sponsor. No records may be transferred to another location or party without 
written notification to the Sponsor.
9.9. Source Documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 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.
9.10. Study and Site Closure
The Sponsor or designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures or GCP guidelines.

Inadequate recruitment of patients by the Investigator.

Discontinuation of further study intervention development.
9.11. Publication Policy
The conditions regulating dissemination of the information derived from this study are 
described in the Clinical Trial Agreement.


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Robert C, Arnault JP, Mateus C et al. RAF inhibition and induction of cutaneous squamous 
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Appendix 1. Contraceptive Guidance
Female patients of childbearing potential must agree to take appropriate precautions to avoid 
pregnancy from Screening through 30 days after the last dose of study treatment.
Male patients should use a condom during treatment and through 90 days after the end of 
systemic exposure to study treatment. If the male patient has a partner that is of child-bearing 
potential, the partner should also use contraception through 90 days after the end of systemic 
exposure to study treatment. In addition, male patients must refrain from donating sperm 
during the study through 90 days after the end of systemic exposure of study treatment. 
Males who have had a vasectomy qualify as having met the requirement for a highly 
effective birth control method.
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). If fertility is unclear (e.g., amenorrhea in adolescents 
or athletes) and a menstrual cycle cannot be confirmed before first dose of study treatment, 
additional evaluation should be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal.
2. Premenopausal female with 1 of the following:

Documented hysterectomy.

Documented bilateral salpingectomy.

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., mullerian agenesis androgen insensitivity), Investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the patient’s 
medical records, medical examination or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 


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a.
A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). However, 
if patients have less than 12 months of amenorrhea, confirmation of 
menopause requires more than one FSH measurement. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
Contraception Guidance:
NOTE: 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 for females of childbearing potential during 
participation in this study.
The contraception guidelines outlined below are adapted from the recommendations related 
to contraception and pregnancy testing in clinical studies guidance document (Clinical Trial 
Facilitation Group Guidelines 2014). Patients must agree to use highly effective methods of 
contraception if it is mandated locally or when, in the judgment of the Investigator, 
compliance with acceptable methods is likely to be suboptimal. 
The following methods have been classified as being highly effective (i.e., failure rate < 1% 
per year when used consistently and correctly) in preventing a pregnancy:

Complete abstinence from heterosexual intercourse during the entire period of risk 
associated with the study treatments; the reliability of sexual abstinence should be 
evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the patient.

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o
Oral.
o
Intravaginal.
o
Transdermal.

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral.
o
Injectable.
o
Implantable.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).


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
Bilateral tubal occlusion.

Vasectomized partner (considered highly effective provided the vasectomized male 
has received medical assessment of surgical success and that the male is a female 
patient’s sole sexual partner).
Acceptable birth control methods characterized as having a failure rate of more than 1% per 
year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action.

Male or female condom with or without spermicide.

Cap, diaphragm or sponge with spermicide.


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Appendix 2. Recommended Dose Modifications for Encorafenib-related* Adverse 
Events
Severity of Adverse Event
Dose Modifications
New Primary Malignancies
Non-cutaneous RAS mutation-positive malignancies
Permanently discontinue.
Uveitis
Grade 1-3
If Grade 1 or 2 does not respond to specific ocular 
therapy, or for Grade 3 uveitis, withhold encorafenib 
and binimetinib for up to 6 weeks.

If improved, resume at same or reduced dose.

If not improved, permanently discontinue.
Grade 4 
Permanently discontinue encorafenib and binimetinib.
Other Eye Disorders (i.e., non-Uveitis 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 days.
1. If resolved to Grade ≤ 1 in ≤ 21 days, resume 
treatment at 1 reduced dose level of 
encorafenib and binimetinib.
2. If not resolved to Grade ≤ 1 in ≤ 21 days, 
permanently discontinue encorafenib and 
binimetinib and close follow-up with 
ophthalmic monitoring until stabilization or 
resolution.
Grade 4
Permanently discontinue encorafenib and binimetinib 
and immediate follow-up with ophthalmic monitoring 
until stabilization or resolution.
QTc Prolongation
QTcF > 500 ms and ≤ 60 ms increase from baseline
1st occurrence: 

Temporarily interrupt dosing of encorafenib 
until QTcF < 500 ms. Then resume treatment 
at 1 reduced dose level of encorafenib.
2nd occurrence:

Temporarily interrupt dosing of encorafenib 
treatment until QTcF < 500 ms. Then resume 
treatment at 1 reduced dose level of 
encorafenib. 
3rd occurrence: 

Permanently discontinue encorafenib.
QTcF > 500 ms and > 60 ms increase from baseline
Permanently discontinue.


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Severity of Adverse Event
Dose Modifications
Hepatotoxicity
Grade 2 AST or ALT increased
Maintain encorafenib dose.

If no improvement within 4 weeks, withhold 
encorafenib until improved to Grade 0-1 or to 
pretreatment/baseline levels and then resume 
at the same dose.
Grade 3 or 4 AST or ALT increased
See Other Adverse Reactions
Dermatologic (Except Hand-foot Skin Reactions)
Grade 2
If no improvement within 2 weeks, withhold until 
Grade 0-1. Resume at same dose if first occurrence or 
reduce dose if recurrent.
Grade 3
Withhold until Grade 0-1. Resume at same dose if first 
occurrence or reduce dose if recurrent.
Grade 4
Permanently discontinue.
Hand-foot Skin Reaction (HFSR)/Palmar-plantar Erythrodysesthesia Syndrome (Dose Adjustment for 
Encorafenib ONLY)
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 


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Severity of Adverse Event
Dose Modifications
level or 1 reduced dose level 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 level of encorafenib.

Consider referral to dermatologist and manage 
HFSR per dermatologist’s recommendation.
> 3rd occurrence:
Interrupt dosing of encorafenib until resolved to 
Grade ≤1, decision to resume treatment with 
encorafenib at one reduced dose level or permanently 
discontinue encorafenib should be based upon the 
Investigator’s discretion.
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 level 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 level.
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 binimetinib.
Other Adverse Reactions (including renal, haemorrhage). Additional renal guidance is provided in 
Section 7.3.9.
Recurrent Grade 2 or 
First occurrence of any Grade 3
Withhold for up to 4 weeks.

If improves to Grade 0-1 or to 
pretreatment/baseline levels, resume at 
reduced dose.

If no improvement, permanently discontinue.


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Severity of Adverse Event
Dose Modifications
First occurrence of any Grade 4
Permanently discontinue or withhold for up to 4 weeks.

If improves to Grade 0-1 or to 
pretreatment/baseline levels, then resume at a 
reduced dose. 

If no improvement, permanently discontinue.
Recurrent Grade 3
Consider permanently discontinuing.
Recurrent Grade 4
Permanently discontinue.
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Appendix 3. Recommended Dose Modifications for Binimetinib-related* Adverse 
Events
Severity of Adverse Event
Dose Modifications
Cardiomyopathy
Asymptomatic, absolute decrease in LVEF of 
> 10% from baseline that is also below the 
LLN
Withhold binimetinib for up to 4 weeks, evaluate LVEF 
every 2 weeks.
Resume binimetinib at a reduced dose if the following are 
present:

LVEF is at or above the LLN and

Absolute decrease from baseline is 10% or less 
and

Patient is asymptomatic.
If LVEF does not recover within 4 weeks permanently 
discontinue binimetinib.
Grade 3-4 (Symptomatic congestive heart 
failure or absolute decrease in LVEF of > 20% 
from baseline that is also below LLN)
Permanently discontinue binimetinib. Closely monitor 
LVEF until resolution or up to 16 weeks.
Venous Thromboembolism
Uncomplicated DVT or PE
Withhold binimetinib.

If improves to Grade 0-1, resume at a reduced 
dose.

If no improvement, permanently discontinue 
binimetinib.
Life threatening PE
Permanently discontinue binimetinib.
Serous Retinopathy
Symptomatic serous retinopathy/ Retinal 
pigment epithelial detachments
Withhold binimetinib for up to 10 days.

If improves and becomes asymptomatic, resume 
at the same dose.

If not improved, resume at a lower dose level or 
permanently discontinue binimetinib.
Retinal Vein Occlusion (RVO)
Any Grade
Permanently discontinue binimetinib.
Uveitis
Grade 1-3
If Grade 1 or 2 does not respond to specific ocular 
therapy, or for Grade 3 uveitis, withhold binimetinib and 
encorafenib for up to 6 weeks.

If improved, resume at same or reduced dose.

If not improved, permanently discontinue 
binimetinib.
Grade 4 
Permanently discontinue.
Other Eye Disorders (i.e., Non-retinal Events, non-Uveitis 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 days.


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Severity of Adverse Event
Dose Modifications

If resolved to Grade ≤ 1 in ≤ 21 days, resume 
treatment at 1 reduced dose level 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 resolution.
Grade 4
Permanently discontinue encorafenib and binimetinib and 
immediate follow-up with ophthalmic monitoring until 
stabilization or resolution.
Interstitial Lung Disease
Grade 2
Withhold binimetinib for up to 4 weeks.

If improved to Grade 0-1, resume at a reduced 
dose.

If not resolved within 4 weeks, permanently 
discontinue.
Grade 3 or Grade 4
Permanently discontinue.
Hepatotoxicity
Grade 2 AST or ALT increased
Maintain binimetinib dose.

If no improvement within 2 weeks, withhold 
binimetinib until improved to Grade 0-1 or to 
pretreatment/baseline levels and then resume at 
the same dose.
Grade 3 or 4 AST or ALT increased
See Other Adverse Reactions
Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations
Grade 4 asymptomatic CPK elevation or
Any Grade CPK elevation with symptoms or 
with renal impairment
Withhold binimetinib dose for up to 4 weeks.

If improved to Grade 0-1 resume at a reduced 
dose.

If not resolved within 4 weeks, permanently 
discontinue binimetinib.
Dermatologic 
Grade 2
If no improvement within 2 weeks, withhold until Grade 
0-1. Resume at same dose if first occurrence or reduce 
dose if recurrent.
Grade 3
Withhold until Grade 0-1. Resume at same dose if first 
occurrence or reduce dose if recurrent.
Grade 4
Permanently discontinue.
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 level 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 level.


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Severity of Adverse Event
Dose Modifications
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 binimetinib.
Other Adverse Reactions (including 
haemorrhage)
Recurrent Grade 2 or 
First occurrence of any Grade 3
Withhold for up to 4 weeks.

If improves to Grade 0-1 or to 
pretreatment/baseline levels, resume at reduced 
dose.

If no improvement, permanently discontinue.
First occurrence of any Grade 4
Permanently discontinue or withhold for up to 4 weeks.

If improves to Grade 0-1 or to 
pretreatment/baseline levels, then resume at a 
reduced dose. 

If no improvement, permanently discontinue.
Recurrent Grade 3
Consider permanently discontinuing.
Recurrent Grade 4
Permanently discontinue.
*For adverse events that may be related to both encorafenib and binimetinib, guidance is provided for the other agent 
also.


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Appendix 4. Response Evaluation Criteria in Solid Tumours (RECIST), Version 1.1
This scale is used for the assessment of extracranial response.
Measurability of Tumour at Baseline
Definitions
At baseline, tumour lesions/lymph nodes will be categorized measurable or non-measurable 
as follows:
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.
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, lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by reproducible 
imaging techniques.
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.

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 


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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 metastases 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.
Specifications by Methods of Measurements
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.
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 imaging, imaging evaluation should be undertaken since it is more objective 
and may also be reviewed at the end of the study.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.


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CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances.
Endoscopy, laparoscopy: The utilization of these techniques for objective tumour evaluation 
is not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials were recurrence following complete 
response or surgical resection is an endpoint.
Tumour markers: Tumour markers alone cannot be used to assess objective tumour response. 
If markers are initially above the upper normal limit, however, they must normalize for a 
patient to be considered in complete response. Because tumour markers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease specific 
basis.
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumour types such as germ cell 
tumours, where known residual benign tumours can remain).When effusions are known to be 
a potential adverse effect of treatment (e.g., with certain taxane compounds of angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment can be considered if the measurable tumour has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease.
Tumour Response Evaluation
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). 
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 


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(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 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’).
Response Criteria
This section provides the definitions of the criteria used to determine objective tumour 
response for target lesions.
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.


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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.
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 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 


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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’.
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.
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 ‘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.


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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 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET 
imagine can be identified according to the following algorithm:
1. 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.
2. 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.
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 


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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’. 
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs. 
Table A1 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline.
Table A1: 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


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When patients have non-measurable (therefore non-target) disease only, Table A2 is to be 
used.
Table A2: 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.
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 is made at an 
assessment, usually the case is also considered NE at that time point, unless a 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. 
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. 
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.


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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 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.


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Appendix 5. Modified Response Evaluation Criteria in Solid Tumors (mRECIST), 
Version 1.1
This scale is used for the assessment of brain lesion response.
Modifications to RECIST v1.1 for Assessment of Brain Lesions
The modifications to RECIST v1.1 impact the number and the minimal size of the target 
brain lesions selected at baseline. Up to 5 lesions may be selected as target lesions; all brain 
lesions beyond these 5 target lesions will be regarded as nontarget lesions. Measurable 
lesions are defined as those that can be accurately measured in at least 1 dimension with the 
longest diameter ≥5 mm when evaluated with gadolinium-enhanced MRI.
Gadolinium-enhanced MRI is the only imaging modality accepted for the assessment of 
brain lesions.

The technical specification of the MRI scanning sequence will be optimized for the 
evaluation of brain lesions, which must be measured in the same anatomic plane 
using the same imaging examinations. Whenever possible the same scanner should be 
used (Eisenhauer et al, 2009). 

As a modification to RECIST v1.1, target lesions as small as 5 mm may be selected, 
however the scanning should follow RECIST v1.1: contiguous slices of maximum 
thickness corresponding to half the size of the lesion. All measurements must be 
taken and recorded in millimeters (mm) using a ruler or calipers.

Image Acquisition guidelines provide the slice thickness requirements that should be 
used following RECIST v1.1 criteria.
Evaluation of Target Brain Lesions
Definitions for assessment of target brain lesion(s) are as follows:
Complete Response (CR): Disappearance of all target lesions. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters (e.g., percent change from baseline).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum of diameters recorded since the treatment started (e.g., 
percent change from nadir, where nadir is defined as the smallest sum of diameters recorded 
since treatment start). In addition, the sum must have an absolute increase of at least 5 mm. 
Not Evaluable (NE): Cannot be classified by 1 of the 4 preceding definitions.


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Special Notes on the Assessment of Target Brain Lesions
If a target brain lesion disappears and reappears at a subsequent time point it should continue 
to be measured. The response at the time when the lesion reappears will depend upon the 
status of other lesions. For example, if the disease had reached a CR status then PD would be 
documented at the time of reappearance. However, if the response status were PR or SD, the 
diameter of the reappearing lesion should be added to the remaining diameters and response 
determined based on percent change from baseline and percent change from nadir.
Evaluation of Non-target Brain Lesions
Definitions for assessment of non-target brain lesion(s) are as follows:
Complete Response (CR): Disappearance of all non-target lesions. 
Non-CR/Non-PD: The persistence of 1 or more non-target lesion(s) identified as a site of 
disease.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
Not Applicable (NA): No non-target brain lesions at baseline.
Not Evaluable (NE): Cannot be classified by 1 of the 4 preceding definitions.
Special Notes on the Assessment of Non-target Brain Lesions
Non-target brain lesions that are not assessed at a particular timepoint based on the SoA 
(Table 3) should be excluded from the response determination (e.g., non-target response does 
not have to be “Not Evaluable”).
New Lesions
New brain malignancies denoting disease progression must be unequivocal. Lesions 
identified in follow up in an anatomical location not scanned at baseline are considered new 
lesions.
Any equivocal new lesion should continue to be followed. Treatment can continue at the 
discretion of the Investigator until the next scheduled assessment. If at the next assessment 
the new lesion is considered to be unequivocal, progression should be documented.
Time Point Response for Brain Lesions
Table A3 presents the intracranial response at an individual time point for all possible 
combinations of tumor response in target and non-target brain lesions, with or without the 
appearance of new brain lesions for patients with measurable (as defined in Section 7.2.1 and 
Section 7.2.2) intracranial disease at baseline.
Patients with a global deterioration of health status that requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 


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“symptomatic deterioration.” Objective response status is determined by evaluations of 
disease burden. Every effort should be made to document the objective progression even 
after discontinuation of treatment.
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the 
residual lesion be investigated (e.g., fine needle aspirate or biopsy) to confirm the CR.
Table A3: Evaluation of Brain Lesion Response
Target Lesions
Non-target Lesions
New Lesions
Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Best Overall Brain Metastasis Response: All Time Points for Brain Lesions
The best overall brain metastasis response is defined as the best response recorded from the 
start of treatment until progression of brain metastasis and will be determined 
programmatically by the Sponsor based on the Investigator’s assessment of brain metastasis 
response at each time point. Only tumor assessments performed before the start of any 
subsequent anticancer therapies and not later than 30 days after last dose of study drug will 
be considered in the assessment of best overall brain metastasis response. Clinical 
deterioration or clinical progression noted on the completion eCRF will not be considered as 
documented disease progression.
To be assigned a status of brain metastasis SD, follow-up disease assessment must meet the 
SD criteria at least once after the first dose of study treatment for a minimum of 6 weeks.
If the minimum time for SD is not met, the best response will depend on subsequent 
assessments. For example, if an assessment of PD follows the assessment of SD and SD does 
not meet the minimum time requirement, the best response will be PD. Alternatively, patients 
lost to follow up after an SD assessment who do not meet the minimum time criterion will be 
considered NE.


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Appendix 6. Criteria for Evaluation of Global Response
This appendix provides definitions for global assessment of target and non-target lesion(s).
Evaluation of Target Lesions
Target lesion response is based on all (i.e., brain and extracranial) target lesions, up to a total 
of 10 lesions. The sum of longest diameters of all target lesions will be used to determine 
response. Definitions for assessment of response for target lesion(s), based on 
mRECIST v1.1 for brain lesion and RECIST v1.1 for extracranial lesions, are as follows:
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes must be < 10 mm on the short axis.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from 
baseline).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
quality for PD.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as a reference the smallest sum of diameters recorded since the treatment 
started (i.e., percent change from nadir, where nadir is defined as the smallest sum of 
diameters recorded since treatment start). In addition, the sum must have an absolute increase 
from nadir of at least 5 mm.
Not Applicable (NA): No extracranial target lesions at baseline.
Not Evaluable (NE): Cannot be classified by 1 of the 5 preceding definitions.
Special Notes on the Assessment of Target Lesions
If lymph nodes are documented as target lesions, the short axis is added to the sum of the 
diameters (i.e., sum of diameters is the sum of the longest diameters for non-nodal lesions 
and the short axis for nodal lesions). When lymph nodes decrease to non-pathological size 
(i.e., short axis < 10 mm), they should still have a measurement reported in order not to 
overstate progression.
If at a given assessment time point all target lesions identified as baseline are not assessed, 
the sum of diameters cannot be calculated for purposes of assessing CR, PR or SD, or for use 
as the nadir for future assessments. However, the sum of the diameters of the assessed lesions 
and the percent change from nadir should be calculated to ensure that progression has not 
been documented. If an assessment of PD cannot be made, the response assessment should be 
NE.
All target lesions (nodal and non-nodal) should have their measurements recorded even when 
very small (e.g., 2 mm). If lesions are present but too small to measure, 5 mm should be 


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recorded and should contribute to the sum of the diameters unless it is likely that the lesion 
has disappeared, in which case 0 mm should be reported.
If a target lesion disappears and reappears at a subsequent time point it should continue to be 
measured. The response at the time when the lesion reappears will depend upon the status of 
the other lesions. For example, if the disease had reached a CR status then PD would be 
documented at the time of reappearance. However, if the response status was PR or SD, the 
diameter of the reappearing lesions should be added to the remaining diameters and response 
determined based on percent change from baseline and percent change from nadir.
Evaluation of Non-target Lesions
Non-target lesion response is based on all (that is, brain and extracranial) non-target lesions. 
Definitions for assessment of response for non-target lesions are as follows:
Complete Response (CR): The disappearance of all non-target lesions. All lymph nodes 
identified as a site of disease at baseline must be non-pathological (i.e., < 10 mm short axis).
Non-CR/Non-PD: The persistence of 1 or more non-target lesion(s) or lymph nodes 
identified as a site of disease at baseline ≥10 mm short axis.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
Not Applicable (NA): No brain or extracranial non-target lesions at baseline.
Not Evaluable (NE): Cannot be classified by 1 of the 5 preceding definitions.
Special Notes on the Assessment of Non-target Lesions
In the presence of measurable disease, progression on the basis of solely non-target disease 
requires substantial worsening such that even in the presence of SD or PR in target disease, 
the global tumor burden has increased sufficiently to merit discontinuation of therapy.
In the presence of non-measurable-only disease, consideration should be given to whether or 
not the increase in global disease burden is comparable in magnitude to the increase that 
would be required to declare PD for measurable disease.
Sites of non-target lesions that are not assessed at a particular time point based on the SoA 
(Table 3) should be excluded from the response determination (i.e., non-target response does 
not have to be “Not Evaluable”).
Time Point Response
Table A4 presents the response at an individual time point for all possible combinations of 
tumor responses in all brain and extracranial target and non-target lesions with or without the 
appearance of new lesions.


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Patients with a global deterioration of health status that requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Objective response status is determined by evaluations of 
disease burden. Every effort should be made to document the objective progression even 
after discontinuation of treatment.
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the 
residual lesion be investigated (e.g., fine needle aspirate or biopsy) to confirm the CR.
Table A4: Evaluation of Global Response
Target Lesions
Non-target Lesions
New Lesions
Global Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Best Overall Global Response: All Time Points
The best overall global response is the best response recorded from the start of treatment 
until progression of brain metastasis or extracranial disease and will be determined 
programmatically by the Sponsor based on the Investigator’s assessment of global response 
(brain metastasis and extracranial disease) at each time point. Only tumor assessments 
performed before the start of any subsequent anticancer therapies and not later than 30 days 
after last dose of study drug will be considered in the assessment of best overall global 
response. Clinical deterioration or clinical progression noted on the completion eCRF will 
not be considered as documented disease progression. 
To be assigned a status of overall global stable disease (SD), follow-up disease assessment 
must meet the SD criteria at least once after the first dose of study treatment for a minimum 
of 6 weeks.
If the minimum time for SD is not met, the best response will depend on subsequent 
assessments. For example, if an assessment of PD follows the assessment of SD and SD does 
not meet the minimum time requirement, the best response will be PD. Alternatively, patients 
lost to follow up after an SD assessment who do not meet the minimum time criterion will be 
considered NE.
















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Appendix 8. Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as DILI.  Patients who experience 
a transaminase elevation above 3 × ULN should be monitored more frequently to determine 
if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations (>2 ×
ULN) by several days or weeks.  The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory sample).  In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased.  This occurrence is still regarded as a potential DILI.  
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases 
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patients’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  


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The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase.  Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  The ratio (R-value) of ALT (or AST 
when ALT is not available) activity to ALP activity expressed as multiples of ULN can be 
used to categorize the injury pattern of DILI as hepatocellular (R ≥5), cholestatic (R ≤2) or 
mixed (>2- <5) (CIOMS. 2020). 
R = 
ALT/ULN
ALP/ULN
A detailed history, including relevant information, such as review of ethanol, 
acetaminophen/paracetamol (either by itself or as a coformulated product in prescription or 
over-the-counter medications), recreational drug, supplement (herbal) use and consumption, 
family history, sexual history, travel history, history of contact with a jaundiced person, 
surgery, blood transfusion, history of liver or allergic disease, and potential occupational 
exposure to chemicals, should be collected.  Further testing for acute hepatitis A, B, C, D, 
and E infection and liver imaging (e.g., biliary tract) and collection of serum samples for 
acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.






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Appendix 10. ALTERNATIVE MEASURES DURING PUBLIC EMERGENCIES
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 global pandemic and will become effective for other public emergencies only 
upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
10.10.1 Eligibility
While SARS-CoV2 testing is not mandated for this study, local clinical practice standards for 
testing should be followed. A patient should be excluded if he/she has a positive test result 
for SARS-CoV2 infection, is known to have asymptomatic infection, or is suspected of 
having SARS-CoV2. Patients with active infections are excluded from study participation as 
per Section 5.2 Exclusion criterion # 21. Active infection requiring systemic therapy. 
When the infection resolves, the patient may be considered for re-screening. 
10.10.2 Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study patients at scheduled visits per the Schedule of 
Activities (Section 1.3) or unscheduled visits. Telehealth visits may be used to continue to 
assess patient safety and collect data points. Telehealth includes the exchange of healthcare 
information and services via telecommunication technologies (e.g., audio, video, video-
conferencing software) remotely, allowing the patient and the investigator to communicate 
on aspects of clinical care, including medical advice, reminders, education, and safety 
monitoring. The following assessments must be performed during a telehealth visit: 

Review and record study treatment(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 7.4.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the patient is adhering to the contraception method(s) required in the protocol. 
Refer to Appendix 1 and Section 10.10.3.1 of this appendix regarding pregnancy 
tests.
Study patients must be reminded to promptly notify site staff about any change in their health 
status.
10.10.3 Alternative Facilities for Safety Assessments
10.10.3.1 Laboratory Testing
If a study patient is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local 


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regulations. The local laboratory may be a standalone institution or within a hospital. The 
following safety laboratory evaluations may be performed at a local laboratory:  

Refer to Section 7.3.7 Clinical Safety Laboratory Assessments, Table 11 for the list of 
safety laboratory evaluations, including pregnancy testing required per protocol.
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible.  The local laboratory reports should be filed in the patient’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF. 
If a patient requiring pregnancy testing cannot visit a local laboratory for pregnancy testing, a 
home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be used by the 
patient to perform the test at home, if compliant with local regulatory requirements. The 
pregnancy test outcome should be documented in the patient’s source documents/medical 
records and relevant data recorded on the CRF. Confirm that the patient is adhering to the 
contraception method(s) required in the protocol. 
10.10.3.2 Imaging
If the patient is unable to visit the study site for safety imaging assessments (e.g., ECHO or 
MUGA), the patient may visit an alternative facility to have the safety imaging assessments
performed. Qualified study site personnel must order, receive, and review results. 
10.10.3.3 Electrocardiograms
If the patient is unable to visit the study site for ECGs, the patient may visit an alternative 
facility to have the ECGs performed. Qualified study site personnel must order, receive, and 
review results. 
10.10.4 Study Treatment
If the safety of a trial patient is at risk because they cannot complete required evaluations or 
adhere to critical mitigation steps, then discontinuing that patient from study treatment must 
be considered.
Study drugs may be shipped by courier to study patients if permitted by local regulations and 
in accordance with storage and transportation requirements for the study drugs. Pfizer does 
not permit the shipment of study drugs by mail. The tracking record of shipments and the 


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chain of custody of study drugs must be kept in the patient’s source documents/medical 
records.
The following is recommended for the administration of study drugs for patients who have 
active [confirmed (positive by regulatory authority-approved test) or presumed (test 
pending/clinical suspicion)] SARS-CoV2 infection:

For symptomatic patients with active SARS-CoV2 infection, study drugs should be 
delayed for at least 14 days from the start of symptoms. This delay is intended to allow 
the resolution of symptoms of SARS-CoV2 infection.

Prior to restarting treatment, the patient should be afebrile for 72 hours, and SARS-
CoV2-related symptoms should have recovered to ≤ Grade 1 for a minimum of 72 
hours.  Notify the study team when treatment is restarted.

Continue to consider potential drug-drug interactions as described in protocol 
Section 6.5 for any concomitant medication administered for treatment of SARS-CoV2 
infection.
10.10.5 Home Health Visits
A home health care service may be utilized to facilitate scheduled visits per the Schedule of 
Activities. Home health visits include a healthcare provider conducting an in-person study 
visit at the patient’s location, rather than an in-person study visit at the site. The following 
may be performed during a home health visit:

Physical exam including dermatological lesions and vital signs

Review and record study treatment(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 7.4

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the patient is adhering to the contraception method(s) required in the protocol. 
Refer to Appendix 1 and Section 10.10.3.1 of this appendix regarding pregnancy 
tests.
10.10.6 Adverse Events and Serious Adverse Events
If a patient has COVID-19 during the study, this should be reported as an adverse event (AE) 
or serious adverse events (SAE) and appropriate medical treatment provided. Temporary 
discontinuation of the study treatment may be medically appropriate until the patient has 
recovered from COVID-19.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 


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10.10.7 Efficacy Assessments
If the patient is unable to visit the study site for imaging assessments (e.g., CT, MRI, X-ray, 
FDG-PET), the patient may visit an alternative facility to have the imaging assessments
performed. Qualified study site personnel must order, receive, and review results. 
10.10.8 Steering Committee
There will be no impact on the Steering Committee Charter. The Steering Committee will 
continue to be consulted during public health emergencies.


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Appendix 11. Protocol Amendment Summary of Changes
DOCUMENT HISTORY
Document
Date
Amendment 4 (Version 4)
04 January 2021
Amendment 3 (Version 3)
07 August 2020
Amendment 2 (Version 2)
13 March 2020
Amendment 1 (Version 1)
08 April 2019
Original Version 0
14 November 2018
Amendment 4 (04 January 2021)
The purpose of this amendment is in response to requests from Health Canada for safety 
Section 7.4.6 Cardiovascular and Death Events, Appendix 8 Liver Safety: Suggested Actions 
and Follow-up Assessments, and Appendix 9 ECG Findings of Potential Clinical Concern. 
Details are provided in the table below.
Section # and Name
Description of Change
Brief Rationale
Section 7.4.6 
Cardiovascular and Death 
Events
Section was revised to remove “not 
applicable” to further detail 
investigator’s responsibilities for AE 
reporting.
Clarification of Safety reporting for 
cardiovascular and death events.
Appendix 8 Liver Safety: 
Suggested Actions and 
Follow-up Assessments
Added the following additional 
criteria and reference to CIOMS 
2020;  The ratio (R-value) of ALT 
(or AST when ALT is not available) 
activity to ALP activity expressed as 
multiples of ULN can be used to 
categorize the injury pattern of DILI 
as hepatocellular (R ≥5), cholestatic
(R ≤2) or mixed (>2- <5) (CIOMS 
2020). 
R =ALT/ULN
      ALP/ULN
Inclusion of Health Canada 
recommendations to inform 
investigators of the CIOMS standards 
regarding DILI, with regard to Hy’s 
Law criteria. 
Appendix 9 ECG 
Findings of Potential 
Clinical Concern
Added the following additional 
criteria; Additional clarifications for 
Canada: QTcF prolongation >30 
msec from baseline that is 
associated with an arrhythmic event 
(ventricular tachycardia, ventricular 
fibrillation or flutter, syncope, 
seizures, torsade de pointes, or 
sudden death).
Inclusion of Health Canada 
recommendations for additional ECG 
criteria that may qualify as serious 
adverse events.




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Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
4.1 Overall Design
4.3 Justification for Dose
6.7.1 General Procedures
for Dose Modifications
6.7.2 Intra-Patient Dose 
Escalation
Text added to allow patients to dose 
escalate from 450 mg QD 
encorafenib to 600 mg QD 
encorafenib after 4 weeks of 
tolerability at the 450 mg QD 
encorafenib provided pre-defined 
criteria are met.
In order to improve efficacy for patients 
with brain metastasis, intra-patient dose 
escalation of encorafenib will be 
allowed for patients who are able to 
tolerate the standard combination dose 
of encorafenib and binimetinib.
4.2 Discussion of Study 
Design
Added discussion to describe 
allowing intra-patient dose-
escalation in Phase 2 for patients 
who tolerate the standard dosing 
regimen during the first 4 weeks 
(Cycle 1) of treatment.
Added this information to address the 
updated study design by including intra-
patient dose escalation in this 
amendment. 
4.3.2 High Dose 
Encorafenib
Section clarified.
Redundant information for the 
CMEK162X2110 study deleted with 
reference made to Section 2.2.5.
5.1 Inclusion Criterion #6
Inclusion Criterion #7d
Added clarification that prior SRS 
was allowed as long as there is 1 non 
irradiated measurable lesion.
Defined total daily dose of 
corticosteroids
Added clarification to the Inclusion 
Criterion #6 that prior SRS was allowed 
as long as there is one non irradiated 
measurable lesion to align with Section 
7.1.1.
Clarified definition of stable or 
decreasing doses of corticosteroids.
6.1 Study Treatment 
Administered
Clarified QD arm for encorafenib 
Clarified QD encorafenib dosing to 
account for those patients that qualify 
for dose escalation.
6.3.1 Patient Numbering
Changed the page for documenting 
reasons for patients failing to be 
randomized or starting study 
treatment from the Screening 
Disposition page to the eCRF. 
Clarified the page for documenting 
reasons for patients not being 
randomized or starting treatment.
6.7 Dose Modification
For patients who require a dose 
modification, a clarification was 
added to prevent patients who dose 
reduce from 600 mg QD encorafenib 
to 450 mg QD encorafenib to re-
escalate back to 600 mg QD 
encorafenib.
In order to ensure patient safety, 
patients who cannot tolerate the 600 mg 
QD encorafenib dose can be reduced to 
450 mg QD encorafenib and will not be 
allowed to dose re-escalate back up to 
600 mg QD encorafenib.
6.13 Withdrawal of 
Consent
New section added for patients who 
withdraw consent.
A separate section on patients who 
withdraw consent has been added to 
align with Pfizer standard operating 
procedures.
7.4 Adverse Events and 
Serious Adverse Events
The following Sections 7.4.1 to 7.4.5 
were added to the Section 7.4 
Adverse Events and Serious Adverse 
Events revised to align with Pfizer 
standard operating procedures.


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Section # and Name
Description of Change
Brief Rationale
replacing the previous Section 7.4.1 
to 7.4.5.
7.4.1 Time Period and Frequency for 
Collecting AE and SAE information,
7.4.2 Methods of Detecting AEs and 
SAEs, 7.4.3 Follow-up of AEs and 
SAEs, 7.4.4 Regulatory Reporting 
Requirements for SAEs, 7.4.5 
Exposure During Pregnancy or 
Breastfeeding and Occupational 
Exposure.
The follow Sections were added:
7.4.6 Cardiovascular and Death 
Events
7.4.7 Disease-Related event/and or 
Disease-Related Outcomes Not 
Qualifying as AEs and SAEs.
7.4.8 Adverse Events of Special 
Interest
7.4.9 Medical Devices Deficiencies
7.4.10 Medication Errors
7.5 Product Complaints
Added clarification to report product 
complaints within 1 business day.
Added to align with Pfizer mandatory 
requirements for the investigator to 
notify Pfizer about a product complaint 
with 1 business day of discovery
7.6 Treatment Overdose
Clarified per Pfizer standard 
operational procedures.
Additional clarifications to align with 
Pfizer standard operational procedures.






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Section # and Name
Description of Change
Brief Rationale
Secondary Objectives 
and Endpoints, 3. 
Objectives and Endpoints 
Table 4
determined not to be safe during the 
Safety Lead-in phase, analysis will be 
completed on the standard dose.
1.1 Synopsis Table 2 
Key Study Design 
Elements, 4.1 Overall 
Design, 4.2 Discussion 
of Study Design
Approximately 110 patients will be 
enrolled in the study (9 in the safety 
lead-in and 100 in Phase 2), patients 
will be stratified by baseline tumor 
burden in the brain (1 to 2 brain 
lesions vs. ≥ 3 brain lesions) and prior 
local therapy (yes vs. no), design 
change. 
The study design has been revised 
with pick the winner approach and 
interim analysis no longer being 
explored.
1.2. Schema
Figure 1: Study Schema
Study Schema revised to reflect the 
change in study design for the Phase 2 
portion of the study.
Pick the winner study design approach 
and the requirement for an interim 
analysis are not needed for the revised 
study design.
1.3. Schedule of 
Activities, (SoA) Table 3
IWRS clarified, Karnofsky Status 
added to the SoA, coagulation and 
urinalysis requirements during the 
treatment period clarified.
Clarification. Karnofsky Status was 
missing from SoA and added with the 
ECOG PS.  On treatment coagulation 
assessment clarified for patients that 
are on anticoagulation treatment 
should have parameters monitored 
throughout the study as clinically 
indicated. Urinalysis simplified and 
can now be assessed as clinically 
indicated.
2.1.3. Systemic 
Treatment for BRAF-
mutant Melanoma Brain 
Metastasis, 2.2.1. 
Encorafenib, and 2.2.2. 
Binimetinib 
Clarified market approval for 
binimetinib and encorafenib
Added approvals by EMA and other 
authorities.
5.1. Inclusion Criteria #3, 
#5, and #6.
Clarification to (#3) diagnosis, (#5) 
tumor tissue, and (#6) brain lesions
Clarifications to Inclusion Criteria. 
5.1 Inclusion Criterion 
#7
(#7a) Patients may receive prior local 
therapy for brain metastasis, (#7c) 
Patients on prior immunotherapy are 
permitted, (#7d) Patients on 
corticosteroids can be included if on a 
stable dose for at least 2 weeks prior to 
enrollment.
Modification regarding allowable prior 
local therapy based on investigator
feedback regarding standard of care 
treatment for patients with 
asymptomatic brain metastases 
including patients using 
corticosteroids. 
5.2. Exclusion Criteria 
#1, #2, #11, and #20
(#1) Clarified patients with 
symptomatic brain metastasis. (#2) 
Added clarification to exclude patients 
on prophylactic or preventive anti-
epileptic therapy. Moved requirements 
for patients using corticosteroids for 
brain metastasis to Inclusion criterion 
# 7d. (#11) added clarification for 
Added example of symptomatic brain 
metastasis. Clarified requirements 
regarding patients on anti-epileptic 
therapy. Added clarification to major 
surgery and other malignancies.


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Section # and Name
Description of Change
Brief Rationale
major surgery. (#20) Clarification to 
other malignancies. 
5.2. Exclusion Criterion 
#7
Patients have had prior local therapy 
including craniotomy or WBRT are 
permitted, therefore added clarification 
to acceptable recovery window before 
enrollment. 
Modification regarding allowable prior 
local therapy based on investigator 
feedback regarding standard of care 
treatment for patients with 
asymptomatic brain metastases.
5.2. Exclusion Criterion 
#9
Patients treated in the adjuvant setting 
with BRAF or MEK inhibitor(s) 
change from < 12 months to 
< 6 months prior to enrollment. 
Patients treated in the adjuvant setting 
with BRAF or MEK inhibitors 
changed from ≥ 12 months to ≥ 6 
months prior to enrollment are 
eligible. 
Modification regarding allowable prior 
therapy of BRAF or MEK inhibitor (s) 
based on investigator feedback 
regarding standard of care treatment 
for patients with metastatic disease.
6.3. Randomization
Clarified the IWRS will be used to 
enroll patients (randomization and 
cohort assignment), for study drug 
assignment, and for ordering study 
drug supplies. 
Clarification.
6.5.2. Prohibited 
Concomitant Therapy
Clarification added regarding 
palliative radiation therapy to target 
lesions.
Note added to clarify palliative 
radiation therapy to target lesions is 
prohibited.
6.6 High-dose Safety 
Assessment
Clarification
Clarification to high-dose 
determination of safe as opposed to 
tolerable to be consistent with study 
objectives.
6.7.1. General 
Procedures for Dose 
Modification
Revised dose modifications to clarify 
dose re-escalation and dose reductions.
Updated as per the current local 
prescribing instructions for 
encorafenib and binimetinib.
7.1. Screening 
Procedures
Clarified the requirement for baseline 
scans during the screening period. 
Baseline scans from other institutions 
are acceptable, provided the sites 
obtain copies of the radiological scans.
To ensure that all baseline scans are 
available for central review.
7.1.1. Baseline 
Documentation of 
Intracranial Target and 
non-Target Lesions
New Section added
Additional details added for baseline 
documentation of intracranial target 
lesions.
7.1.2. Baseline 
Documentation of 
Extracranial Target and 
non-Target Lesions
New Section added
Additional details added for baseline 
documentation of extracranial target 
lesions.
7.2.1. Radiological 
Tumor Evaluation
Clarification to screening MRI of brain 
and spine.
Added clarification that brain and 
spine MRI is required at screening to 
be consistent with the Schedule of 
Activities.




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evidence that the elevation is not due to decreased hepatic function, which could affect 
encorafenib and/or binimetinib exposures.
Section # and Name
Description of Change
Brief Rationale
Protocol Title Page
EudraCT Number is now available and 
has been added to the title page of the 
protocol.
To provide the EudraCT Number for 
the study.
1.3 Schedule of 
Activities, (SoA) Table 3
ECHO/MUGA assessment on Cycle 1 
Day 1 removed.
ECHO/MUGA is performed at 
Screening and throughout the study. 
Removal of the Cycle 1 Day 1 
ECHO/MUGA avoids the possibility 
that a patient might undergo these tests 
in close proximity. This is consistent 
with other Array-sponsored studies of 
encorafenib/binimetinib in 
combination.
5.1 Inclusion Criteria 
Inclusion criterion 9e was modified to 
require eligible patients to have total 
bilirubin ≤1.5 × ULN. Patients with 
documented Gilbert syndrome or 
hyperbilirubinemia due to non-hepatic 
cause may be enrolled following 
discussion and agreement with the 
Array Medical Monitor.
This change limits the study 
population to patients with normal 
hepatic function or mild hepatic 
impairment per US NCI guidelines.

SAP_001.pdf: 
Protocol C4221006 (ARRAY-818-201) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
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Protocol C4221006 (ARRAY-818-201)
A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + 
Binimetinib Evaluating a Standard-dose and a High-dose Regimen in 
Patients With BRAFV600-Mutant Melanoma Brain Metastasis
Statistical Analysis Plan 
(SAP)
Version:
2.0
Date: 18 September 2020


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PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................7
2.1. Study Objectives, Endpoints, and Estimands............................................................7
2.1.1. Primary Estimands........................................................................................9
2.1.2. Additional Estimands..................................................................................10
2.2. Study Design ...........................................................................................................11
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................13
3.1. Safety Lead-in .........................................................................................................13
3.1.1. Primary Endpoint........................................................................................13
3.2. Phase 2.....................................................................................................................13
3.2.1. Primary Endpoint........................................................................................13
3.2.2. Efficacy Secondary Endpoints....................................................................13
3.2.2.1. Extracranial Response Rate.......................................................13
3.2.2.2. Global Response Rate ...............................................................13
3.2.2.3. Disease Control Rate.................................................................13
3.2.2.4. Duration of Response................................................................13
3.2.2.5. Progression-free Survival..........................................................14
3.2.2.6. Overall Survival ........................................................................14
3.2.3. Other Secondary Endpoints........................................................................14
3.2.3.1. Pharmacokinetic Endpoints.......................................................14
3.3. Baseline Variables...................................................................................................14
3.4. Safety Endpoints .....................................................................................................15
3.4.1. Adverse Events...........................................................................................15
3.4.2. Laboratory Data..........................................................................................15
3.4.3. Vital Signs Data..........................................................................................15
3.4.4. Electrocardiograms Data ............................................................................15
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4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................16
5.1. Hypotheses and Decision Rules ..............................................................................16
5.1.1. Hypotheses and Sample Size Calculation...................................................16
5.1.1.1. Safety Lead-in ...........................................................................17
5.1.1.2. Phase 2.......................................................................................17
5.1.2. Decision Rules............................................................................................17
5.1.2.1. Safety Lead-in ...........................................................................17
5.1.2.2. Phase 2.......................................................................................18
5.2. General Methods .....................................................................................................18
5.2.1. Data Handling After the Cut-off Date ........................................................19
5.2.2. Analyses to Assess the Impact of COVID-19 Pandemic............................19
5.2.3. COVID-19 Anchor Date.............................................................................20
5.2.4. Definition of Study Day..............................................................................20
5.2.5. On-treatment Period....................................................................................20
5.2.6. Date of Last Contact ...................................................................................20
5.2.7. Unscheduled Assessments..........................................................................21
5.2.8. Tumor Assessment Date.............................................................................21
5.2.9. Adequate Baseline Tumor Assessment ......................................................21
5.2.10. Adequate Post-baseline Tumor Assessment.............................................22
5.2.11. Standard Derivations and Reporting Conventions ...................................22
5.2.12. Analyses for Binary and Categorical Endpoints.......................................22
5.2.13. Analyses for Continuous Endpoints .........................................................22
5.2.14. Analyses for Time-to-Event Endpoints ....................................................22
5.3. Methods to Manage Missing Data ..........................................................................23
5.3.1. Missing Dates .............................................................................................23
5.3.2. Missing Pharmacokinetic Data...................................................................27
5.3.3. Missing Biomarker Data.............................................................................27
6. ANALYSES AND SUMMARIES ......................................................................................27
6.1. Primary Endpoints...................................................................................................27
6.1.1. Safety Lead-in.............................................................................................27
6.1.2. Phase 2........................................................................................................28


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6.2. Efficacy Secondary Endpoints ................................................................................30
6.2.1. Extracranial Response Rate........................................................................30
6.2.2. Global Response Rate.................................................................................30
6.2.3. Disease Control Rate ..................................................................................31
6.2.4. Duration of Response .................................................................................31
6.2.5. Progression-free Survival ...........................................................................32
6.2.6. Overall Survival..........................................................................................33
6.2.7. Brain Metastasis Response Rate for Safety Lead-in...................................34
6.3. Other Secondary Endpoints.....................................................................................34
6.3.1. Pharmacokinetic Analysis ..........................................................................34
6.3.1.1. Plasma Concentrations of Encorafenib, LHY746, 
Binimetinib and AR00426032...........................................................34
6.3.1.2. Plasma Pharmacokinetic Parameters for Encorafenib, 
LHY746, Binimetinib and AR00426032 ..........................................36
6.3.1.3. Other PK Analysis.....................................................................37
6.5. Baseline and Other Summaries and Analyses.........................................................38
6.5.1. Baseline Summaries....................................................................................38
6.5.1.1. Demographic Summary.............................................................39
6.5.1.2. Baseline and Disease Characteristics ........................................39
6.5.1.3. Medical History.........................................................................39
6.5.1.4. Prior Anticancer Treatments .....................................................39
6.5.2. Study Conduct and Patient Disposition......................................................40
6.5.2.1. Patient Disposition ....................................................................40
6.5.2.2. Protocol Deviations...................................................................41
6.5.3. Study Treatment Exposure .........................................................................42
6.5.3.1. Dose Modification.....................................................................43
6.5.4. Concomitant Medications...........................................................................43
6.5.5. Subsequent Anticancer Therapies/Procedures............................................44
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6.6. Safety Summaries and Analyses .............................................................................44
6.6.1. Adverse Events...........................................................................................44
6.6.2. Deaths .........................................................................................................47
6.6.3. Laboratory Data..........................................................................................47
6.6.4. Vital Signs ..................................................................................................50
6.6.5. Electrocardiograms.....................................................................................51
6.6.6. Neurological Symptoms .............................................................................52
6.6.7. ECOG Performance Status .........................................................................52
6.6.8. Echocardiogram/Multi-gated Acquisition ..................................................52
6.6.9. Ophthalmic Examination............................................................................53
6.6.10. Pregnancy Tests........................................................................................53
6.6.11. Comments.................................................................................................53
6.6.12. Procedures.................................................................................................53
7. INTERIM ANALYSES.......................................................................................................53
8. REFERENCES ....................................................................................................................54
9. APPENDICES .....................................................................................................................55
LIST OF TABLES
Table 1: Summary of Change ....................................................................................................6
Table 2: Characteristics of DLT Probability During the DLT Evaluation Period...................18
Table 3: PFS and DOR Outcome and Event Dates..................................................................32
Table 4: PFS Censoring Reasons and Hierarchy.....................................................................33
Table 5: Pharmacokinetic Blood Sampling Times ..................................................................34
Table 6: Clinical Notable ECG Criteria...................................................................................52
LIST OF FIGURES
Figure 1: Study Schema...........................................................................................................12
APPENDICES
Appendix 1. List of Abbreviations...........................................................................................55




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2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C4221006 (ARRAY-818-201). This 
document may modify the plans outlined in the protocol; however, any major modifications 
of the primary endpoint and key secondary endpoint definition or corresponding analyses 
will also be reflected in a protocol amendment.
The study plans to have two parts with Safety Lead-in followed by Phase 2. At the time of 
this document development, 3 dose-limiting toxicities (DLTs) have been observed in 
9 evaluable patients enrolled in the Safety Lead-in of the study. The protocol defines the 
high-dose regimen of 300mg BID encorafenib + 45mg QD binimetinib combination therapy 
deemed not safe if 3 DLTs or more (ie, ≥33%) are observed in 9 evaluable patients in the 
Safety Lead-in. Therefore the study continues to Phase 2 without the high-dose regimen.
The SAP version 2.0 is developed based on this study design scenario, ie, if the high-dose 
treatment is determined not to be safe in the Safety Lead-in, no patients will be enrolled into 
the high-dose arm, up to 100 patients will be enrolled into 2 cohorts in the standard-dose arm
and no randomization will be used in the Phase 2 part of the study.
2.1. Study Objectives, Endpoints, and Estimands
Primary Objective
Primary Endpoint
Safety Lead-in

Evaluate the safety of a high-dose 
regimen of encorafenib + binimetinib 
combination therapy in patients with 
BRAFV600-mutant melanoma who 
have asymptomatic brain metastasis.
Safety Lead-in

Incidence of DLTs.

Incidence and severity of AEs graded 
according to the NCI CTCAE version 4.03 
and changes in clinical laboratory parameters, 
vital signs and ECGs.

Incidence of dose interruptions, dose 
modifications and discontinuations due to 
AEs.
Phase 2
If the high-dose regimen is determined to be 
safe based on the results of the Safety Lead-in 
phase, then

Evaluate the antitumor activity in brain 
metastases of the standard and high dose 
regimens of encorafenib + binimetinib 
combination therapy in patients with 
BRAFV600-mutant melanoma who have 
asymptomatic brain metastasis.
Phase 2

BMRR per mRECIST v1.1.


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If the high-dose regimen is determined not to 
be safe based on the results of the Safety 
Lead-in phase, then

Evaluate the antitumor activity in brain 
metastases of the standard dosing regimen 
of encorafenib + binimetinib combination 
in patients with BRAFV600-mutant 
melanoma who have asymptomatic brain 
metastasis.
Secondary Objectives
Secondary Endpoints

Further evaluate the antitumor activity 
of encorafenib + binimetinib 
combination therapy in patients with 
BRAFV600-mutant melanoma who 
have asymptomatic brain metastasis.

Extracranial response rate per RECIST v1.1.

Global response rate (brain metastasis 
response per mRECIST v1.1 and extracranial 
response per RECIST v1.1).

DCR:

for brain metastasis response per 
mRECIST v1.1;

for extracranial response per RECIST 
v1.1;

for global response (brain metastasis per 
mRECIST v1.1 and extracranial per 
RECIST v1.1).

DOR:

for brain metastasis response per 
mRECIST v1.1;

for extracranial response per RECIST 
v1.1;

for global response (brain metastasis per 
mRECIST v1.1 and extracranial per 
RECIST v1.1).

PFS:

for brain metastasis per mRECIST v1.1;

for global assessment (brain metastasis 
per mRECIST v1.1 and extracranial 
disease per RECIST v1.1).

BMRR per mRECIST v1.1 for Safety Lead-in 
only.




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
Variable: brain metastasis response defined as best overall response (BOR) of 
confirmed complete response (CR) or confirmed partial response (PR) in brain 
metastasis by Investigator assessment per mRECIST v1.1 from date of the first dose
until disease progression, death due to any cause, or start of subsequent anticancer 
therapy, whichever occurs first.

Intercurrent events: hypothetical strategy will be applied for the intercurrent event of 
starting new anticancer therapy. Any tumor assessments after starting subsequent 
anticancer therapy will be excluded in the calculation of BMRR. 

Population-level summary measure: BMRR defined as proportion of patients who 
have achieved a confirmed BOR of CR or PR in brain metastasis by Investigator
assessment per mRECIST v1.1 and corresponding exact Clopper-Pearson 2-sided 
90% confidence interval (CI) and 95% CI.  
2.1.2. Additional Estimands 
Supportive Estimand 1 (BMRR):

Population: same as primary estimand of BMRR.

Variable: confirmed + unconfirmed brain metastasis response defined as BOR of 
confirmed or unconfirmed CR or PR in brain metastasis by Investigator assessment
per mRECIST v1.1 from date of the first dose until disease progression, death due to 
any cause, or start of subsequent anticancer therapy, whichever occurs first. 

Intercurrent events: same as primary estimand of BMRR. 

Population-level summary measure: confirmed + unconfirmed BMRR defined as 
proportion of patients who have achieved a BOR of confirmed or unconfirmed CR or 
PR in brain metastasis by Investigator assessment per mRECIST v1.1 and 
corresponding exact Clopper-Pearson 2-sided 95% CI.
Supportive Estimand 2 (BMRR):

Population: all patients as defined by the inclusion/exclusion criteria in Section 5.1 
and Section 5.2 in the study protocol to reflect the patients targeted by the clinical 
question.

Variable: same as primary estimand of BMRR.

Intercurrent events: same as primary estimand of BMRR.

Population-level summary measure: BMRR and corresponding exact
Clopper-Pearson 2-sided 95% CI.  


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2.2. Study Design
This is a multicenter, randomized open-label Phase 2 study to assess the safety, efficacy and 
PK of 2 dosing regimens of encorafenib + binimetinib combination therapy in patients with 
BRAFV600-mutant melanoma with asymptomatic brain metastasis. Approximately 
110 eligible patients will be enrolled, including 9 patients in a single-arm Safety Lead-in. 
After a Screening Period, treatment will be administered in 28-day cycles and will continue 
until disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent 
anticancer therapy, death. Once the patient discontinues study treatment, the Treatment 
Period will end, and the patient will enter the Follow-up Period. 
The first 9 evaluable patients in the high-dose treatment will constitute the high-dose Safety 
Lead-in cohort. 
As the high-dose treatment is determined not to be safe in the Safety Lead-in, no patients will 
be enrolled into Arm B, and up to 100 patients will be enrolled into 2 cohorts in the 
standard-dose Arm A:

Cohort 1: Up to 50 patients with BRAFV600 cutaneous melanoma with metastases to 
the brain confirmed by MRI, asymptomatic, and with prior local therapy (eg, 
stereotactic radiosurgery [SRS] or stereotactic radiotherapy [SRT]). 

Cohort 2: Up to 50 patients with BRAFV600 cutaneous melanoma with metastases 
to the brain confirmed by MRI, asymptomatic, without prior local therapy (eg, SRS or 
SRT). Phase 2 enrollment will close when either Cohort 1 or 2 reaches 
approximately 50 patients.
Patients who are able to tolerate the standard dose of encorafenib (450 mg QD) plus 
binimetinib (45 mg BID) during the first 4 weeks of treatment (Cycle 1) should be 
dose-escalated to 600 mg encorafenib QD plus 45 mg binimetinib BID provided they meet 
the criteria defined in Section 6.7.2 in the protocol. 
A schematic of the study design is presented in Figure 1


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Figure 1: Study Schema


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Safety Lead-in
3.1.1. Primary Endpoint
The primary endpoint for the Safety Lead-in is incidence of DLTs estimated based on data 
from DLT-evaluable patients during Cycle 1. A DLT is defined as any AE or laboratory 
abnormality (unexplained by underlying disease, disease progression, intercurrent illness, or 
concomitant therapies) that either meets the criteria described in the study protocol (Table 7) 
or results in the inability to tolerate at least 75% of the planned dose of binimetinib or 
encorafenib during Cycle 1.  
3.2. Phase 2
3.2.1. Primary Endpoint
Confirmed BMRR is defined as the proportion of patients who have achieved a BOR of 
confirmed CR or confirmed PR by Investigator assessment in brain metastasis per
mRECIST v1.1.
The definition of BOR is described in Section 6.1.2.  
3.2.2. Efficacy Secondary Endpoints
3.2.2.1. Extracranial Response Rate 
Extracranial response rate is defined as the proportion of patients with a BOR of confirmed 
CR or confirmed PR in extracranial lesions by Investigator assessment per Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). 
3.2.2.2. Global Response Rate 
Global response rate is defined as the proportion of patients with a BOR of confirmed CR or 
confirmed PR by Investigator assessment in brain metastasis and extracranial lesions per 
mRECIST v1.1 and RECIST v1.1, respectively. 
3.2.2.3. Disease Control Rate
Disease control rate (DCR) is defined as the proportion of patients with a BOR of CR, PR or 
SD by Investigator assessment.
3.2.2.4. Duration of Response 
Duration of response (DOR) is defined as the time from date of the first radiographic 
response (CR or PR) to the earliest documented disease progression or death due to any 
cause. 




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Unscheduled assessments may be considered baseline assessment if they meet the criteria 
above. Data reported at the End of Treatment (EOT) visit are not eligible for baseline 
selection. The ECG baseline will be the average of triplicate ECG measurements obtained 
before the start of treatment on cycle 1 day 1.
3.4. Safety Endpoints
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified. Safety data collected outside the on-treatment period will be listed but not 
summarized.
3.4.1. Adverse Events
An AE is considered a treatment-emergent adverse event (TEAE) if the event starts on or 
after the first dosing day and time/start time, if collected, but before the last dose +30 days, or 
start of subsequent anticancer drug therapy minus 1 day, whichever occurs first. Any events 
that started prior to date of the first dose are not considered TEAEs. If an AE starts on the 
same day as date of the first dose, it will be considered treatment emergent unless the CRF
data indicates otherwise via explicitly recording time for AE onset and treatment dosing.
Adverse events will be coded using current Medical Dictionary for Regulatory Activities 
(MedDRA). Severity of AEs will be graded using the NCI-CTCAE v 4.03 toxicity grading 
scale.
3.4.2. Laboratory Data
Hematology, chemistry and coagulation tests results will be programmatically graded 
according to the NCI CTCAE version 4.03 for relevant parameters. Additional details are 
provided in Section 6.6.3.
3.4.3. Vital Signs Data
Vital signs data includes weight, pulse, systolic blood pressure (BP), and diastolic BP will be 
summarized. Additional details are provided in Section 6.6.4.
3.4.4. Electrocardiograms Data
Clinically notable ECG values during the on-treatment period will be summarized. 
Additional details are provided in Section 6.6.5.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per standard operating procedures.




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5.1.1.1. Safety Lead-in
There is no statistical hypothesis for the Safety Lead-in. 
The primary endpoint of the Safety Lead-in is incidence of DLTs. Up to 9 evaluable patients 
will be enrolled to receive the high-dose encorafenib + binimetinib combination therapy.
The safety and PK data will be evaluated by the Steering Committee after these 9 evaluable 
patients have been followed for a minimum of 28 days. 
5.1.1.2. Phase 2
The sample size calculation is based on the primary endpoint of BMRR per mRECIST v1.1
by Investigator assessment. The study is designed to test the null hypothesis of BMRR ≤30% 
for patients with BRAFV600-mutant melanoma brain metastasis, which is considered not 
sufficiently clinically meaningful to warrant further study. The alternative hypothesis is 
BMRR >30% with the assumption that the true BMRR is at least 50%.
If the high-dose treatment is determined not to be safe in the Safety Lead-in, no patients will 
be enrolled into the high-dose treatment arm. Up to 100 eligible patients will be enrolled into 
2 cohorts in the standard-dose treatment arm. Phase 2 enrollment will close when either 
Cohort 1 or 2 reaches the enrollment of 50 patients. The sample size consideration is based 
on an exact binomial test with a 1-sided alpha of 0.05 for each cohort.

Cohort 1: Patients with locally confirmed BRAFV600 cutaneous melanoma with 
metastases to the brain confirmed by MRI, asymptomatic, and with prior local therapy 
(eg, SRS or SRT). 

Cohort 2: Patients with locally confirmed BRAFV600 cutaneous melanoma with 
metastases to the brain confirmed by MRI, asymptomatic, without prior local therapy 
(eg, SRS or SRT). 
No formal statistical comparison will be conducted between the 2 cohorts. 
5.1.2. Decision Rules
5.1.2.1. Safety Lead-in
The target DLT rate during Cycle 1 in the Safety Lead-in is <33% (ie, <3 out of 9 evaluable 
patients with DLTs). The high-dose treatment will be considered tolerable if the observed 
Cycle 1 DLT rate is <33%. Table 2 provides a comparison of the characteristics of this DLT 
evaluation rule and the traditional 3 + 3 rules based on 9 patients. 


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Table 2: Characteristics of DLT Probability During the DLT Evaluation Period
True DLT Rate 
During DLT Evaluation 
Period 
Probability of Dose Declared 
Toxic Using 3 + 3 Rules
Probability of Observed DLT 
Rate ≥33% in 9 Patients 
During DLT Evaluation Period
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
5.1.2.2. Phase 2
Under the assumption that the true BMRR ≥50%, the null hypothesis of BMRR ≤30% will be 
rejected if at least 21 brain metastasis responses per mRECIST v1.1 are observed in a cohort 
of 50 patients. With approximately 50 eligible patients, the study will provide approximately 
90% power with a 1-sided type I error rate of 5%.
5.2. General Methods
Unless otherwise specified, all analyses will be performed separately for the Safety Lead-in
and for the Phase 2 portion of the study. 
Qualitative/categorical data will be summarized by frequency counts and percentages. 
Percentages will be calculated using the number of patients in the relevant treatment arm or 
subgroup as the denominator. Continuous data will be summarized using appropriate 
descriptive statistics (eg, mean, standard deviation, median, minimum, and maximum) by 
treatment arm.
For reporting conventions, minimum and maximum values will be presented with the same 
decimal precision as collected in the raw data; mean, median, and quartiles should generally 
be presented to one more decimal place than the raw data; standard deviation should be 
displayed to two more decimal places than the raw data. Percentages will be reported to one 
decimal place. Unless otherwise noted, for all percentages, the number of patients in the 
analysis set for the treatment arm who have an observation will be the denominator.
Table summaries will be presented as follows. For Phase 2 portion of the study, patients in a 
cohort escalating to 600 mg encorafenib QD may also be summarized separately.
For Phase 2, the following analyses will be performed by cohort and overall (Cohort 1 + 
Cohort 2): 

Demographics and other baseline disase characteristics summary.

Patient disposition.

Protocol deviations.


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
Efficacy analysis.

Safety analysis.
The following analyses will be performed by cohort only: 

Study treatment exposure.

Concomitant medication.

Subsequent anticancer therapies/procesures.
Data listings will be sorted by cohort, patient identifier, parameter and the corresponding date 
of assessment. The listing source will be included in the footer of the listings. 
Statistical analyses detailed in this SAP will be conducted using SAS®, version 9.4 or higher 
(SAS Institute, Inc.). Noncompartmental PK analyses will be performed with Phoenix®
WinNonlin® version 6.4 or higher (Certara USA, Inc., Princeton, NJ). 
5.2.1. Data Handling After the Cut-off Date
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
All events with a start date before or on the cutoff date and an end date after the cutoff date 
will be considered as continuing at the cutoff date. The same rule will be applied to events 
starting before or on the cutoff date and not having a documented end date. 
5.2.2. Analyses to Assess the Impact of COVID-19 Pandemic
The study enrollment occurs during the COVID-19 pandemic period. Therefore, the 
following data summaries and analyses may be performed to assess the impact of COVID-19
on the trial population and study data. Additional analyses may be added in a SAP 
amendment if they are considered necessary to evaluate the outcome of the trial. Details of 
these summaries and analyses are included in the respective sections. 

A listing of all patients affected by COVID-19 related study disruption.

A listing of protocol deviations related to COVID-19.

COVID-19 related AEs and deaths.

Summary of missing tumor assessments due to COVID-19.


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5.2.3. COVID-19 Anchor Date
If additional analyses are needed to assess the impact of COVID-19 on the trial population 
and the study data, an anchor date will be used as a start date for COVID-19 pandemic 
related periods based on Pfizer guidance and standard operating procesure (SOP):

For global pandemic reference date: Use the date the World Health Organization 
designated COVID-19 as a global pandemic - March 11, 2020.

For China reference date: Use the date COVID-19 was identified as the causative 
agent of outbreak in Wuhan by the China Center for Disease Control and Prevention -
January 9, 2020.
When producing data summaries intended to show the potential impacts of COVID-19 on the 
study, data will be presented as “before” and “during,” where the anchor date is included in 
the “during” group.
A different anchor date may be used for purposes of regulatory submission should the 
regulatory authority requests. 
5.2.4. Definition of Study Day
The study day for assessments occurring on or after the first dose of study treatment (eg, 
adverse event onset, laboratory date) will be calculated as:
Study day = Date of the assessment/event - start date of study treatment +1. 
The study day for assessments occurring prior to the first dose of study treatment (eg, 
baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event -start date of study treatment.
The study day will be displayed in all relevant data listings.
5.2.5. On-treatment Period
On-treatment period is defined as the time from the first dose date of any study drug through 
(minimum of last dose of study treatment +30 days, start day of subsequent anticancer 
therapy - 1 day). 
5.2.6. Date of Last Contact
The date of last contact will be derived for patients not known to have died at the data cutoff 
date using the latest complete date (ie, imputed dates will not be used in the derivation) 
among the following:

All patient assessment dates (eg, blood draws (laboratory, Pharmacokinetics (PK)), 
vital signs, performance status, ECG, tumor assessments, hemodynamic assessment);

Start and stop dates of concomitant therapies including non-drug treatments or 
procedures;


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
Start and end dates of anticancer therapies administered after study treatment 
discontinuation including systemic therapy, radiation, and surgeries;

AE start and end dates;

Last date of contact collected on the survival follow-up electronic case report form
(eCRF) (do not use date of survival follow-up assessment unless status is ‘alive’);

Study treatment start and end dates;

Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up or death).
Only dates associated with actual examinations of the patient will be used in the derivation. 
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed or dates data were entered into the eCRF will not be used. 
Assessment dates after the data cutoff date will not be applied to derive the last contact date.
5.2.7. Unscheduled Assessments
Unless otherwise specified, unscheduled assessments will not be displayed in summary tables 
by nominal visit/timepoint.  Unscheduled assessments will be used when deriving baseline 
and worst case on-treatment for safety analyses (except where noted for baseline ECGs).  
Additionally, unscheduled tumor assessments will be used for efficacy analyses (eg, defining 
date of progression/censoring, best overall response, date of last contact).
5.2.8. Tumor Assessment Date
If there are multiple scan dates associated with a tumor evaluation, ie, radiological 
assessments occur over a series of days rather than the same day, the earliest scan date 
associated with the evaluation will be used as the date of the assessment. 
5.2.9. Adequate Baseline Tumor Assessment
An adequate baseline tumor assessment is defined as follows: 

Baseline assessments of all lesions (target, and non-target) must be within 28 days 
prior to or on the same day as date of first dose. 

All lesions (target and non-target) must have non-missing assessments. 
Note: for target lesions, an actual measurement should be recorded and it should 
meet the criteria for being measurable and for non-target lesions the actual status at 
baseline should indicate that the lesion was present).


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5.2.10. Adequate Post-baseline Tumor Assessment
An adequate post-baseline tumor assessment is defined as an assessment where a response of 
CR, PR, SD, non-CR/non-PD, or PD can be determined.  Time points where the response is 
NE or no assessment was performed will not be used for determining the censoring date.
5.2.11. Standard Derivations and Reporting Conventions
The following conversion factors will be used to convert days into weeks, months or years: 
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Percentages will be reported to one decimal place. The rounding will be performed to closest 
integer/first decimal using the common mid-point between the two consecutive values. Eg, 
5.1 to 5.4 will be rounded to an integer of 5, and 5.5 to 5.9 will be rounded to an integer of 6.
5.2.12. Analyses for Binary and Categorical Endpoints
Binary and categorical endpoints will be summarized by frequency counts and percentages 
along with corresponding exact 2-sided Clopper-Pearson 95% CI. Unless otherwise 
specified, the calculation of proportions will include the missing category. Therefore counts 
of missing observations will be included in the denominator and presented as a separate 
category.
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients with an assessment at that visit, unless otherwise specified.
5.2.13. Analyses for Continuous Endpoints
Continuous endpoints will be summarized using descriptive statistics ie, number of 
non-missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation, minimum, maximum and first and third quartile (Q1 and Q3). PK summaries will 
also include coefficient of variation percent (%CV).
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients with an assessment at that visit, unless otherwise specified.
5.2.14. Analyses for Time-to-Event Endpoints
Time to event endpoints will be summarized using the Kaplan-Meier method1 and estimated 
survival curves will be displayed graphically when appropriate. Graphs will describe the 
number of patients at risk over time. The median, quartiles, and probabilities of an event at 
particular points in time will be estimated by the Kaplan-Meier method. Confidence intervals 
for medians and quartiles are based on the Brookmeyer-Crowleymethod.2 Confidence 
intervals for the estimated probability of event at a particular timepoint will be generated 
using the log(-log) method with back transformation to a confidence interval on the 
untransformed scale. Summaries of the number and percentages of patients with an event 
and reason for censoring will also be provided on summary tables and/or figures.


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5.3. Methods to Manage Missing Data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
Any imputations will occur at the analysis dataset level. Additionally, in all patient data 
listings imputed values will be presented and flagged as imputed.
Missing statistics, eg, when they cannot be calculated, should be presented as ‘ND’ for not 
done, ‘NR’ for not reached or ‘NA’ for not applicable.  For example, if N=1, the measure of 
variability cannot be computed and should be presented as ‘ND’ or ‘NA’. 
5.3.1. Missing Dates
For purposes of data listings, dates will reflect only the information provided by the 
Investigator on the eCRF.
If start dates for adverse events or concomitant medications are completely missing a worst 
case approach will be taken whereby the events will be considered treatment emergent and 
the medications will be considered concomitant.  If only partial information are available (eg, 
only a month and year or only a year) and the partial information provide sufficient 
information to indicate the dates are prior to the start of study treatment (eg, month/year less 
than month/year of first dose) then these will be considered to have started prior to treatment; 
otherwise a similar worst case approach will apply and these will be considered to have 
started after treatment.
Missing or Partial Death Dates
Missing or partial death dates will be imputed based on the last contact date:

If the entire date is missing it will be imputed as the day after the date of last contact 
(see derivation of date of last contact in Section 5.2.6).

If the day or month is missing, death will be imputed to the maximum of the full 
(non-imputed) day after the date of last contact and the following:

Missing day: 1st day of the month and year of death, or

Missing day and month: January 1st of the year of death.
Date of First and Last Dose of Study Treatment
No imputation will be done for first dose date.  
Date of last dose of study drug, if unknown or partially unknown, will be imputed as follows:

If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use 
the cutoff date for the analysis as the last dosing date.  Note: the study team should 
confirm that the patient is actively receiving dose at the time of the data cutoff.


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
If the last date of study drug is completely or partially missing and there is EITHER 
an End of Treatment eCRF page OR a death date available (within the data cutoff 
date), then impute as follows:

If only Year is available and Year < Year of min (EOT date, death date), impute 
the date as 31DECYYYY.

If both Year and Month are available and Year = Year of min (EOT date, death 
date) and Month < Month of min (EOT date, death date), impute as last day of the 
month.

For all other cases, impute as min (EOT date, death date).
Date of Start of New Anticancer Therapy
Incomplete dates for start date of new anticancer therapy will be imputed as follows and will 
be used for determining censoring dates for efficacy analyses.  PD date below refers to PD 
date by Investigator assessment. If the imputation results in an end date prior to the imputed 
start date then the imputed start date should be set to the end date.

The end date of new anticancer therapy will be included in the imputations for start 
date of new anticancer therapy.  If the end date of new anticancer therapy is:

completely missing then it will be ignored in the imputations below;

partially missing with only year (YYYY) available then the imputations below 
will consider 31DECYYYY as the end date of the new anticancer therapy;

partially missing with only month and year  available then the imputations below 
will consider the last day of the month for MMMYYYY as the end date of the 
new anticancer therapy.

For patients who have not discontinued study treatment at the analysis cut-off date, 
last dose of study treatment is set to the analysis cut-off date in the imputations 
below. 

If the start date of new anticancer therapy is completely or partially missing then the 
imputed start date of new anticancer therapy is derived as follows:

Start date of new anticancer therapy is completely missing.
Imputed start date = min [max(PD date +1, last dose of study treatment +1), end 
date of new anticancer therapy].

Only year (YYYY) for start of anticancer therapy is available.


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IF YYYY < Year of min [max(PD date +1, last dose of study treatment +1), end 
date of new anticancer therapy]  HEN imputed start date = 31DECYYYY; 
ELSE IF YYYY = Year of min [max(PD date +1, last dose of study treatment 
+1), end date of new anticancer therapy];
THEN imputed start date = min [max(PD date +1, last dose of study treatment 
+1), end date of new anticancer therapy];
ELSE IF YYYY > Year of min [max(PD date +1, last dose of study treatment 
+1), end date of new anticancer therapy];
THEN imputed start date = 01JANYYYY.

Both Year (YYYY) and Month (MMM) for start of anticancer therapy are 
available
IF
YYYY = Year of min [max(PD date +1, last dose of study treatment +1), end 
date of new anticancer therapy], AND
MMM < Month of min [max(PD date +1 day, last dose of study treatment +1 
day), end date of new anticancer therapy].
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY;
ELSE IF
YYYY = Year of min [max(PD date +1, last dose of study treatment +1), end 
date of new anticancer therapy], AND
MMM = Month of min [max(PD date +1 day, last dose of study treatment +1 
day), end date of new anticancer therapy] 
THEN 
imputed start date = min [max(PD date +1 day, last dose of study treatment +1 
day), end date of new anticancer therapy]);
ELSE IF
YYYY = Year of min [max(PD date +1, last dose of study treatment +1), end 
date of new anticancer therapy], AND
MMM > Month of min [max(PD date + 1 day, last dose of study treatment +1 
day), end date of new anticancer therapy].
THEN 
imputed start date = 01 MMM YYYY;


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ELSE IF
YYYY < Year of min [max(PD date +1, last dose of study treatment +1), end 
date of new anticancer therapy].
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY;
ELSE IF
YYYY > Year of min [max(PD date +1, last dose of study treatment +1), end 
date of new anticancer therapy].
THEN 
      imputed start date = 01 MMM YYYY.
AE Dates
AE Onset Date:
If completely missing, the onset date will be set to first dose date if date of the first dose is 
less than AE stop date. Otherwise if date of the first dose is after AE stop date, then set the 
onset date to the earliest of non-missing AE stop date or informed consent date.
AE Stop Date:
If completely missing, the stop date will be imputed as the latest of the end of study date, 
death date, last dose date of the study treatment, or onset date.
Partial AE Date:
Partial AE date will be imputed bases on the imputation rule for “Other Missing or Partial 
Dates”. If the AE onset date is imputed from a partial AE date and date of the first dose falls 
in the same month as the AE onset date, the following will be done:

The AE onset date is reset to date of the first dose.
If AE stop date is imputed, and less than date of the first dose, set the AE stop date to date of 
the first dose.
Other Missing or Partial Dates
Imputation methods for other partial dates are as follows:

If the day of the month is missing for a start date used in a calculation, the 1st of the 
month will be used to replace the missing date. 

If both the day and month are missing, the first day of the year is used. 


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
For stop dates, the last day of the month, or last day of the year is used if the day or 
day and month are missing, respectively. 
These rules are used unless the calculations result in negative time durations (eg, date of 
resolution cannot be prior to date of onset). In these case, the resolution and onset dates will 
be the same and the duration will be set to 1 day. 
5.3.2. Missing Pharmacokinetic Data
Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of geometric mean profiles, concentrations will be set to missing 
if one of the following cases is true:

A concentration has been reported as ND (ie, not done) or NS (ie, no sample);

A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist.
Summary statistics will not be presented at a particular timepoint if more than 50% of the 
data are missing.  For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data.
5.3.3. Missing Biomarker Data
No missing data will be imputed.
6. ANALYSES AND SUMMARIES
The primary analysis will take place after all patients in the Efficacy Set meet the following 
criteria: 

had at least 2 post-baseline tumor assessments, or discontinued from the study or had 
disease progression/death at any time on the study;

all patients with an initial brain metastasis response have been followed up for at least 
6 months.
Efficacy analyses will be performed using the Efficacy Set. Key efficacy analyses will also 
be repeated using the FAS. All safety analyses will be performed using the Safety Set. 
6.1. Primary Endpoints 
6.1.1. Safety Lead-in
The number and proportion of patients experiencing DLTs during Cycle 1 will be 
summarized by SOC and PT based on maximum toxicity grade. Analyses of DLT will be 
performed on Dose-determining Set.


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All DLTs and their attributes will be presented in data listings sorted by patient identifier, AE 
and date of onset of the AE.
6.1.2. Phase 2
Main Analysis:
BMRR will be calculated by dividing the number of patients with a BOR of confirmed CR or 
confirmed PR in brain metastasis by the number of patients in the Efficacy Set in the 
respective cohort. The corresponding exact Clopper-Pearson 2-sided 90% CI and 95% CI 
will be calculated.
BOR is defined as the best response recorded from date of the first dose of study treatment
until progression by Investigator assessment at each time point. Only tumor assessments 
performed before the start of any subsequent anticancer therapies will be considered in the 
assessment of BOR. Clinical deterioration or clinical progression noted on the End of Study 
completion eCRF will not be considered as documented disease progression. BOR will be 
determined according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart and documented before 
progression and start of new anticancer therapy. 

PR = at least two determinations of PR or better (and not qualifying for a CR) at least 
4 weeks apart and documented before progression and start of new anticancer 
therapy.

SD (for patients with at least one measurable lesion at baseline)= at least one SD 
assessment (or better and not qualifying for CR or PR) ≥6 weeks after date of the first 
dose and before progression and start of new anticancer. 

Non-CR/Non-PD (for patients with only non-target disease at baseline) = at least one 
Non-CR/Non-PD assessment (or better and not qualifying for CR or PR) ≥6 weeks 
after date of the first dose and before progression and the start of new anticancer
therapy. 

PD = progression ≤16 weeks after date of the first dose (and not qualifying for CR, 
PR or SD.

Not Evaluable (NE) = all other cases.
The frequency (number and percentage) of patients with BOR in brain metastatis of CR, PR, 
SD, PD, non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline), and NE will be tabulated.
Patients with a BOR in brain metastatis of “Not Evaluable” based on confirmed responses 
will be summarized by reason for having unknown status. The following reasons will be 
used: 

No adequate baseline assessment.


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
No post-baseline assessments due to early death (ie, death ≤16 weeks after the start 
date).

No post-baseline assessments due to COVID-19 (ie, patients miss tumor assessment 
visits due to COVID-19 pandemic).

No post-baseline assessments due to other reasons.

All post-baseline assessments have overall response NE.

New anticancer therapy started before first post-baseline assessment.

SD of insufficient duration (<6 weeks after date of the first dose without further 
evaluable tumor assessments). 

PD >16 weeks after date of the first dose (ie, tumor assessment of PD was >16 weeks 
after date of the first dose and there was no tumor assessment in between).
Special and rare cases where BOR is NE due to both SD of insufficient duration (SD <6 
weeks after date of the first dose) and late PD (PD >16 weeks after date of the first dose) will 
be classified as “SD of insufficient duration”.
A figure for duration of exposure and BOR in brain metastasis (confirmed) per mRECIST 
v1.1 will be created. 
A waterfall plot will be created to show the best percentage change from baseline in the sum 
of longest diameters of all target brain metastases. Patients with baseline and at least one 
post-baseline brain metastasis assessment will be included in the waterfall plot.
Individual brain metastasis measurements, overall brain metastasis response assessments per 
mRECIST v1.1 and target and non-target response by timepoint per mRECIST v1.1 will be 
listed by patient and assessment date. 
Sensitivity/Supplementary Analyses

BMRR based on confirmed + unconfirmed response (CR or PR) in brain metastasis 
will be calculated along with corresponding exact Clopper-Pearson 2-sided 95% CI.

BMRR based on confirmed response (CR or PR) in brain metastasis will be 
calculated using the FAS. 


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6.2. Efficacy Secondary Endpoints
6.2.1. Extracranial Response Rate 
Extracranial response rate will be calculated by dividing the number of patients with a BOR 
of CR or PR in extracranial lesions by the number of patients in the Efficacy Set in the
respective cohort. The corresponding exact Clopper-Pearson 2-sided 95% CI will be 
calculated.
Details for the determination of BOR are provided in Section 6.1.2.
Two sets of extracranial response rates will be summarized, one based on confirmed 
responses and one based on confirmed + unconfirmed responses in extracranial lesions. 
Patients with extracranial response rate ‘Not Evaluable’ will be summarized by reason for 
having unknown status (see Section 6.1.2 for reasons).
A figure for duration of exposure and best overall extracranial response (confirmed) per 
RECIST v1.1 will be created. 
A waterfall plot will be created to show the best percentage change from baseline in the sum 
of longest diameters of target extracranial lesions. Patients with baseline and at least one 
post-baseline extracranial tumor assessment will be included in the waterfall plot. 
Individual extracranial lesion measurements, overall extracranial response assessments, and 
target and non-target response by timepoint per RECIST v1.1 will be listed.
6.2.2. Global Response Rate 
Global response rate will be calculated by dividing the number of patients with a BOR of CR 
or PR in both brain and extracranial lesions by the number of patients in the Efficacy Set in 
the respective cohort. The corresponding exact Clopper-Pearson 2-sided 95% CI will be 
calculated. 
Details for the determination of BOR are provided in Section 6.1.2.
Two sets of global response rates will be summarized, one based on confirmed responses and 
one based on confirmed + unconfirmed responses in global (brain and extracranial) lesions. 
Patients with global response rate ‘Not Evaluable’ will be summarized by reason for having 
unknown status (see Section 6.1.2 for reasons).
A figure for duration of exposure and best overall global response (confirmed) will be 
created. 
A waterfall plot will be created to show the best percentage change from baseline in the sum 
of longest diameters of all target lesions (brain and extracranial). Patients with baseline and 
at least one post-baseline tumor assessment will be included in the waterfall plot. 


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Overall global response assessments and timepoint response will be listed by patient and 
assessment date.  
6.2.3. Disease Control Rate
DCR will be calculated for brain metastasis per mRECIST v1.1, extracranial lesion response 
per RECIST v1.1 and global response along with corresponding exact
Clopper-Pearson 2-sided 95% CI.  
6.2.4. Duration of Response
DOR will be calculated for patients with a confirmed response (CR or PR) for brain 
metastasis per mRECIST v1.1, extracranial per RECIST v1.1 and global response (brain 
metastasis and extracranial lesions) as follows: 
DOR (months) = (date of event or censoring – date of first CR or PR + 1)/30.4375 
If a patient with a CR or PR did not have an event at the time of the analysis cutoff or with an 
event more than 16 weeks (for the first 11 cycles after treatment start date) or 24 weeks (after 
Cycle 11) after the last adequate tumor assessment, the patient will be censored on the date of 
the last adequate tumor assessment that documented no progression. In addition, if a new 
anticancer therapy is started prior to an event, the patient will be censored on the date of the 
last adequate tumor assessment that documented no progression prior to the start of the new 
anticancer therapy.
Adequate post-baseline assessment are defined in Section 5.2.10. 
The censoring and event date options to be considered for DOR analysis are presented in 
Table 3. 
Kaplan-Meier estimates will be presented together with a summary of associated statistics 
including the median DOR time with 2-sided 95% CI. Details are provided in 
Section 5.2.14. DOR rates at 3, 6, 9, 12 and 15 months will be estimated with corresponding 
2-sided 95% CIs. 
In addition, a plot of time to and duration of response for patients with a confirmed response
(swimmer plot) will be created. 


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Table 3: PFS and DOR Outcome and Event Dates 
Situation
Date of 
Progression/Censoring
Outcome
No adequate baseline assessmenta
Date of first dosea
Censored a
PD or death 
-
after at most one missing or inadequate post-
baseline tumor assessment, or
-
≤8 weeks ((±3-day window) after date of 
first dose
Date of PD or death
Event
PD or death 
-
after >=2 missing or inadequate post-
baseline tumor assessment, or
Date of last adequate tumor 
assessmentb documenting no 
PD prior to new anticancer 
therapy, or missed tumor 
assessments
Censored
No PD
New anticancer therapy given prior to PD or death
a   This criterion only applies to PFS censoring. If the participant dies ≤8 weeks after date of first dose and and 
did not initiate new anticancer therapy, the death is an event with date on death date (8 weeks is 2 times the 
length of the first 2 tumor assessment intervals). 
b   If there are no adequate post-baseline assessments prior to the PD or death, then the time without adequate 
assessment should be measured from the date of fist dose; if the criteria is met, the censoring will be on the 
date of first dose.
6.2.5. Progression-free Survival
PFS will be calculated for brain metastasis per mRECIST v1.1 and global assessment (brain 
metastasis and extracranial lesions) as follows: 
PFS (months) = (date of event or censoring – date of first dose +1)/30.4375
The algorithm to derive the outcome, event dates and reasons for censoring for PFS will be 
the same as that to derive those for the analysis of DOR (Section 6.2.4). The censoring and 
event date options to be considered for PFS analysis are presented in Table 3. 
PFS time will be estimated using the same Kaplan-Meier method as described for DOR in 
Section 6.2.4. The PFS rate at 3, 6, 9, 12, 15 and 18 months will be estimated with 
corresponding 2-sided 95% CIs.
Frequency (number and percentage) of participants with each event type (PD or death) and 
censoring reasons will be presented along with the overall event and censor rates. Reasons 
for censoring will be summarized according to the categories in Table 4.
In addition, time to progression/censoring, event, and censoring reasons will be listed. 


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Table 4: PFS Censoring Reasons and Hierarchy 
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline 
assessment
2
Start of new anticancer therapy before event
Start of new anticancer 
therapy
3 
Event after 2 or more missing or inadequate post-
baseline tumor assessment/start date
Event after missing or 
inadequate assessments
4
No event and [withdrawal of consent date ≥ date of 
first dose OR End of study (EOS) = Subject refused 
further follow-up] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition 
page 
Lost to follow-up
6
No event and [EOS present OR disposition page for 
any phase after screening says participant will not 
continue into any subsequent phase of the study] and 
no adequate post-baseline tumor assessment 
No adequate post-baseline 
tumor assessment
7 
No event and none of the conditions in the prior 
hierarchy are met 
Ongoing without an event
6.2.6. Overall Survival
OS will be calculated in months as follows: 
OS (months) = (date of death or censoring – date of first dose +1)/30.4375
OS time will be estimated using the same Kaplan-Meier method as described for DOR in 
Section 6.2.4. The OS rate at 6, 12, 18, 24, 30 and 36 months will be estimated with 
corresponding 2-sided 95% CIs.
Frequency (number and percentage) of patients with death events and censoring reasons will 
be presented by cohor along with the overall event and censor rates. The event and ensoring 
reasons are as follows:

Death:

Death due to COVID-19.

Ongoing and no death.

Withdrawal of consent.

Lost to follow-up.


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The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
6.2.7. Brain Metastasis Response Rate for Safety Lead-in
BMRR per mRECIST v1.1 will also be calculated for Dose-determining Set patients in the 
Safety Lead-in portion of the study. An exact two-sided 95% CI of BMRR will be reported. 
6.3. Other Secondary Endpoints 
6.3.1. Pharmacokinetic Analysis
Plasma concentrations and PK parameters will be determined for encorafenib and its 
metabolite (LHY746) and binimetinib and its metabolite (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 abbreviated as CxDy. C1D1 is defined as single dose (ie, first dose) and C1D15 is 
defined as multiple dose. 
If a patient experiences emesis after dosing on C1D15, a full PK sampling schedule will be 
implemented on C2D1.  In this situation, the C2D1 data will be summarized in PK tables and 
summary figures along with other patients’ C1D15 data, and the C1D15 data for the affected 
patient will only be listed for information.  Throughout the following text, all references to 
C1D15 includes C2D1 records in patients experiencing emesis on C1D15 rather than their 
C1D15 data. 
6.3.1.1. Plasma Concentrations of Encorafenib, LHY746, Binimetinib and AR00426032
Plasma concentrations of encorafenib, LHY746, binimetinib and AR00426032 will be 
quantitated at the time points indicated in Table 5: 
Table 5: Pharmacokinetic Blood Sampling Times
Study Visit
Timing of Sample
Allowed Windowa
C1D1
0.5 hours postdose
±5 min
1.5 hours postdose
±5 min
3 hours postdose
±10 min
6 hours postdose
±20 min
C1D15
Predose
-30 min
0.5 hours postdose
±5 min
1.5 hours postdose
±5 min
3 hours postdose
±10 min
6 hours postdose
±20 min
C2D1b
Predose
-30 min
C3D1
Predose
-30 min
a Predose samples must be within 30 minutes of, but before, the following dose.
b When more sampling is performed on C2D1 due to emesis on C1D15, the sample times and windows will be 
the same as for C1D15.


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All plasma concentration values of each analyte for each patient in the PK set will be 
included in the bioanalytical plasma concentration listings. Individual concentration records 
will be flagged for the affected visit if any of the following occur on the day of PK sampling:
a.
Patient had vomiting:

within 4 hours following study drug administration on the day of PK sampling for 
post-dose samples (C1D1, C1D15 and C2D1 when more sampling is performed 
on that day due to emesis on C1D15); or

at any time over the preceding 24 hours for pre-dose samples (C1D15, C2D1 and 
C3D1).
b. Prescription dosing was not performed for at least 4 consecutive days prior to C1D15, 
C2D1 or C3D1).
c.
Patient received a higher or lower dose compared to planned treatment
d. PK sampling time was outside the allowed window (as shown in Table 5) or the 
elapsed time was not calculable.
The plasma concentrations of encorafenib, LHY746, binimetinib and AR00426032 will be 
summarized by dose, treatment cohort or arm and combined arms as applicable for all 
nominal time points, including predose (trough) concentrations for C2D1 and C3D1, using 
the following descriptive statistics: n (number of patients with non-missing values), m 
(number of non-zero [ie, > below the limit of quantification (BLQ)] concentrations), 
arithmetic mean, standard deviation, coefficient of variation (CV), geometric mean, 
geometric CV, minimum, median and maximum. An individual concentration-time data 
point may be excluded from the calculation of summary statistics if any of the above flags 
[a-d] apply.  Concentrations below the BLQ will be set to zero for calculation of all summary 
statistics; geometric mean and geometric CV will set to missing if at least one BLQ value is 
included in the data being summarized. The arithmetic mean with standard deviation plasma 
concentration-versus-time profiles will be presented graphically for each analyte using both 
linear and semi-logarithmic scales by treatment arm on C1D1 and C1D15. Individual plasma 
concentration-time profiles (with median overlaid) 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 figures; for individual figures, 
actual times will be used.


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6.3.1.2. Plasma Pharmacokinetic Parameters for Encorafenib, LHY746, Binimetinib 
and AR00426032
Pharmacokinetic parameters for patients in the PK set will be determined by treatment arm
for encorafenib, LHY746, binimetinib and AR00426032 when possible and appropriate.
The individual plasma concentration-time data for each analyte will be evaluated with 
noncompartmental analysis (NCA) using Phoenix WinNonlin®, version 8.0 or higher. 
Actual blood collection times and doses on the day of PK sampling will be used for PK 
calculations. All BLQ values before the observed maximum plasma concentration (Cmax) 
will be set to 0; all BLQ values after Cmax will be considered as missing.  
The following parameters will be calculated for encorafenib, LHY746, binimetinib and 
AR00426032 on C1D1 and C1D15: 
PK 
Parameter
Definition
AUC0-6
Area under the plasma concentration-time curve from zero to 6 hours after drug 
administration 
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 a dosing interval (C1D15 only)
To estimate AUCtau,ss, the concentration measured at predose on C1D15 will be 
imputed as the concentration at the end of the dosing interval (ie, 12 or 24 hours, as 
appropriate) assuming steady-state has been attained
Cmax
Maximum observed plasma concentration after drug administration 
Cmin
Minimum observed plasma concentration after drug administration
Ctrough
Measured concentration at the end of a dosing interval
Tmax
Time to reach Cmax
Tlast
Time of last PK sample 
MRCmax
Ratio of Cmax values of the metabolite compared to parent, corrected for molecular 
weight, for AR00426032/ binimetinib and LHY746/Encorafenib
MRAUClast
Ratio of AUClast values of the metabolite compared to parent, corrected for molecular 
weight, for AR00426032/ binimetinib and LHY746/Encorafenib
RAUC
Accumulation ratio, calculated as: C1D15 AUC0-6/C1D1 AUC0-6
RCmax
Accumulation ratio, calculated as: C1D15 Cmax/C1D1 Cmax
C1D15 parameters will also be determined for C2D1 when more sampling is performed on 
that day due to emesis on C1D15.
The area under the curve (AUC) parameters will be calculated according to the linear-up log-
down trapezoidal rule. All AUC, Cmax, Cmin, and Ctrough values (AUClast/D, AUC0-6/D, 
AUCtau, /D, Cmax/D, Cmin/D and Ctrough/D) will also be provided as dose-normalized 
values. Additional PK parameters may be calculated at the discretion of the 
pharmacokineticist.






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6.5.1.1. Demographic Summary
The following demographic will be summarized by number and percentage:

Gender (male, female).

Age (<65, ≥65).

Race (White, Black or Afriacan American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other, Not Reported).

Ethnicity (Hispanic/Latino, not-Hispanic/Latino).
Age (continuous) will be summarized with descriptive statistics (mean, median, standard 
deviation, minimum, and maximum).  
6.5.1.2. Baseline and Disease Characteristics 
The following baseline and disease characteristics will be summarized:

Location of primary tumor.

Stage at initial diagnosis.

Stage at study entry.

Tumor histology.

Time since initial diagnosis, defined as [date of first dose – date of initial 
diagnosis]/30.4375.

Baseline tumor burden in the brain (1 to 2 brain lesions vs. ≥3 brain lesions).

Lactate dehydrogenase (LDH) level at baseline.

ECOG performance status.

Local and central laboratory assessments of BRAF status. Local assessment results 
will be based on the data collected on the “Local BRAF Results” eCRF page.
6.5.1.3. Medical History 
Medical history reported at the time of the Screening will be coded using the latest Medical 
Dictionary for Regulatory Activities (MedDRA) terminology available at the time of 
reporting. Medical history will be summarized by primary system organ class (SOC) and 
preferred term (PT). Each patient will be counted only once within each PT or SOC.
6.5.1.4. Prior Anticancer Treatments 
Prior anticancer treatments include systemic therapy, radiation and surgery.
The number and percentage of patients who received, separately, any prior anticancer
systemic treatment, radiotherapy, or surgery will be summarized. 


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Prior anticancer systemic treatment will be summarized as follows:

Total number of regimens (there can be more than one medication per regimen), 

Number of regimens for checkpoint inhibitor. The final list of checkpoint inhibitors 
will be provided upon medical review of all prior anticancer therapies.

Setting at last medication.

Best response at last medication (defined as the best response during the last 
treatment regimen recorded).

Reason for discontinuation at last medication.

Time (in months) from end of last medication to study start date.

Time (in months) from start of last medication to disease progression. The last 
medication is defined based on the last end date of all prior regimen components.
Prior anticancer systemic treatment will also be summarized by Anatomical Therapeutic 
Chemical (ATC) class and preferred term. 
For prior anticancer radiotherapy, information about the last radiotherapy (based on end date) 
will be summarized: time (in months) between radiotherapy and start of study treatment, 
location and best response. In addition, prior local brain radiotherapy will be summarized 
(location = “Brain” in the Prior Cancer Treatment Radiation CRF page).  
For prior anticancer surgery, the time (months) between last surgery and start of study 
treatment, site, location, whether the surgery was palliative, and the result will be 
summarized. In addition, prior local brain surgery will be summarized (location = “Brain” in 
the Prior Cancer Treatment Surgery CRF page).  
All prior anticancer therapies will be presented in a data listing separately for systemic 
treatment, radiotherapy, and surgery.
Incomplete dates will be handled as described in Section 5.3.1.
6.5.2. Study Conduct and Patient Disposition
6.5.2.1. Patient Disposition
The disposition summary will be created for the Safety Lead-in and the Phase 2 portion of 
the study separately.
The following disposition categories will be summarized:

Number (%) of patients who received at least one dose of study drug.


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
Number (%) of patients who are still on treatment.

Number (%) of patients who discontinued the treatment:

Primary reasons for treatment discontinuation.

Number (%) of patients who discontinued the treatment but are still in long-term
follow-up.

Number (%) of patients who discontinued the study:

Primary reasons for study discontinuation.
The number and percent of participants enrolled by region, country and site, and the number 
and percent of participants in each analysis set as described in Section 4 will also be 
summarized.
Screen failure patients are those who were screened, but never started the study treatment for 
any reason. The data collected on these patients will not be included in any analyses. 
COVID-19 Related Disposition 
A listing of all patients affected by COVID-19 related study disruption will be created. The 
listing will present subject number identifier by investigational site, and a description of 
COVID-19 related events including: 

Protocol deviations.

Adverse events treatment.

Treatment discontinuation.

Study discontinuation.

Death.
6.5.2.2. Protocol Deviations
Potentially important protocol deviations (PIPDs) will be compiled prior to database closure 
and will be summarized by category and also presented in a listing. Categories will be 
assigned by the study Clinician.
In addition, PIPDs related to COVID-19 will be presented in a separate listing. 


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6.5.3. Study Treatment Exposure
Duration of Exposure

Intended treatment duration (days) = end of treatment date – date of first dose of 
study drug +1. 

If a patient permanently discontinues both binimetinib and encorafenib, end of 
treatment date is the date of last dose of the study drug;

If a patient permanently discontinues binimetinib but is still on single-agent 
encorafenib treatment, end of treatment date is the date of last dose of encorafenib 
treatment.

Actual treatment duration (days) = date of last non-zero dose of the study 
drug - date of first dose of study drug +1
Cumulative Dose
Cumulative dose is defined as:

Intended cumulative dose (mg) = sum of all protocol specified doses across
intended treatment duration.

Actual cumulative dose (mg) = sum of all actual doses that the patient received
across actual treatment duration.
For patients who did not take any drug the actual cumulative dose is by definition equal to 
zero. 
Dose Intensity

Intended dose intensity (mg/day) = intended cumulative dose / intended treatment 
duration.

Actual dose intensity (mg/day) = actual cumulative dose / intended treatment 
duration.

Relative dose intensity (%) = 100* (actual dose intensity / intended dose intensity).
A summary of exposure, including duration of exposure, cumulative dose, actual dose 
intensity, and relative dose intensity (including categories <50%, 50%-<75%, 75%-<90%, 
90%-<110%, and ≥110%, if applicable), will be presented for each study drug.  
Actual treatment duration will be summarized in months including descriptive statistics (n, 
mean, median, minimum, maximum) and will also be categorized by time intervals (eg, 
<1 months, 1-3 months, etc. as appropriate for the protocol) for which frequency counts and 
percentages of patients will be provided. 


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Actual treatment duration, cumulative dose, actual dose intensity, and relative dose intensity 
will also be listed for each patient by treatment arm.
6.5.3.1. Dose Modification
Dose modification will be summarized based on the the dosing data collected on the study 
treatment CRF page. 
Dose Reduction
Dose reductions are permitted for encorafenib and binimetinib and will be summarized based 
on the dose modification data collected on the respective study medication eCRF page. 
The number and percentage of patients with at least one dose reduction as well as a 
breakdown of dose reductions (1/2/≥3) will be summarized.  
Reasons for dose reductions will also be summarized.  Patients can contribute to more than 
one reason if multiple dose reductions occurred for different reasons, but will only be 
counted once per reason.  Percentages will be calculated based on the total number of 
patients in the safety analysis set.
Dose Interruption
A dose interruption will be indicated in the study medication eCRF. For encorafenib (Safety 
Lead-in) and binimetinib, a total dose of 0 mg in the morning and/or in the evening indicates 
a dose interruption. If a patient had a total dose of 0 mg both in the morning and in the 
evening, it is counted as one dose interruption for this patient. For encorafenib (Phase 2), a 
dosing record with a total daily dose of 0 mg for one or more days indicates a dose 
interruption. If the start and stop date of two dose interruption records are consecutive, it will 
be counted as one dose interruption.
Dose interruption will be summarized based on the dose modification data collected on the 
eCRF page. However, in order not to over count 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.
The number and percentage of patients with dose interruptions and the corresponding reasons 
will be summarized. Patients can contribute to more than one reason if multiple dose 
interruptions occurred for different reasons, but will only be counted once per reason.  
Percentages will be calculated based on the total number of patients in the safety analysis set.
6.5.4. Concomitant Medications
Concomitant medications are medications, other than study medications, which started prior 
to first dose of study treatment and continued during the on-treatment period (see 
Section 5.2.5) as well as those started during the on-treatment period.  Concomitant 


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medications will be coded in the WHO Drug coding dictionary and will be tabulated by ATC 
classification level 2 and PT (level 4) by decreasing frequency. In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used.  A patient will
be counted only once within a given drug name, even if he/she received the same medication 
at different times. 
All concomitant medications will be presented in a data listing. 
Incomplete dates will be handled as described in Section 5.3.1.
6.5.5. Subsequent Anticancer Therapies/Procedures
Number of patients with any anticancer treatment after discontinuation of study treatment 
will be summarized by type of therapy (systemic treatment, radiotherapy, and surgery). 
Summary statistics will be created for the data collected on the “Subsequent Cancer 
Treatment Systemic” eCRF page. 
Subsequent anticancer systemic treatment will be summarized by ATC class and preferred 
term and will also be presented in a listing.
Incomplete dates will be handled as described in Section 5.3.1.
6.6. Safety Summaries and Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. 
6.6.1. Adverse Events
All analyses will be based on TEAEs as defined in Section 3.4.1 unless otherwise specified. 
AEs not considered treatment emergent will be flagged in data listings.
Seriousness, toxicity grade, action taken (interruption, reduction, and withdraw) of AEs are 
as reported by the Investigator on the “Adverse Events” CRF.
A high level summary of AEs will include the number and percent of patients with:

Any TEAEs.

Serious TEAEs.

TEAEs with CTCAE Grade ≥3.

Related TEAEs to:

Encorafenib;


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
Binimetinib;

Both encorafenib and binimetinib.

Related serious TEAEs:

Encorafenib;

Binimetinib;

Both encorafenib and binimetinib.

TEAEs leading to dose interruption of:

Encorafenib;

Binimetinib;

Both encorafenib and binimetinib.

TEAEs leading to dose reduction of:

Encorafenib;

Binimetinib;

Both encorafenib and binimetinib.

TEAEs leading to permanent discontinuation from:

Encorafenib;

Binimetinib;

Both encorafenib and binimetinib.

TEAEs leading to dose reduction of any study drug due to COVID-19.

TEAEs leading to permanent discontinuation from any study drug due to COVID-19.
Each unique AE at the PT level in each treatment arm of the study for a patient is included in 
the count. 


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Adverse Events by SOC and PT
The following summaries will be created by SOC and PT by decreasing frequency:

TEAEs by maximum toxicity grade (all causality).

TEAEs by maximum toxicity grade (treatment related).

COVID-19 related TEAEs (all causality).

Serious TEAEs by maximum toxicity grade (all causality).

Serious TEAEs by maximum toxicity grade (treatment related).

TEAEs leading to dose reduction of any study drug due to COVID-19.

TEAEs leading to permanent discontinuation from any study drug due to COVID-19.
An event will be considered treatment related if the Investigator considered the event related 
to the study drug or this information is unknown.
Adverse Events by PT Only
The following summaries will be created by AE PT by decreasing frequency:

TEAEs (all causality) experienced by ≥10% of patients in Safety Lead-in and in at 
least one cohort for Phase 2.

Treatment related TEAEs experienced by ≥10% of patients in at least one cohort
(Phase 2).

TEAEs with CTCAE Grade ≥3 (all causality) by PT and maximum toxicity grade.

Serious TEAEs (all causality).

COVID-19 related serious TEAEs (all causality).
Adverse Events Leading to Dose Modification by PT 
The following summaries will be created by PT by decreasing frequency:

TEAEs leading to dose interruptions by maximum toxicity grade (all causality).

TEAEs leading to dose reductions by maximum toxicity grade (all causality).

TEAEs leading to permanent discontinuation by maximum toxicity grade (all 
causality).
The AE by PT summary will be created separately for:

Encorafenib;


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
Binimetinib.
Each patient will be counted only once within each PT.  
Adverse Events in Patients with Dose Escalation in Phase 2
TEAEs leading to dose interruptions, dose reductions and permanent discontinuation will also 
be summarized by PT for patients who escalate to encorafenib 600 mg QD in Phase 2.
All AEs and their attributes will be presented in data listings sorted by patient identifier, AE 
and date of onset of the AE.
6.6.2. Deaths
All deaths, deaths within 30 days after last dose of study drug, deaths within 30 days after 
first dose of study drug as well as the primary reason for death, will be tabulated based on 
information from the “Death Details” and “Disposition Long-term Follow-Up” eCRFs. 

Number of deaths.

Number of deaths within 30 days after last dose of study treatment.

Number of deaths within 30 days after first dose of study treatment.

Primary cause of death.
In addition, if there are ≥5 deaths due to COVID-19, a separate death summary will be 
created. 
Date and cause of death will be provided in patient data listing together with selected dosing 
information (study treatment received, date of first/last administration, dose).
6.6.3. Laboratory Data
Laboratory results will be converted to International System of Units (SI) units which will be 
used for applying toxicity grades and for all summaries. 
As described in Section 3.3, baseline is defined as the last completed assessment prior to date 
of first dose for the safety assessments. If there are multiple assessments that meet the 
baseline definition on the same day without the ability to determine which was truly last, then 
the worst grade will be assigned as the baseline grade. 
Laboratory results will be programmatically classified according to NCI-CTCAE version 
4.03.  Non-numerical qualifiers will not be taken into consideration in the derivation of grade 
(eg, hypokalemia Grade 1 and Grade 2 are only distinguished by a non-numerical qualifier 
and therefore Grade 2 will not be derived). In summary statistics the number and percentage 
of patients corresponding to grades that only include non-quantitative criteria will be 
displayed as a blank or NA (not assessed) rather than 0.  If there is any overlap between 


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grade criteria (eg, CTCAE grading criteria for Creatinine Increased – a value can fall into one 
range based on comparison to ULN and another range based on comparison to baseline), the 
highest (worst) grade would be assigned to that record.  Grade 5 is defined in the CTCAE 
criteria guidance as an event with an outcome of death.  Since laboratory data does not 
collect an outcome, Grade 5 is not used when programmatically grading laboratory data.
Grade 0 or Outside Toxicity Reference (OTR) is not defined specifically in the CTCAE 
guidance.  However, programmatically this is used as a category to represent those patients
who did not meet any of the Grades 1 to 4 criteria.  If the laboratory value is evaluable for 
CTCAE criteria grading (numeric value is present, valid units and ranges are present as 
required to allow conversion to standard units and grading), and does not qualify for any of 
the Grade 1-4 criteria for a given lab test, then the value is assigned as Grade 0 or OTR.
Abnormalities will be described using the worst grade post-baseline.  When determining the 
maximum post-baseline grade for a given patient and CTCAE test, the maximum across all 
analytes and assessments contributing to that CTCAE test will be used.  Several laboratory 
tests have bi-directional grading criteria defined so that both low (hypo) and high (hyper) 
values can be graded separately.  Each criterion will be summarized separately.  In the cases 
where a value is graded as a Grade 1, 2, 3, or 4 for one of the directions, that value will also 
be assigned as a Grade 0 for the opposite direction for that test.  For example, a value 
meeting the criteria for Grade 3 Hypercalcemia will be classified as a Grade 0 Hypocalcemia.  
For CTCAE terms that can be derived using one of several laboratory tests, the maximum 
post-baseline grade for a given patient and CTCAE term will be the maximum across all 
possible laboratory tests.
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported by the lab.  
When only percentages are available (this is mainly applicable for neutrophils and 
lymphocytes, because the CTCAE grading is based on the absolute counts), the absolute 
value is derived as follows: 
Derived differential absolute count = (WBC count) × (Differential %value/100)
If the investigator reports both the absolute and % value for Neutrophils or Lymphocytes 
from the same laboratory sample date and patient, ONLY the absolute value will be graded.  
The % value will not be graded in this scenario.   
If the % value is converted to the differential absolute count for grading and the LLN for the 
differential absolute count is not available (only LLN for % is available) then Grade 1 will be 
assigned if the following conditions are met:

Lymphocyte count decreased:  

derived absolute count does not meet Grade 2-4 criteria, and

% value < % LLN value, and


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
derived absolute count ≥800/mm3.

Neutrophil count decreased:

derived absolute count does not meet Grade 2-4 criteria, and

% value < % LLN value, and

derived absolute count ≥1500/mm3.
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium. 
Corrected Calcium is calculated from Albumin and Calcium as follows:

Corrected Calcium (mg/dL) = measured total calcium (mg/dL) – 0.8 × [serum 
albumin (g/dL)-4].
Laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages). If both central and local labs are collected for a subject, summaries of worst 
on-treatment abnormalities will be based on both local and central lab data.
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges). The following summary tables will be created:

Shift summary of laboratory parameters during the on-treatment period by maximum 
CTCAE grade.  

Shift summary of laboratory parameters from ≤ Grade 2 at baseline to ≥ Grade 3 
post-baseline.

Shift summary of laboratory test results with no CTCAE criteria by worst on-
treatment assessment.  
All laboratory test results will be presented in a data listing sorted by patient identifier, 
laboratory test, and date/time of collection. The CTCAE grades and the classifications 
relative to the laboratory reference ranges will be presented. Values outside laboratory 
normal ranges will be flagged where appropriate and the central laboratory data and local 
laboratory data will be flagged accordingly.
Drug Induced Liver Toxicity
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), Alkaline Phosphatase 
(ALP), and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. 
The ratios of test result over the ULN will be calculated and classified for these three 
parameters during the on-treatment period.   


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Summary of liver function tests will include the following categories. The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized:

ALT ≥3×ULN, ALT ≥5xULN, ALT ≥10×ULN, ALT ≥20×ULN.

AST ≥3×ULN, AST ≥5xULN, AST ≥10×ULN, AST ≥20×ULN.

(ALT or AST) ≥3×ULN, (ALT or AST) ≥5×ULN, (ALT or AST) ≥10×ULN, (ALT 
or AST) ≥20×ULN.

TBILI ≥2×ULN.

Concurrent  ALT ≥3×ULN and TBILI ≥2×ULN.

Concurrent AST ≥3×ULN and TBILI ≥2×ULN.

Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN.

Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN and ALP >2×ULN.

Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN and ALP ≤2×ULN or 
missing.
Concurrent measurements are those occurring on the same date. 
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages. 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment arms, by graphically displaying:

Peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin=2×ULN.

Peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
AST=3×ULN and total bilirubin=2×ULN.
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a 
post-baseline TBILI ≥2×ULN, ALT≥3×ULN or AST ≥3×ULN will be provided.
6.6.4. Vital Signs
Vital signs data includes weight, pulse, systolic blood pressure (BP), and diastolic BP.  
Measurements were only to be provided once per timepoint.  If multiple assessments are 
provided per timepoint, the maximum value will be used for reporting.


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The following criteria define clinically notable vital sign abnormalities:

Clinically notable elevated values:

Systolic 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.

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; 

Weight: ≥20% decrease from baseline;

Body temperature [C]: ≤36 C.
All assessments, including unscheduled assessments will be considered.  A patient can be 
included in multiple categories if different criteria are met at different timepoints.   
Number and percentage of patients with at least one post-baseline vital sign abnormality will 
be summarized.
Patients with clinically notable vital sign abnormalities will be presented in a data listing. 
Clinically notable values will also be flagged in this listing.
6.6.5. Electrocardiograms
Potential effects of treatment with study drug on ECG parameters will be assessed by ECG 
interval analysis of heart rate, pulse rate, QRS, QT, and QT interval corrected for heart rate 
(QTc). Triplicate measurements will be obtained at screening and pre-dose on Cycle 1 Day 1 
according to the schedule of assessments in the protocol. 
The average of the machine-read triplicate ECG measurements collected closest to but prior 
to the first dose of study drug will serve as each patient’s baseline QT, QTcF, and heart rate 
value for all post-dose comparisons. The QT, QTcF, and heart rate data collected on the 
eCRF page will be used in the summary.


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Number and percentages of patients with clinically notable ECG values during the 
on-treatment period will be summarized. The clinically notable ECG values are defined in
Table 6. 
Patients with clinically notable ECG values will be presented in a data listing. Clinically 
notable values will also be flagged in this listing.
Table 6: 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% and to a value >100 bpm
Decrease from baseline >25% and to a value <50 bpm
6.6.6. Neurological Symptoms
Neurological symptom data will be presented in a data listing.
6.6.7. ECOG Performance Status
ECOG performance status at each time point will be presented in a data listing.
6.6.8. Echocardiogram/Multi-gated Acquisition
Left ventricular ejection fraction (LVEF) abnormalities are defined according to CTCAE 
grade version 4.03. Patients will be considered as having a LVEF abnormality if the worst 
post value is grade 2, 3 or 4 according to the following classification: 

Grade 0: Non-missing value below Grade 2.

Grade 2: LVEF between 40% and 50% or absolute change from baseline 
between -10% and < -20%.

Grade 3: LVEF between 20% and 39% or absolute change from baseline lower than 
or equal to -20%.

Grade 4: LVEF lower than 20%.
A shift table using CTCAE grades to compare baseline to the worst post-baseline LVEF 
value will be produced.
Different modalities to assess LVEF might be used for the same patient. The shift table will 
be provided regardless of the modality.
All LVEF assessments will be presented in a data listing.


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6.6.9. Ophthalmic Examination
All ophthalmic examinations, ie, tonometry, visual acuity, fundoscopy, slit lamp, optical 
coherence tomography, and fluorescein angiography, will be presented in a data listing.
6.6.10. Pregnancy Tests
Results of all pregnancy tests will be presented in a data listing.
6.6.11. Comments
All comments entered into the electronic data capture (EDC) system by personnel at the 
study sites will be presented in a data listing.
6.6.12. Procedures
Results of all procedures collected on the Procedures eCRF will be presented in a data listing.
7. INTERIM ANALYSES
No formal interim analysis is planned for this study.


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8. REFERENCES
1.
Kaplan EL, Meier P. (1958). Nonparametric Estimation from Incomplete Observations. 
Journal of the American Statistical Association 53:457-481.
2.
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival 
Time, Biometrics 38, 29 - 41.


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9. APPENDICES
Appendix 1. List of Abbreviations
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomic Therapeutic Chemical
AUC
area under the curve
BID
twice a day
BP
blood pressure
BLQ
below the limit of quantification
BMRR
brain metastasis response rate
BOR
best overall response
BRAF
B-RAF proto-oncogene, serine/threonine-protein kinase
CI
confidence interval
Cmax
maximum observed concentration
CR
complete response
CSR
clinical study report
CV
coefficient of variation
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
DOR
duration of response
ECOG
Eastern Cooperative Oncology Group
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
FAS
full analysis set
LDH
lactate dehydrogenase
LLN
Lower limit of normal
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
ms
millisecond(s)
mRECIST
modified Response Evaluation Criteria in Solid Tumors
NA
not applicable
NCI
National Cancer Institute
NE
non-evaluable
OS
overall survival
OTR
outside toxicity reference
PD
progressive disease
PFS
progression-free survival
PIPDs
potentially important protocol deviations


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Abbreviation
Term
PK
pharmacokinetic(s)
PR
partial response
PT
preferred term
Q1
first quartile
Q3
third quartile
QD
once daily
QT
QT interval
QTcF
corrected QT (Fridericia method)
RANO-BM
Response Assessment in Neuro-Oncology Brain Metastases
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SOC
system organ class
SOP
standard operating procedure
SRS
stereotactic radiosurgery
SRT
stereotactic radiotherapy
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WBC
white blood cell
WHO 
World Health Organization