Conditions: Healthy
Keywords: Encorafenib Rabeprazole Healthy adult participants
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 18
Healthy volunteers: yes

Brief summary:
Relative bioavailability study to evaluate the pharmacokinetics of two new encorafenib formulations

Detailed description:
In order to decrease the size of the current formulated encorafenib capsule and improve the physical stability, 2 new encorafenib tablet formulations have been developed.

This study is intended to select the optimal tablet formulation for commercialization based on the tablet pharmacokinetics.

A preliminary assessment of the effect of a proton-pump inhibitor on the pharmacokinetics of the 2 encorafenib tablet formulations will also be conducted to assist in the formulation selection.

Arms:
arm 1: Participants will receive a single encorafenib dose formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the formulation after administration of 20 mg rabeprazole every evening for 5 days. arm 2: Participants will receive a single encorafenib dose of the second formulation, a single encorafenib dose of the second formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the second formulation after administration of 20 mg rabeprazole every evening for 5 days.

Interventions: intervention 1: Encorafenib capsule formulation (CAP) intervention 2: Encorafenib first formulation intervention 3: Encorafenib second formulation intervention 4: Rabeprazole tablet
Intervention descriptions: intervention 1: A single encorafenib dose of the CAP formulation intervention 2: first formulation intervention 3: second formulation intervention 4: Proton-pump inhibitor

Protocol document:
Prot_000.pdf: 
Encorafenib
Protocol C4221024
Protocol Amendment 1, 27 June 2022
PFIZER CONFIDENTIAL
Page 1
Title Page
A PHASE 1, RANDOMIZED, OPEN-LABEL STUDY IN HEALTHY 
PARTICIPANTS TO ESTIMATE THE BIOAVAILABILITY OF TWO NEW 
ENCORAFENIB FORMULATIONS RELATIVE TO THE CURRENT
FORMULATION AND TO EVALUATE THE EFFECT OF A PROTON-PUMP 
INHIBITOR ON ENCORAFENIB PLASMA PHARMACOKINETICS
.
Study Intervention Number:
PF-07263896
Study Intervention Name:
Encorafenib
US IND Number:
111003
EudraCT Number:
N/A
ClinicalTrials.gov ID:  
Not Available
Pediatric Investigational Plan Number:
N/A
Protocol Number:
C4221024
Phase:
1
Brief Title: A Phase 1 Relative Bioavailability Study Evaluating two new Encorafenib
Formulations
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Document History
Document
Version Date
Amendment 1
27 June 2022
Original protocol
05 May 2022
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs and any global protocol administrative change 
letter(s).
Protocol Amendment Summary of Changes Table
Amendment 1 (27 June 2022)
Overall Rationale for the Amendment: In response to the COVID-19 pandemic, COVID-
19 assessments were incorporated into the protocol template to minimize risk for participants 
and staff. PCRUs have now changed their COVID-19 procedures to not require testing and 
temperature checks at screening. This amendment is designed to update the protocol based on 
the new PCRU COVID-19 procedures.
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
Table 1 Periods 1, 2 
and 3
COVID-19 test 
removed at 
screening 
Updated to 
accommodate new 
COVID-19 
Guidelines at the 
PCRU that no longer
require COVID-19 
testing at screening. 
Substantial
Table 1 Periods 1, 2 
and 3
Temperature check 
removed at 
screening 
Updated to 
accommodate new 
COVID-19 
Guidelines at the 
PCRU that no longer 
require a temperature 
check at screening. 
Substantial
Section 5.2 
Exclusion Criteria
Updated language 
to exclude 
participants with a 
positive COVID-
19 test at first 
admission
Updated to 
accommodate new 
COVID-19 
Guidelines at the 
PCRU that no longer 
require COVID-19 
testing at screening. 
Substantial
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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 8.3.5 
COVID-19 Specific 
Assessments
COVID-19 test 
removed at 
screening
Updated to 
accommodate new 
COVID-19 
Guidelines at the 
PCRU that no longer 
require COVID-19 
testing at screening. 
Substantial
Section 5.3.2 Meals 
and Dietary 
Restrictions
Section was 
updated to align 
with exclusion 
criterion 6 on 
restrictions of 
food/drink that can 
be taken before 
encorafenib 
dosing. 
Changed to correct 
protocol 
inconsistency. 
Nonsubstantial
Section 6.1.1 
Administration 
Rabeprazole 
formulation was 
mistakenly noted 
as a capsule and 
was changed to a 
tablet.
Rabeprazole will be 
administered as a 
tablet at the PCRU.
Nonsubstantial
Table 1 Periods 1, 2 
and 3
Reference updated
Table referenced the 
wrong section of the 
protocol.
Nonsubstantial
Section 9.5 Sample 
Size Determination
90% confidence 
intervals for 
AUCinf and Cmax 
were estimated 
based on 9 
participants instead 
of 18.
Nine participants 
were required for the 
PPI drug-drug 
interaction of the 
study. However, the 
90% CIs were 
calculated for 18 
participants instead 
of 9 participants. 
Thus, the 90% CI 
data were updated 
based on 9 
participants.
Nonsubstantial
Table 9 Confidence 
Interval Estimation 
of PK Endpoints for 
PPI Effect
90% confidence 
intervals for 
AUCinf and Cmax 
were estimated 
based on 
Nine participants 
were required for the 
PPI drug-drug 
interaction of the 
study. However, in 
Nonsubstantial
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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
9 participants 
instead of 18.
Table 9, the 90% CIs 
were calculated for 
18 participants 
instead of 9 
participants. Thus, 
the 90% CI data in 
Table 9 were updated 
based on 9 
participants.
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
1. PROTOCOL SUMMARY...................................................................................................11
1.1. Synopsis ..................................................................................................................11
1.2. Schema ....................................................................................................................17
1.3. Schedule of Activities .............................................................................................18
2. INTRODUCTION ...............................................................................................................23
2.1. Study Rationale .......................................................................................................23
2.2. Background .............................................................................................................24
2.2.1. Nonclinical Pharmacology..........................................................................24
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................25
2.2.3. Nonclinical Safety ......................................................................................25
2.2.4. Clinical Overview.......................................................................................25
2.3. Benefit/Risk Assessment.........................................................................................26
2.3.1. Risk Assessment.........................................................................................27
2.3.2. Benefit Assessment.....................................................................................28
2.3.3. Overall Benefit/Risk Conclusion................................................................28
3. OBJECTIVES AND ENDPOINTS.....................................................................................28
4. STUDY DESIGN.................................................................................................................28
4.1. Overall Design.........................................................................................................28
4.2. Scientific Rationale for Study Design.....................................................................30
4.2.1. Choice of Contraception/Barrier Requirements .........................................31
4.2.2. Collection of Retained Research Samples..................................................31
4.3. Justification for Dose ..............................................................................................31
4.3.1. Encorafenib Dose Rationale .......................................................................31
4.3.2. Rabeprazole Drug Selection and Dose Rationale.......................................32
4.4. End of Study Definition ..........................................................................................32
5. STUDY POPULATION......................................................................................................32
5.1. Inclusion Criteria.....................................................................................................32
5.2. Exclusion Criteria....................................................................................................33
5.3. Lifestyle Considerations..........................................................................................35
5.3.1. Contraception..............................................................................................35
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5.3.2. Meals and Dietary Restrictions...................................................................36
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................36
5.3.4. Activity .......................................................................................................37
5.4. Screen Failures ........................................................................................................37
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................37
6.1. Study Intervention(s) Administered........................................................................37
6.1.1. Administration............................................................................................38
6.2. Preparation, Handling, Storage, and Accountability...............................................38
6.2.1. Preparation and Dispensing........................................................................39
6.3. Assignment to Study Intervention...........................................................................40
6.4. Blinding...................................................................................................................40
6.5. Study Intervention Compliance...............................................................................40
6.6. Dose Modification...................................................................................................40
6.7. Continued Access to Study Intervention After the End of the Study......................40
6.8. Treatment of Overdose............................................................................................40
6.9. Prior and Concomitant Therapy ..............................................................................41
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................41
7.1. Discontinuation of Study Intervention ....................................................................41
7.2. Participant Discontinuation/Withdrawal From the Study.......................................41
7.2.1. Withdrawal of Consent...............................................................................42
7.3. Lost to Follow-up....................................................................................................43
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................43
8.1. Administrative and Baseline Procedures.................................................................43
8.2. Efficacy Assessments..............................................................................................44
8.3. Safety Assessments .................................................................................................44
8.3.1. Physical Examinations................................................................................44
8.3.2. Vital Signs ..................................................................................................45
8.3.2.1. Blood Pressure and Pulse Rate..................................................45
8.3.3. Electrocardiograms.....................................................................................45
8.3.4. Clinical Safety Laboratory Test Assessments ............................................46
8.3.5. COVID-19 Specific Assessments...............................................................47
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8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................47
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......47
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................48
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................48
8.4.2. Method of Detecting AEs and SAEs ..........................................................49
8.4.3. Follow-Up of AEs and SAEs......................................................................49
8.4.4. Regulatory Reporting Requirements for SAEs...........................................49
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................49
8.4.5.1. Exposure During Pregnancy......................................................50
8.4.5.2. Exposure During Breastfeeding ................................................51
8.4.5.3. Occupational Exposure .............................................................52
8.4.6. Cardiovascular and Death Events...............................................................52
8.4.7. Disease -Related Events and/or Disease -Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................52
8.4.8. Adverse Events of Special Interest.............................................................52
8.4.8.1. Lack of Efficacy........................................................................52
8.4.9. Medical Device Deficiencies......................................................................52
8.4.10. Medication Errors.....................................................................................52
8.5. Pharmacokinetics ....................................................................................................53
8.5.1. Plasma for Analysis of Encorafenib ...........................................................53
8.5.2. Derivation of Pharmacokinetic Parameters ................................................54
8.6. Genetics...................................................................................................................55
8.6.1. Specified Genetics ......................................................................................55
8.6.2. Retained Research Samples for Genetics ...................................................55
8.7. Biomarkers ..............................................................................................................55
8.8. Immunogenicity Assessments.................................................................................55
8.9. Health Economics ...................................................................................................55
9. STATISTICAL CONSIDERATIONS ................................................................................55
9.1. Statistical Hypotheses .............................................................................................56
9.2. Analysis Sets ...........................................................................................................56
9.3. Statistical Analyses .................................................................................................56
9.3.1. Pharmacokinetic Analyses..........................................................................56
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9.3.2. Other Safety Analyses ................................................................................57
9.3.3. Other Analyses............................................................................................58
9.3.3.1. Retained Research Sample Analyses ........................................58
9.4. Interim Analyses .....................................................................................................58
9.5. Sample Size Determination.....................................................................................58
9.6. Data Monitoring Committee ...................................................................................59
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................60
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............60
10.1.1. Regulatory and Ethical Considerations ....................................................60
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................60
10.1.2. Informed Consent Process ........................................................................61
10.1.3. Data Protection .........................................................................................62
10.1.4. Committees Structure ...............................................................................62
10.1.4.1. Data Monitoring Committee ...................................................62
10.1.5. Dissemination of Clinical Study Data ......................................................62
10.1.6. Data Quality Assurance ............................................................................63
10.1.7. Source Documents....................................................................................65
10.1.8. Study and Site Start and Closure ..............................................................65
10.1.9. Publication Policy.....................................................................................66
10.1.10. Sponsor’s Medically Qualified Individual..............................................67
10.2. Appendix 2: Clinical Laboratory Tests .................................................................68
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................69
10.3.1. Definition of AE .......................................................................................69
10.3.2. Definition of an SAE ................................................................................70
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................71
10.3.4. Reporting of SAEs....................................................................................75
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................76
10.4.1. Male Participant Reproductive Inclusion Criteria....................................76
10.4.2. Female Participant Reproductive Inclusion Criteria.................................76
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10.4.3. Woman of Childbearing Potential ............................................................76
10.4.4. Contraception Methods.............................................................................77
10.5. Appendix 5: Genetics............................................................................................80
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......81
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................83
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................83
10.7.2. Age-Specific Kidney Function Calculation Recommendations...............83
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations10 ........................................................................................83
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................83
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ...................................84
10.9. Appendix 9: Abbreviations ...................................................................................86
11. REFERENCES ..................................................................................................................91
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LIST OF TABLES
Table 1.
Periods 1, 2 and 3......................................................................................18
Table 2.
Period 4.....................................................................................................21
Table 3.
Pharmacokinetic Assessments..................................................................22
Table 4.
Summary of the Two New Tablet Formulations ......................................23
Table 5.
Trial Design ..............................................................................................29
Table 6.
Summary of Encorafenib Formulations....................................................38
Table 7.
Definitions of PK Parameters...................................................................54
Table 8.
Confidence Interval Estimation of PK Endpoints for Bioavailability......58
Table 9.
Confidence Interval Estimation of PK Endpoints for PPI Effect .............59
Table 10.
Protocol-Required Safety Laboratory Assessments .................................68
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1, Randomized, Open-Label Study in Healthy Participants to 
Estimate the Bioavailability of two new Encorafenib Formulations Relative to the Current 
Formulation and to Evaluate the Effect of a Proton-Pump Inhibitor on Encorafenib Plasma 
Pharmacokinetics
Brief Title: A Phase 1 Relative Bioavailability Study Evaluating two new Encorafenib
Formulations
Regulatory Agency Identification Number(s):
US IND Number:
111003
EudraCT Number:
N/A
ClinicalTrials.gov ID:  
Not Available
Pediatric Investigational Plan Number:
N/A
Protocol Number:
C4221024
Phase:
1
Rationale
In order to decrease the size of the current formulated encorafenib capsule and improve the 
physical stability, 2 new encorafenib tablet formulations have been developed. This study is 
intended to select the optimal tablet formulation for commercialization based on the 
pharmacokinetics. In addition, the present dissolution data does not provide enough 
confidence to exclude the achlorhydric population (PPI effect) from the rBA study. Because 
of this difference, a preliminary assessment of the effect of a proton-pump inhibitor on the 
pharmacokinetics of the 2 encorafenib tablet formulations will also be conducted to assist in 
the formulation selection.
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 
• To estimate the relative BA of 2 new encorafenib 
75-mg tablet formulations 
 
to the commercially available encorafenib 
formulated capsule (CAP) administered under 
fasted conditions to adult healthy participants.
• Plasma AUCinf, AUClast and Cmax for encorafenib 
(alone and with rabeprazole).
Secondary: 
Secondary: 
• To assess the safety and tolerability of the 3 
formulations (
 and CAP) 
encorafenib 75-mg, when given alone and in 
• Overall safety profile as characterized by 
laboratory tests, vital signs, ECGs, and adverse 
events.
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Objectives
Endpoints
combination with rabeprazole in adult healthy 
participants.
• To estimate the effect of rabeprazole on the PK 
of 
.
• Other plasma PK parameters for encorafenib 
(alone and with rabeprazole): Tmax, t1/2, CL/F, and 
Vz/F, if possible. 
Overall Design
This study will be an open-label, randomized, 4-period, 6-sequence study in adult healthy 
participants.
Number of Participants
A sufficient number of participants will be screened to ensure that at least 18 participants are 
enrolled in the study. 
Study Population:
Key inclusion and exclusion criteria are listed below:
Inclusion Criteria 
Participants must meet the following inclusion criteria to be eligible for enrollment into the 
study:
1. Participants must be male or female of non-childbearing potential of 18 years of age 
or older, inclusive, at the time of signing the ICD.
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, physical examination, laboratory tests, and 
cardiac monitoring.
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
4. BMI of 17.5 to 30.5 kg/m2; and a body weight >50 kg (110 lb). 
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:
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1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease. Evidence of any active and uncontrolled bacterial or viral infection.
2. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). 
3. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, 
HBcAb or HCVAb. Hepatitis B vaccination is allowed.
4. Positive COVID-19 test at first admission.
5. Other medical or psychiatric conditions, laboratory test abnormalities, other 
conditions or situations related to COVID-19 pandemic or, in the investigator’s 
judgment, make the participant inappropriate for the study.
6. Use of prescription or non-prescription medications within 7 days prior to the first 
dose of encorafenib with the exception of moderate/potent CYP3A inducers which 
are prohibited within 14 days plus 5 half-lives prior to the first dose. 
7. History of known sensitivity to rabeprazole, substituted benzimidazoles or to any 
component of the rabeprazole formulation.
8. Previous administration with an investigational product (drug or vaccine) within 30 
days. 
9. Known hypersensitivity to encorafenib or its excipients.
10. A positive urine drug or cotinine test.
11. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. 
12. Baseline standard 12 lead ECG that demonstrates clinically relevant abnormalities 
that may affect participant safety or interpretation of study results.
13. AST or ALT level ≥1.5 灤ULN.
14. Total bilirubin level ≥1.5 灤ULN.
15. Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2.
Study Arms and Duration
For Periods 1 through 3, participants will receive a single 75-mg encorafenib formulation 
during each period: 
 (Treatment A), 
 (Treatment B) and CAP (Treatment C) 
formulations, all under fasted conditions. In order to provide the most flexibility, the 
participants may remain in the PCRU from the time of admission on Day -1 of Period 1 until 
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discharge after the 48-hour PK collection in Period 4 based on the discretion of the 
investigator. There will be a minimum 5-day washout period between encorafenib doses in 
these periods. Serial PK samples will be collected prior to and after administration of each 
encorafenib dose.
During Period 4, in order to evaluate the effect of rabeprazole on the encorafenib PK for the 
2 new tablet formulations, participants will receive either a single 75-mg dose of 
 
(Treatment D) or 
 (Treatment E) following 5 days of 20 mg QD rabeprazole. The 
rabeprazole dosing in Period 4 must begin only after the  48-hour PK sample in Period 3 has 
been collected. Serial PK samples will be collected prior to and after encorafenib dosing. 
The total duration of the study will be approximately 90 days including screening. 
Participants will be confined to the PCRU for a maximum of 21 days. Participants who 
withdraw from the study may be replaced at the discretion of the investigator and upon 
consultation with the sponsor.
Statistical Methods
Relative Bioavailability (Periods 1-3): 
Natural log transformed encorafenib AUCinf (if data permit), AUClast and Cmax will be 
analyzed using a mixed effect model with sequence, period and treatment as fixed effects and 
participant within sequence as a random effect. Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% CIs will be obtained from the model. The adjusted 
mean differences and 90% CIs for the differences will be exponentiated to provide estimates 
of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. 
Treatment C (encorafenib CAP) is the Reference Treatment while Treatments A and B 
(
 and 
 tablet formulations) are the Test Treatments. This analysis will include 
only data from Treatments A, B and C.
PPI effect (Period 4) : 
Natural log transformed encorafenib AUCinf (if data permit), AUClast and Cmax will be 
analyzed using ANOVA with treatment and sequence as a fixed effect and subject within 
sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% CIs will be obtained from the model. The adjusted mean differences 
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CIs for the ratios. For the 
 tablet 
formulation, Treatment A (
tablet) is the Reference Treatment while Treatment D 
(
 tablet administered with rabeprazole) is the Test Treatment (this analysis will only 
include data from Treatments A and D). For the 
 tablet formulation, Treatment B 
 tablet) is the Reference Treatment while Treatment E (
 tablet administered 
with rabeprazole) is the Test Treatment (this analysis will only include data from Treatments 
B and E).
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Ethical Considerations:
Potential Risk of Clinical Significance
Participants may experience some adverse events.
Summary of Data/Rationale for Risk
Please see Section 2.2.4 for adverse event data of 
encorafenib in non-cancer participants. See the 
encorafenib IB for additional safety information.
Mitigation Strategy
All participants will be confined in the clinical 
sites with close monitoring and only be discharged 
once all AEs are stabilized. If necessary, a 
participant will be transferred to a facility with an
appropriate level of care to achieve stabilization or 
until SAEs have resolved.
Study Intervention(s) Encorafenib, Rabeprazole
Most common risks associated with encorafenib
include headache, flushing/erythema, paresthesia, 
and feeling hot after a single dose.  
The potential risks are based on AEs reported in 
previous clinical studies with encorafenib in 
healthy participants.
AEs, vital signs, ECGs, and clinical laboratory 
test results will be monitored on an ongoing basis. 
Instructions for managing potential cases of drug-
induced liver injury, should they occur, are 
provided in Appendix 6.
Secondary skin neoplasms are known adverse 
effects of treatment with single-agent BRAF 
inhibitors including encorafenib.
Risk of developing secondary skin neoplasms is 
evident in the oncology treatment setting 
involving BRAF inhibitors including encorafenib.
This adverse event was not reported with any of 
the other 5 clinical studies already conducted with 
healthy participants. Additionally, this event has 
not been observed after a single encorafenib dose 
in any patient studies either.
Most common risks associated with rabeprazole
include pain, pharyngitis, infection, flatulence, and 
constipation.
The potential risks are based on AEs reported in 
the USPI.
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Other
Risk of COVID-19 contamination during study.
During the ongoing pandemic, healthy 
participants could be infected with SARS-COV-2 
virus through study participation. This could lead 
to increased health risk for the participants and 
others in the study.
COVID-19 specific assessments will be conducted 
in this study according to Table 1 and Table 2.
Encorafenib single doses to be administered in this study are not expected to provide any clinical benefit to healthy participants.
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1.2. Schema
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1.3. Schedule of Activities
The SoA tables provide an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA tables, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
The scheduled activities are listed in Table 1 for Periods 1, 2 and 3 and in Table 2 for Period 4.
Table 1.
Periods 1, 2 and 3
Visit Identifier
Abbreviations used 
in this table may be 
found in Section 
10.9.
Screen
Period 1 to Period 3
Early 
Discontinuation
Notes
Days Relative to 
Day 1
Day -28 
to 
Day -2
Day -1
Day 1
Day 2
Day 3
•
All screening should be done ≤ 28 days before the first dose. 
•
Study Day relative to start of study intervention (Day 1).
Hours After Dose
0
2
24
48
•
Hour 0 = predose sample collection
Informed consent
X
•
See Section 10.1.2 for additional information.
CRU confinement
X
→
→
→
→
•
Participants may be discharged on Day 3 after PK sample collection is 
completed at the discretion of the investigator.
Inclusion/exclusion 
criteria
X
X
•
Reviewed at screening and admission.
Medical/medication 
history
X
X
•
Medical history: illegal drug, alcohol and tobacco use. 
•
Medication history: prescription, non-prescription or supplements.
Physical 
examination (full)
X
X
•
A full PE will only be performed either at screening or at admission during 
Period 1.
Safety laboratory
tests
X
X
X
•
Safety lab tests will be collected at screening, admission(s) and discharge, and at 
the discretion of the investigator.
•
See Section 10.2 for additional information on specific clinical laboratory tests.
Demography
X
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Table 1.
Periods 1, 2 and 3
Visit Identifier
Abbreviations used 
in this table may be 
found in Section 
10.9.
Screen
Period 1 to Period 3
Early 
Discontinuation
Notes
Days Relative to 
Day 1
Day -28 
to 
Day -2
Day -1
Day 1
Day 2
Day 3
•
All screening should be done ≤ 28 days before the first dose. 
•
Study Day relative to start of study intervention (Day 1).
Hours After Dose
0
2
24
48
•
Hour 0 = predose sample collection
Height and body 
weight
X
•
See Section 8.3.1
Contraception 
check 
X
X
X
X
•
Contraception check on Day 3 if participant is discharged.
FSH
X
•
See Section 10.4.3 for additional information.
Urine drug testing
X
X
•
Cotinine test included.
•
If participants are confined to the PCRU between periods, Day -1 assessments
not required.
•
See Section 10.2 for additional information.
12-Lead ECG
X
X
X
X
•
See Section 8.3.3 for additional information.
•
Triplicate ECGs will be conducted pre-dose on Day 1. All other ECG 
measurements will be single ECGs.  
Blood pressure and 
pulse rate
X
X
X
X
•
See Section 8.3.2 for additional information.
HIV, HBsAg, 
HBcAb, HCVAb 
X
•
See Section 10.2 for additional information.
COVID-19 
questionnaire
X
X
•
Per local PCRU procedures.
COVID-19 PCR
testing
X
•
See Section 8.3.5 and Section 10.2 for additional information.
•
Per local PCRU procedures.
COVID-19 check 
temperature
X
•
Per local PCRU procedures.
Encorafenib 
administration
X
•
See Section 6.1.1 for additional information.
Pharmacokinetic 
blood sampling for 
encorafenib
X
→
→
→
X
•
Refer to Table 3 and Section 8.5 for additional information.
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Table 1.
Periods 1, 2 and 3
Visit Identifier
Abbreviations used 
in this table may be 
found in Section 
10.9.
Screen
Period 1 to Period 3
Early 
Discontinuation
Notes
Days Relative to 
Day 1
Day -28 
to 
Day -2
Day -1
Day 1
Day 2
Day 3
•
All screening should be done ≤ 28 days before the first dose. 
•
Study Day relative to start of study intervention (Day 1).
Hours After Dose
0
2
24
48
•
Hour 0 = predose sample collection
Retained Research 
Sample for 
Genetics (Prep D1) 
X
(Peri
od 1 
only
)
•
Prep D1 Retained Research Samples for Genetics: If not collected on the 
designated collection day, collect at the next available time point when 
biospecimens are being collected in conjunction with a participant visit. See 
Section 8.6.2.
Concomitant 
treatment(s)
X
X
X
→
→
→
X
•
See SeSection 6.9 for additional information.
Serious and 
nonserious AE 
monitoring
X
X
X
→
→
→
X
•
See Section 8.4.3 for follow-up AE and SAE assessments.
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Table 2.
Period 4
Visit Identifier
Abbreviations used 
in this table may be 
found in Section 
10.9.
Period 4
F/U
Early 
Discontinuation
Notes
Days Relative to 
Day 1
Day -
5
Day -4 
to Day 
-1
Day 1
Day 
2
Day 3
29-
35 
Days
•
Day relative to start of study intervention (Day 1).
•
Follow-up may occur via telephone. Contact and must occur 29 to 35 days after 
administration of the final dose of study intervention
Hours After Dose
0
2
24
48
•
Hour 0 = predose sample collection
CRU confinement
X
→
→
→
→
X 
Safety laboratory
tests
X
X
•
See Section 10.2 for additional information on specific clinical laboratory tests.
Contraception 
check 
X
X
•
See Section 10.4 for additional information.
12-Lead ECG
X
X
X
•
See Section 8.3.3 for additional information.
•
Triplicate ECGs will be conducted pre-dose on Day 1. All other ECG 
measurements will be single ECGs.  
Blood pressure and 
pulse rate
X
X
X
•
See Section 8.3.2 for additional information.
Rabeprazole 
administration
X
X
•
See Section 6.1.1 for additional information.
Encorafenib 
administration
X
•
See Section 6.1.1 for additional information.
Pharmacokinetic 
blood sampling for 
encorafenib
X
→
→
→
X
•
Refer to Table 3 and Section 8.5 for additional information.
CRU discharge 
X
Concomitant 
treatment(s)
X
X
X
→
→
→
X
X
•
See Section 6.9 for additional information.
Serious and 
nonserious AE 
monitoring
X
X
X
→
→
→
X
X
•
See Section 8.4.3 for follow-up AE and SAE assessments.
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Table 3.
Pharmacokinetic Assessments
Notes
Study Day
1
2
3
Day relative to start of study 
intervention (Day 1).
Hours Before/After Dose
0
0.5
1
1.5
2
2.5
3
3.5
4
6
8
10
12
24
48
Hour 0 = predose sample collection
Encorafenib administration
X
Encorafenib PK blood sampling 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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2. INTRODUCTION
Encorafenib is a kinase inhibitor indicated, in combination with binimetinib, for the treatment 
of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K 
mutation, as detected by an FDA-approved test, or in combination with cetuximab, for the 
treatment of patients with mCRC with a BRAF V600E mutation, as detected by an FDA-
approved test, after prior therapy.
2.1. Study Rationale 
Formulated drug product containing encorafenib is currently available as a 75-mg size double 
zero capsule for commercial uses. At the approved dose for metastatic melanoma (450 mg
QD), patients are required to swallow 6 capsules each day within a short period of time. The 
capsule burden and challenge for many patients to consistently ingest six double-zero 
capsules has been noted during clinical development and subsequently post-
commercialization. Patients have often requested the option to open the capsules because 
they are too large to swallow. Additionally, there is an effort to improve the physical stability
of encorafenib for primary packaging flexibility. Therefore, there is a need for a formulation
that is smaller in size with improved stability; this is the basis for evaluation of the BA of the 
alternate formulation relative to the CAP for future commercial use. 
Alternative formulations have been developed as IR tablets, to deliver the 75-mg dose in a 
10mm standard round tablet, improve physical stability, and are intended to provide an 
alternative dosage form to be used for all patients, especially those who have difficulty in 
swallowing the commercial capsules.
Two encorafenib tablet formulations are being evaluated in this clinical study. Both novel 
formulations contain the same HME composition which contains encorafenib within an
amorphous solid dispersion. The formulations differ in the extragranular excipients chosen to 
compress the tablet cores. Specifically, the formulation designated as 
contains only 
 as the extragranular diluent and the formulation designated as 
contains 
 as the extragranular diluents. These 2
tablet formulations are differentiated in terms of dissolution release profile and the clinical 
evaluation of both tablet core compositions will provide elucidation of formulation design 
space which can be used to inform future commercial formulation design strategies for 
encorafenib. For clarity, details regarding the 2 tablet formulations are provided in Table 4.
Table 4.
Summary of the Two New Tablet Formulations
Name and Description
Tablet Abbreviation
Description
 
Immediate-release tablet   
formulated with
 as the single 
extragranular diluent
    
Immediate-release tablet   
formulated with both 
 and 
 as extragranular diluents
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This study is intended to select the optimal tablet formulation for commercialization based on 
the PK. In addition, a preliminary assessment of the effect of a PPI on the PK of the 2
encorafenib tablet formulations will also be conducted to assist in the formulation selection.
2.2. Background 
Encorafenib is a novel oral small-molecule kinase inhibitor, which suppresses the 
RAF/MEK/ERK pathway in tumor cells expressing the BRAF V600E mutation. Similar to 
other selective small molecule RAF kinase inhibitors, encorafenib inhibits COT and RAF-1 
(CRAF), BRAF, as well as BRAF V600E in cell-free assays. However, this class of inhibitor 
does not inhibit RAF/MEK/ERK signaling in cells expressing wild-type BRAF. In the human 
melanoma cell line A375 (BRAF V600E), encorafenib potently inhibits phospho-MEK, 
phosphor-ERK and proliferation, resulting in cell cycle arrest and apoptosis. Given the high 
degree of selectivity against other kinases, encorafenib has no antiproliferative activity in 
tumor cell lines that express wild-type BRAF and is highly selective for BRAF V600E/D/K 
containing cell lines, with the greatest sensitivity observed in BRAFmt melanoma and CRC 
lineages. Encorafenib has been clinically evaluated in the oncology setting as a single agent 
and in combination with other targeted agents, as well as in healthy subjects for 
bioavailability, human ADME, food effect, hepatic impairment and DDIs.
2.2.1. Nonclinical Pharmacology
Encorafenib is a highly selective ATP-competitive small-molecule RAF kinase inhibitor 
which suppresses the RAF/MEK/ERK pathway in tumor cells expressing BRAFV600E. For 
example, the half-maximal response concentration (EC50) for suppression of pMEK and 
pERK in A375 human melanoma cells are 2 nM and 3 nM, respectively. Suppression of the 
RAF/MEK/ERK pathway causes cell cycle arrest which leads to inhibition of cell 
proliferation with an EC50 = 4 nM. Similar to other selective small-molecule RAF kinase 
inhibitors, encorafenib inhibits CRAF, BRAF, as well as BRAF V600E in cell-free assays; 
however, this class of inhibitor does not inhibit RAF/MEK/ERK signaling in cells expressing 
wild-type BRAF. Given both the high degree of selectivity of encorafenib for the RAF 
kinases in biochemical assays (only 2/75 non-RAF kinases inhibited at concentrations 
<1 μM), and the failure of encorafenib to inhibit wild-type RAF kinases in cells, encorafenib 
has no antiproliferative activity in tumor cell lines that express wild-type BRAF.
Encorafenib’s predominant circulating metabolite, LYH746 (also known as M42.5A), was 
assessed for its off-target activity on 56 G-protein-coupled receptors, transporters, ion 
channels, nuclear receptors and enzymes since this metabolite represented 15.5% of total 
radioactivity in plasma in the human ADME study. The results showed activities of > 50% 
inhibition at 10 μM were found on kinase insert domain receptor (half-maximal inhibitory 
concentration [IC50] = 1.8 μM, n = 1) and PDE4D (IC50 = 4.2 μM, n = 2), showing 
significantly less potency than encorafenib. LHY746 was also evaluated in in vitro activity 
studies and confirmed to be inactive with respect to inhibiting melanoma cell proliferation.
For more detailed information, refer to the current encorafenib IB.
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2.2.2. Nonclinical Pharmacokinetics and Metabolism
Encorafenib is a substrate of P-gp and is associated with a high apparent passive 
permeability. Binding to human plasma proteins was ~86%. Distribution into rat tissues was 
rapid. There was no distribution to the CNS; brain and spinal cord and no retention in the 
melanin-rich tissues. 
For all species investigated, monohydroxylation, N-dealkylation, and subsequent 
glucuronidation represented the major metabolic pathways. Glucuronidation, both direct and 
indirect, occurred more readily in humans than in other species. Encorafenib is metabolized 
by CYP 3A4, CYP2C19, and CYP2D6. CYP3A4 was predicted to be the major enzyme 
contributing to total oxidative clearance of encorafenib in human liver microsomes (~83.3%), 
followed by CYP2C19 and CYP2D6 (~16.0% and 0.71%, respectively). 
In vitro experiments indicate that encorafenib is a relatively potent reversible inhibitor of 
uridine 5'-diphospho-glucuronosyltransferase-glucuronosyltransferase (UGT) 1A1, CYP2B6, 
CYP2C9, and CYP3A4/5, and also a time-dependent inhibitor of CYP3A4. Encorafenib 
induced CYP1A2, CYP2B6, CYP2C9, and CYP3A4 in human primary hepatocytes. Finally, 
encorafenib was found to be a weak inhibitor of BCRP, and a potent inhibitor of renal 
transporters OCT 2, OAT 1, OAT3 and hepatic transporters OCT1, OATP1B1 and 
OATP1B3. For more detailed information, refer to the current encorafenib IB.
2.2.3. Nonclinical Safety
Preclinical safety pharmacology data do not indicate a clinical risk for QTc prolongation, or 
adverse effects on the CNS or respiratory system for encorafenib or its primary metabolite, 
LHY746. 
The GLP Ames and chromosomal aberration assays as well as a rat micronucleus study 
indicate that encorafenib is not genotoxic. 
Encorafenib showed a potential for phototoxicity in a screen 3T3 NRU in vitro assay. 
Additionally, encorafenib did not show a sensitizing potential in the murine LLNA TIER I 
assay, although revealed a weak irritating potential. However, it tested negative in the 
primary skin irritation assay in rabbits.
For more detailed information, refer to the current encorafenib IB.
2.2.4. Clinical Overview
As of the data cutoff date of 11 May 2020, a total of 2117 healthy subjects and patients have 
received at least 1 dose of encorafenib, either as a single agent or in combination with other 
targeted agents. These patients constitute the encorafenib safety population, which includes 
97 healthy subjects, 7 subjects with hepatic impairment and 2013 patients with advanced 
cancer (410 patients who received single-agent encorafenib and 1614 patients who received 
encorafenib combination therapy, with 11 patients who received both single-agent 
encorafenib and encorafenib + binimetinib combination therapy and 4 patients who received 
encorafenib + binimetinib combination therapy in 2 different studies). Based on the 
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experience from these studies, encorafenib has demonstrated an acceptable and manageable 
safety profile. 
Rabeprazole will be used in Period 4 of this study for assessment of the potential effect of a 
PPI on the PK of the HME formulations (
and 
 Rabeprazole is a commonly 
used PPI able to reduce gastric acid. The approved dose for delayed release rabeprazole (for 
gastroesophageal reflux disease) is 20-mg QD. 
The first generation encorafenib capsule  was previously studied with rabeprazole 20-mg in a 
Phase 1, open-label, 2-arm, parallel-group, fixed-sequence study. The results show that co-
administration of 100-mg encorafenib with rabeprazole had no overall effect on the extent of 
exposure and peak exposure to encorafenib, when 100-mg encorafenib was co-administered 
with multiple oral once-daily doses of 20-mg rabeprazole, relative to when 100-mg 
encorafenib was administered alone. The administration of a single 100 mg oral dose of 
encorafenib in the presence of multiple oral doses of 20-mg rabeprazole was safe (as 
evidenced by the absence of Grade 3/severe, Grade 4/life-threatening, and Grade 5/death as 
well as the absence of subject discontinuation deemed necessary by the Investigator due to 
AEs). In Period 4 of this study, 20 mg rabeprazole QD will be administered for 5 days to 
explore the potential effect of a PPI on PK of both new tablet formulations.
For detailed clinical information, refer to the current encorafenib IB. For additional 
information regarding rabeprazole, please refer to the current rabeprazole USPI.
2.3. Benefit/Risk Assessment
Encorafenib is not expected to provide any clinical benefit to healthy participants. This study 
is designed primarily to generate safety, tolerability, and pharmacokinetic data for further 
clinical development of new tablet formulation and to inform the critical formulation 
compositional design parameters for commercial formulation development for encorafenib.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of encorafenib may be found in the current encorafenib IB which is the SRSD 
for this study.
Information about the known and expected benefits and risks and reasonably expected AEs 
of rabeprazole may be found in the rabeprazole USPI.
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Participants may experience some adverse events.
Summary of Data/Rationale for Risk
Please see Section 2.2.4 for adverse event data of 
encorafenib in non-cancer participants. See the 
encorafenib IB for additional safety information.
Mitigation Strategy
All participants will be confined in the clinical 
sites with close monitoring and only be discharged 
once all AEs are stabilized. If necessary, a 
participant will be transferred to a facility with an
appropriate level of care to achieve stabilization or 
until SAEs have resolved.
Study Intervention(s) Encorafenib, Rabeprazole
Most common risks associated with encorafenib
include headache, flushing/erythema, paresthesia, 
and feeling hot after a single dose.  
The potential risks are based on AEs reported in 
previous clinical studies with encorafenib in 
healthy participants.
AEs, vital signs, ECGs, and clinical laboratory 
test results will be monitored on an ongoing basis. 
Instructions for managing potential cases of drug-
induced liver injury, should they occur, are 
provided in Appendix 6.
Secondary skin neoplasms are known adverse 
effects of treatment with single-agent BRAF 
inhibitors including encorafenib.
Risk of developing secondary skin neoplasms is 
evident in the oncology treatment setting 
involving BRAF inhibitors including encorafenib.   
This adverse event was not reported with any of 
the other 5 clinical studies already conducted with 
healthy participants. Additionally, this event has 
not been observed after a single encorafenib dose 
in any patient studies either.
Most common risks associated with rabeprazole
include pain, pharyngitis, infection, flatulence, and 
constipation.
The potential risks are based on AEs reported in 
the USPI.
Other
Risk of COVID-19 contamination during study.
During the ongoing pandemic, healthy participants 
could be infected with SARS-COV-2 virus through 
study participation. This could lead to increased 
health risk for the participants and others in the 
study.
COVID-19 specific assessments will be conducted 
in this study according to Table 1 and Table 2.
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2.3.2. Benefit Assessment
No clinical benefit is expected for participants enrolled in this study, but the results from this 
study are intended to develop and eventually commercialize a new encorafenib formulation 
to extend the use of encorafenib in patients who have trouble swallowing the capsule 
formulation currently on the market.
2.3.3. Overall Benefit/Risk Conclusion
Encorafenib single doses to be administered in this study are not expected to provide any 
clinical benefit to healthy participants. This study is designed primarily to generate PK data 
for evaluation of a new encorafenib formulation. Single oral doses of 50-mg and 100-mg 
encorafenib have been safely administered previously to approximately 90 healthy 
participants in 5 healthy participant clinical studies. 
More detailed information about the known and expected benefits, risks, and reasonably 
expected AEs of encorafenib may be found in the current encorafenib IB, which is the SRSD 
for this study.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
• To estimate the relative BA of 2 new 
encorafenib 75-mg tablet formulations (
and 
 to the commercially available 
encorafenib formulated capsule (CAP) 
administered under fasted conditions to adult 
healthy participants.
• Plasma AUCinf, AUClast and Cmax for encorafenib
(alone and with rabeprazole).
Secondary:
Secondary: 
• To assess the safety and tolerability of the 3 
formulations (
 and CAP) 
encorafenib 75-mg, when given alone and in 
combination with rabeprazole in adult healthy 
participants.
• To estimate the effect of rabeprazole on the PK 
of 
 and 
• Overall safety profile as characterized by 
laboratory tests, vital signs, ECGs, and adverse 
events.
• Other plasma PK parameters for encorafenib
(alone and with rabeprazole): Tmax, t1/2, CL/F, and 
Vz/F, if possible.
4. STUDY DESIGN
4.1. Overall Design
This study will be an open-label, randomized, 4-period, 6-sequence study in adult healthy 
participants.
Periods 1 through 3 will estimate the relative bioavailability of the 2 new encorafenib tablet 
formulations (
and
 compared to the commercially available CAP formulation 
using a 75-mg encorafenib single dose administered under fasted condition. Period 4 will 
explore the potential effect of a PPI (rabeprazole) on the PK of encorafenib administered as 
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the 
and 
tablet formulations. Participants will receive either the 
or
formulation with rabeprazole in Period 4.
Participants will be randomized into 1 of 6 treatment sequences as outlined in Table 5.
For Periods 1 through 3, participants will receive a single 75-mg encorafenib formulation
during each period:
(Treatment A), 
(Treatment B) and CAP (Treatment C) 
formulations, all under fasted conditions. In order to provide the most flexibility, the 
participants may remain in the PCRU from the time of admission on Day -1 of Period 1 until 
discharge after the 48-hour PK collection in Period 4 based on the discretion of the 
investigator. There will be a minimum 5-day washout period between encorafenib doses in 
these periods. Serial PK samples will be collected prior to and after administration of each 
encorafenib dose.
During Period 4, in order to evaluate the effect of rabeprazole on the encorafenib PK for the 
2 new tablet formulations, participants will receive either a single 75-mg dose of 
(Treatment D) or 
(Treatment E) following 5 days of 20 mg QD rabeprazole. The 
rabeprazole dosing in Period 4 must begin only after the 48-hour PK sample in Period 3 has 
been collected. Serial PK samples will be collected prior to and after encorafenib dosing. 
Approximately 18 participants will be enrolled into the study. Each participant will receive 4
single 75-mg doses of encorafenib during Periods 1 through 4, and in addition, 20-mg 
rabeprazole QD for 5 days in Period 4. 
The total duration of the study will be approximately 90 days including screening. 
Participants will be confined to the PCRU for a maximum of 21 days. Participants who 
withdraw from the study may be replaced at the discretion of the investigator and upon 
consultation with the sponsor.
Table 5.
Trial Design
Treatment 
Sequence
Period 
1
Washout
Period 2
Washout
Period 3
Washout
Period 4
1 (N=3)
A
At least 5
day
washouta
B
At least 5
day
washouta
C
At least 5
day
washouta
D
2 (N=3)
A
C
B
E
3 (N=3)
B
C
A
D
4 (N=3)
B
A
C
E
5 (N=3)
C
A
B
D
6 (N=3)
C
B
A
E
a.between successive encorafenib doses
Treatments: 
•
Treatment A (Test 1 for BA evaluation, Reference 1 for PPI effect): A single 75 mg 
encorafenib dose as the 
formulation will be administered on the morning of Day 1 
after an overnight fast of at least 10 hours. 
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•
Treatment B (Test 2 for BA evaluation, Reference 2 PPI effect): A single 75 mg 
encorafenib dose as the
formulation will be administered on the morning of Day 
1 after an overnight fast of at least 10 hours. 
•
Treatment C (Reference for BA evaluation): A single 75 mg encorafenib dose as CAP
formulation will be administered on the morning of Day 1 after an overnight fast of at 
least 10 hours.
•
Treatment D (Test 1 for PPI evaluation): 20 mg rabeprazole will be administered 
approximately 1 hour prior to dinner on Day -5 through Day -1. A single 75 mg 
encorafenib dose as 
formulation will be administered on the morning of Day 1 
after an overnight fast of at least 10 hours.
•
Treatment E (Test 2 for PPI evaluation): 20 mg rabeprazole will be administered 
approximately 1 hour prior to dinner on Day -5 through Day -1. A single 75 mg 
encorafenib dose as 
formulation will be administered on the morning of Day 1
after an overnight fast of at least 10 hours.
4.2. Scientific Rationale for Study Design
Single doses of encorafenib up to 100-mg have been safely administered to about 90 healthy 
participants in 5 clinical studies ensuring little risk to healthy adult participants in the current 
study (Section 2.2).
Genetic Toxicity: The GLP Ames and chromosomal aberration assays as well as a rat 
micronucleus study indicate that encorafenib is not genotoxic.
Washout period: The mean elimination half-life after a single dose of encorafenib is 
approximately 3.5 hours. Thus, a 18-hour washout period (~5 half-lives) is considered 
adequate for the washout of the encorafenib from plasma. During the study, plasma 
concentrations should typically have dropped to BLQ before administration of the next dose
(ie, no residual concentrations from the prior period) to minimize the carryover from the 
previous treatment. Based on previous clinical experience with encorafenib, a 5-day washout 
period is considered sufficient for plasma encorafenib concentrations to return to BLQ after 
administration of a single dose. Therefore, in this study, a 5-day washout period has been 
selected between successive encorafenib doses for periods with PK collections.
Rationale for Inclusion of PPI Assessment: Encorafenib being a weak base would require 
inclusion of achlorhydric subjects to assess the effect of a PPI on the PK, unless a non-
significant difference (≤15%) between the dissolution profiles of first generation capsules 
and second generation tablets is demonstrated in a medium with pH 3.0–6.8.1,2,3 Selection of 
the exact medium within this pH range has proven to be complex due to various factors.
Considering this, the present dissolution data does not provide enough confidence to exclude 
the achlorhydric population (PPI effect) from the rBA study. Because of this difference, both 
new tablet formulations will also be tested for clinically significant pH dependent 
interactions.
Study Treatment Rationale for Rabeprazole: PPIs are a group of drugs that have strong 
inhibitory effects on acid secretion in the stomach through suppression of the gastric proton 
pump (H, K-ATPase). PPIs exert their effect by increasing gastric pH and are the very 
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important treatment options for acid-related diseases. All PPIs showed inhibitory effect on 
CYP2C9, 2C19, and 3A4 to some extent. Among those PPIs, rabeprazole showed the lowest 
inhibitory potency compared to other PPIs.4,5 In addition, rabeprazole is predominantly 
converted to a thioether metabolite by non-enzymatic reduction and metabolism by CYP 
enzymes is only the minor elimination pathway. Therefore, the impact of enzyme 
polymorphism (such as CYP2C19) would be the lowest for rabeprazole among all PPIs.6,7
Meta-analysis of multiple studies shows that rabeprazole has relatively high antisecretory 
potency among PPIs tested.6 Since acid control by PPIs is a sustained effect, PPIs are 
commonly given daily despite the short elimination half-life (about 2 hours or less).7 Since 
encorafenib is partially metabolized by CYP2C19 there is a potential that rabeprazole may 
increase encorafenib plasma concentrations due to its CYP2C19 inhibitory effect, to 
minimize potential drug interaction between rabeprazole and encorafenib, in this study, 
rabeprazole as 20-mg will be administered in the evening from Day -1 to Day -5, and 75-mg 
encorafenib will be administered in the morning on Day 1 for the evaluation of any potential 
effect of PPI on the PK of encorafenib. With the short half-life of rabeprazole, there will be 
minimal systemic exposure of rabeprazole at the time of rabeprazole administration in the 
current design.
4.2.1. Choice of Contraception/Barrier Requirements
Nonclinical studies suggest risk for severe manifestations of developmental toxicity at 
relevant clinical exposures for encorafenib. Therefore, the use of a highly effective method of 
contraception is required for male participants and their female partners of childbearing 
potential (see Appendix 4). Only female participants on non-childbearing status will be 
enrolled.
4.2.2. Collection of Retained Research Samples
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.3. Justification for Dose
4.3.1. Encorafenib Dose Rationale
The approved dose of encorafenib for the treatment of metastatic melanoma is 450-mg QD
(administered as six 75-mg capsules, in combination with binimetinib) and 300-mg QD
(administered as four 75-mg capsules, in combination with cetuximab) for mCRC. In clinical 
study CLGX818X2101, the MTD for encorafenib was determined to be 450-mg QD and 
encorafenib has demonstrated dose proportional PK from 50 to 700-mg following single-
dose administration in patients. Single 50-mg and 100-mg doses of encorafenib have been 
administered to approximately 90 adult healthy participants in 5 clinical studies and were 
well-tolerated and without any reported SAEs.
Based on the safety data of encorafenib and prior clinical experience as described above, a 
single 75-mg dose, with a 5 day washout between successive encorafenib doses, for 4 
periods, is expected to pose little risk to healthy adult participants.
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4.3.2. Rabeprazole Drug Selection and Dose Rationale
Rabeprazole is primarily dosed at 20-mg QD for many of its most common indications 
(healing of erosive or ulcerative GERD, treatment of symptomatic GERD in adults). 
Additionally, the findings from 2 clinical studies8,9 indicate that the rabeprazole dosing 
regimen utilized in this protocol will ensure an intragastric pH>4, thus allowing the 
evaluation of the maximum effect of gastric acid suppression on encorafenib
pharmacokinetics.
4.4. End of Study Definition
The end of the study will be defined as the date of last scheduled procedure shown in Table 2
for the last participant in the trial.
A participant will be considered to have completed the study if they have completed all
periods of the study, including the last scheduled procedure shown in Table 1 and Table 2.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. Use of a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, and race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Participants must be male or female of non-childbearing potential (as defined in 
Appendix 4, Section 10.4.3) of 18 years of age or older, inclusive, at the time of 
signing the ICD.
Refer to Appendix 4 for reproductive criteria for male Section 10.4.1 and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, physical examination, laboratory tests, and 
cardiac monitoring.
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3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Body Weight:
4. BMI of 17.5 to 30.5 kg/m2; and a body weight >50 kg (110 lb).
Informed Consent:
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular (including history of prolonged QT 
syndrome), hepatic, psychiatric, neurological, or allergic disease (including drug 
allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of 
dosing). Evidence of any active and uncontrolled bacterial or viral infection.
2. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
3. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, 
HBcAb or HCVAb. Hepatitis B vaccination is allowed.
4. Positive COVID-19 test at first admission.
5. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory test abnormality or other conditions or 
situations related to COVID-19 pandemic that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study.
Prior/Concomitant Therapy:
6. Use of prescription or non-prescription medications, including vitamins, herbal and 
dietary supplements, grapefruit/grapefruit containing products, and Seville 
orange/Seville orange containing products within 7 days prior to the first dose of
encorafenib with the exception of moderate/potent CYP3A inducers which are 
prohibited within 14 days plus 5 half-lives prior to the first dose of encorafenib. 
(Refer to Section 6.9 Prior and Concomitant Therapy for additional details).
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7. History of known sensitivity to rabeprazole, substituted benzimidazoles or to any 
component of the rabeprazole formulation. (Refer to rabeprazole USPI for additional 
warnings and precautions related to rabeprazole).
Prior/Concurrent Clinical Study Experience:
8. Previous administration with an investigational product (drug or vaccine) within
30 days.
9. Known hypersensitivity to encorafenib or its excipients.
Diagnostic Assessments:
10. A positive urine drug or cotinine test.
11. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.
12. Baseline standard 12-lead ECG that demonstrates clinically relevant abnormalities 
that may affect participant safety or interpretation of study results (eg, QTcF >450 ms
(or a history of prolonged QT syndrome), complete LBBB, signs of an acute or 
indeterminate- age myocardial infarction, ST-T interval changes suggestive of 
myocardial ischemia, second- or third- degree AV block, or serious bradyarrhythmias 
or tachyarrhythmias). If the uncorrected QT interval is >450 ms, this interval should 
be rate-corrected using the Fridericia method only and the resulting QTcF should be 
used for decision making and reporting. If QTcF exceeds 450 ms and or QRS exceeds 
120 ms, the ECG should be repeated twice and the average of the 3 QTcF and/or QRS 
values used to determine the participant’s eligibility. Computer-interpreted ECGs 
should be overread by a physician experienced in reading ECGs before excluding a 
participant.
13. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
•
AST or ALT level ≥1.5 × ULN;
•
Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN.
•
Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (See for
Section 10.7.2 calculation method).
Other Exclusion Criteria:
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14. Male participants who are unwilling or unable to comply with the contraception 
requirement listed in Section 10.4.1.
15. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine).
16. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
17. History of sensitivity to heparin or heparin-induced thrombocytopenia.
18. Participants who currently smoke or use other nicotine products (e.g. chewing 
tobacco, E-cigarettes).
19. Unwilling or unable to comply with the criteria in the Section 5.3 Lifestyle 
Considerations section of this protocol.
20. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Contraception 
The investigator or their designee, in consultation with the participant, will confirm that male 
participants are utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Appendix 4, 
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. It must be confirmed that female participants meet the criteria for non-
childbearing potential. At time points indicated in SoA tables (Table 1 and Table 2), the 
investigator or designee will inform the participant of the need to use highly effective
contraception consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart. Participants need to affirm their consistent and correct 
use of at least 1 of the selected methods of contraception, considering that their risk for 
pregnancy may have changed since the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
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5.3.2. Meals and Dietary Restrictions
•
Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample on Day 1 of each period. Participants must also abstain from all food and 
drink (except water) at least 4 hours post encorafenib dose on Day 1 of each period.
•
Breakfast will not be provided on Day 1 of each treatment period.
•
Water will be permitted until 1 hour prior to encorafenib administration on Day 1 in 
each period. There will be no water restrictions for rabeprazole dosing. Water may be 
consumed without restriction beginning 1 hour after dosing on Day 1 of each period. 
Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices—see 
below) may be consumed with meals and the evening snack.
•
Lunch will be provided approximately 4 to 5 hours after encorafenib dosing on Day 1 
of all periods
•
Dinner will be provided approximately 9 to 10 hours after encorafenib dosing on Day 
1 of all periods.
•
An evening snack may be permitted.
•
Participants will refrain from consuming red wine, grapefruit, or grapefruit -related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of encorafenib until collection of the final PK blood sample on the study.  
•
While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.3. Caffeine, Alcohol, and Tobacco
•
Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of encorafenib dosing on Day 1 until collection of the final PK sample of each 
treatment period.  
•
Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample of each study period. Participants may undergo an alcohol 
breath test or blood alcohol test at any time at the discretion of the investigator.
•
Participants who currently smoke will not be enrolled in this study.
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5.3.4. Activity
•
Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted. 
•
In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after encorafenib dosing on Day 1 of each treatment period
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (ie, screen failures) 
may be rescreened. Rescreened participants should be assigned the same participant number 
as for the initial screening.
Additionally during screening:
•
For eligibility purposes, vital signs, laboratory tests, or ECG results may be repeated 
if an abnormal result is observed at the initial reading;
•
In the event that the participation of a participant in the study is delayed and any 
required screening procedures will be outside of the allowed screening window (28 
days), these screening procedures can be repeated;
•
Participants who are not eligible based on a reversible medical condition or 
mild/acute/intercurrent illness may be re-evaluated after further testing/examination 
or re-screened after the condition has resolved.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and noninvestigational medicinal 
products, medical devices, and other interventions (eg, surgical and behavioral) intended to 
be administered to the study participants during the study conduct.
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.
6.1. Study Intervention(s) Administered
Study interventions administered in this study will be encorafenib and rabeprazole.
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Table 6.
Summary of Encorafenib Formulations
Treatment 
Referencesa
Protocol 
C4221024 
Abbreviation
Route of 
Administration
DMID Description
Treatment A
Treatment D
Oral
 
 
Treatment B
Treatment E
Oral
 
 
Treatment C
CAP
Oral
Encorafenib 75 mg Size 00 
white/flesh hard gelatin 
capsule
a.
Treatment descriptions outlined in Section 4.1.
Encorafenib 75 mg tablets and capsules will be supplied to the CRU in bulk along with 
individual dosing containers for unit dosing.
Delayed release 20 mg rabeprazole will be supplied by the CRU.
6.1.1. Administration
Following an overnight fast of at least 10 hours, participants will receive encorafenib at 
approximately 0800 hours (plus or minus 2 hours) on Day 1 of each period. The investigator 
site personnel will administer encorafenib capsule/tablet during each period with 
approximately 240 mL of ambient temperature water. Participants will swallow the 
capsule/tablet whole, and will not manipulate or chew the capsule/tablet prior to swallowing.
During Period 4, the investigator site personnel will administer a 20 mg rabeprazole tablet
with approximately 240 mL of ambient temperature water without food approximately 1 hour 
prior to the dinner on Day -5 to Day -1. Participants will swallow rabeprazole tablet whole 
and will not manipulate or chew the tablet prior to swallowing.
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for ECG measurements), eating, and 
drinking beverages other than water during the first 4 hours after encorafenib dosing.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 
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2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention.
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to the labeled storage conditions, 
as soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to
report for each excursion will be provided to the site in the IP manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery: as described in the IPM.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
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participant, in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.
Encorafenib tablets and capsules will be prepared at the CRU in the individual dosing 
containers by 2 operators, 1 of whom is an appropriately qualified and experienced member 
of the study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist). The tablets and capsules will be provided in unit dose 
containers and labeled in accordance with Pfizer regulations and the clinical site’s labeling 
requirements. 
The handling of rabeprazole should be according to the product package insert.
6.3. Assignment to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled. The investigator 
will assign participant numbers to the participants as they are screened for the study. Pfizer 
will provide a randomization schedule to the investigator and, in accordance with the 
randomization numbers, the participant will receive the study treatment regimen assigned to 
the corresponding randomization number.
6.4. Blinding
This will be an open label study. 
6.5. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.6. Dose Modification
No dose modifications, dosing interruptions, or dosing delays will be allowed in this healthy 
participant study.
6.7. Continued Access to Study Intervention After the End of the Study
No study intervention will be provided to participants at the end of their study participation.
6.8. Treatment of Overdose
For this study, any dose of encorafenib greater than 75 mg within a 24-hour time period will 
be considered an overdose.
There is no specific treatment for an overdose
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In the event of an overdose, the investigator should:
1. Contact the study medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory test abnormalities 
as medically appropriate and at least until the next scheduled follow-up.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 2 days from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a 
case-by-case basis).
6.9. Prior and Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days prior to the first dose of encorafenib with the exception of 
moderate/potent CYP3A inducers which are prohibited within 14 days plus 5 half-lives prior 
to the first dose of encorafenib. Limited use of nonprescription medications that are not 
believed to affect participant safety or the overall results of the study may be permitted on a 
case-by-case basis following approval by the sponsor.
During the study, acetaminophen (up to 1 g per 24-hour period) and ibuprofen (up to 800 mg 
per 24 hour period) may be administered at the discretion of the PI.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of either study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
If study intervention is permanently discontinued, the participant will not remain in the study 
for further evaluation. See the SoA tables for data to be collected at the time of 
discontinuation of study intervention.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following:
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•
Refused further follow-up;
•
Lost to follow-up;
•
Death;
•
Study terminated by sponsor;
•
At the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA tables for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. The participant will be permanently discontinued from the study 
intervention and the study at that time.
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations will be performed and no 
additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
When a participant withdraws from the study because of an AE or SAE, the AE or SAE must 
be recorded on the case report form (CRF) and reported on the Clinical Trial (CT) SAE 
Report. 
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention 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 participant specifically withdraws consent for any further contact 
with them or persons previously authorized by the participant to provide this information. 
Participants 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 intervention 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 
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the participant 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.
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if the participant 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 participant fails to return to the clinic for a required 
study visit:
•
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study;
•
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;
•
Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative and Baseline Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA tables. Protocol waivers or 
exemptions are not allowed.
Adherence to the study design requirements, including those specified in the SoA tables, is 
essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory test results obtained 
prior to first dose administration meet eligibility criteria.
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A participant who qualified for this protocol but did not enroll from an earlier cohort/group
may be used in a subsequent cohort/group without rescreening, provided laboratory test 
results obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may be used without repeat collection, as appropriate.
Every effort should be made to ensure that protocol -required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol -required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study will be
approximately 230 mL. The actual collection times of blood sampling may change; the time 
of actual collection will be recorded. Additional blood samples may be taken for safety 
assessments at times specified by Pfizer, provided the total volume taken during the study 
does not exceed 550 mL during any period of 56 consecutive days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Prior and Concomitant Therapy sections of the protocol.
8.2. Efficacy Assessments
Efficacy assessments will not be applicable to this study
8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA tables. Unscheduled 
safety measurements may be obtained at any time during the study to assess any perceived 
safety issues.
8.3.1. Physical Examinations
A full physical examination will include, at a minimum, head, ears, eyes, nose, mouth, skin, 
heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
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Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and body weight will also be measured and recorded as per Table 1. For measuring 
body weight, a scale with appropriate range and resolution is used and must be placed on a 
stable, flat surface. Participants must remove shoes, bulky layers of clothing, and jackets so
that only light clothing remains. They must also remove the contents of their pockets and 
remain still during measurement of weight. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.2. Vital Signs
8.3.2.1. Blood Pressure and Pulse Rate
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mmHg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
8.3.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant
has rested quietly for at least 5 minutes in a supine position. 
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Triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes apart; the average of 
the triplicate ECG measurements collected before dose administration on Day 1 of each 
period will serve as each participant’s baseline QTcF value.
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements (the last measurement prior to encorafenib dose in the 
first period). Additional ECG monitoring will occur if a) a postdose QTcF is increased by 
≥60 ms from the baseline and is >450 ms; or b) an absolute QTcF value is ≥500 ms for any 
scheduled ECG. If either of these conditions occurs, then 2 additional ECGs will be collected 
approximately 2 to 4 minutes apart to confirm the original measurement. If the QTcF values 
from these repeated ECGs remain above the threshold value, then a single ECG must be 
repeated at least hourly until QTcF values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement.
If a) a postdose QTcF remains ≥60 ms from the baseline and is >450 ms; or b) an absolute 
QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at the 
discretion of the investigator); or c) QTcF value get progressively longer, the participant
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF
values do not return to less than the criteria listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 8.
8.3.4. Clinical Safety Laboratory Test Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition.
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 28 calendar days after the last dose of study intervention 
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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 or study medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
8.3.5. COVID-19 Specific Assessments
Participants will be tested for SARS-COVID-19 infection by PCR testing prior to being 
admitted to the clinic for confinement (Day -1 of Period 1) and a subsequent COVID-19 test 
will be performed after 4 days (ie, upon completion of 4 × 24 hours of CRU confinement), or 
if they develop COVID-19 like symptoms. 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc).
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 participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant 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.
8.4.1. 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 participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention), through and including a minimum of 28 calendar days after the last 
administration of the study intervention.
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Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues 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 participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant 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 participant permanently discontinues or temporarily discontinues study intervention
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 information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the CT SAE Report Form.
8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 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 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available.
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, 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 participant.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical
study.
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8.4.2. Method 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 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant 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 participant is lost to follow-up (as defined in Section 7.3).
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 participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is provided in Appendix 3.
8.4.4. 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 toward the safety of participants and the safety of a 
study intervention 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 intervention 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 (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
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exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if: 
•
A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.
•
A male participant who is receiving or has discontinued study intervention
inseminates a female partner. 
•
A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP:  
•
A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion or skin contact.
•
A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion or skin contact 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 participant or a participant’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 intervention and until 7 days after 
the 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 participant 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 should be reported 
as an SAE;
•
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 intervention. 
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 (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if: 
•
A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.
•
A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by
ingestion or skin contact.  
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The investigator must report EDB 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 EDB occurs in the setting of environmental exposure, 
the exposure information does not pertain to the participant 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.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form regardless of whether 
there is an associated SAE. Since the information about the occupational exposure does not 
pertain to a participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file.
8.4.6. Cardiovascular and Death Events
Not Applicable.
8.4.7. Disease -Related Events and/or Disease -Related Outcomes Not Qualifying as AEs 
or SAEs
Not Applicable.
8.4.8. Adverse Events of Special Interest
Not Applicable.
8.4.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in this study population.
8.4.9. Medical Device Deficiencies
Not Applicable.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Medication errors are recorded and reported as follows:
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Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
Medication errors include:
•
Medication errors involving participant exposure to the study intervention;
•
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Pharmacokinetics 
8.5.1. Plasma for Analysis of Encorafenib
Blood samples of approximately 3 mL will be collected into appropriately labeled tubes 
containing dipotassium ethylenediaminetetraacetic acid (K2EDTA) or tripotassium 
ethylenediaminetetraacetic acid (K3EDTA) for measurement of plasma concentrations of 
encorafenib as specified in the SoA. Instructions for the collection and handling of biological 
samples will be provided in the laboratory manual or by the sponsor. The actual date and 
time (24-hour clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
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not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF.
Samples will be used to evaluate the PK of encorafenib.
 
 
.
Genetic analyses will not be performed on these plasma samples. Participant confidentiality 
will be maintained.
Samples collected for measurement of plasma concentrations of encorafenib will be analyzed 
using a validated analytical method in compliance with applicable SOPs.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
8.5.2. Derivation of Pharmacokinetic Parameters
PK parameters, as appropriate, will be derived from the encorafenib concentration-time 
profiles as described in Table 7.
Table 7.
Definitions of PK Parameters
Parameter
Definition
Method of Determination
AUClast
Area under the plasma 
concentration time profile from 
time zero to the time of the last 
quantifiable concentration (Clast)
Linear-log trapezoidal method.
AUCinf a
Area under the plasma 
concentration-time profile from 
time zero extrapolated to 
infinite time
AUClast + (Clast/kel). 
where Clast is the predicted plasma 
concentration at the last quantifiable 
time point and kel is the elimination 
rate constant estimated from the log-
linear regression analysis.
Cmax
Maximum plasma concentration
Observed directly from the data.
Tmax
Time for Cmax
Observed directly from the data as 
time of first occurrence.
t1/2a
Terminal plasma elimination 
half-life
Loge(2)/kel
Only those data points judged to 
describe the terminal log-linear 
decline will be used in the regression.
CL/Fa
Apparent clearance after oral 
dose
Dose/AUCinf after oral dose.
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Table 7.
Definitions of PK Parameters
Parameter
Definition
Method of Determination
Vz/Fa
Apparent volume of distribution 
after oral dose
Dose/(AUCinf*kel) after oral dose.
Tlast
The time for Clast
Observed directly from the data
a.
As data permits
Actual PK sampling times will be used in the derivation of PK parameters whenever 
possible. In the case that actual PK sampling times are not available, nominal PK sampling 
time may be used in the derivation of PK parameters.
8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
8.6.2. Retained Research Samples for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA tables, as local regulations and IRBs/ECs allow.
Retained Research Samples may be used for research related to the study intervention(s). 
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in laboratory manual and supporting 
documentation.
8.7. Biomarkers
Biomarkers will not be evaluated in this study.
8.8. Immunogenicity Assessments
Immunogenicity assessments will not be included in this study.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the Statistical Analysis Plan (SAP), which will be 
maintained by the sponsor. The SAP may modify what is outlined in the protocol where 
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appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Statistical Hypotheses
No statistical hypothesis will be tested in this study.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Enrolled 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
screening. A participant will be considered enrolled if the 
informed consent is not withdrawn prior to participating in any 
study activity after screening. Potential participants who are 
screened for the purpose of determining eligibility for the 
study, but do not participate in the study, are not considered 
enrolled, unless otherwise specified by the protocol.
Safety analysis set
All participants randomly assigned to a treatment sequence and 
who take at least 1 dose of encorafenib. Participants will be 
analyzed according to the formulation they actually received.
PK Concentration 
Analysis Set
The PK concentration population is defined as all participants 
randomized and treated who have at least 1 encorafenib 
concentration in at least 1 period.
PK Parameter Analysis 
Set
The PK parameter analysis population is defined as all 
participants randomized and treated who have at least 1 of the 
encorafenib plasma PK parameters of primary interest in at 
least 1 treatment period.
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.3.1. Pharmacokinetic Analyses
Encorafenib PK parameters following a single dose administration will be derived from the 
encorafenib plasma concentration versus time profiles using non-compartmental methods as 
data permit. The PK parameters to be assessed in this study, their definition, and method of 
determination are outlined in Table 6. Encorafenib PK parameters (AUCinf, AUClast, Cmax, 
Tmax, t1/2, CL/F, and Vz/F) will be summarized descriptively by treatment. Individual
participant parameters for AUCinf, AUClast and Cmax will be plotted by treatment and overlaid 
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with geometric mean. Similar presentations will also be made for other PK parameters, if 
considered relevant. Encorafenib concentrations will be listed and summarized descriptively 
by PK sampling time and treatment. Summary profiles (means and medians) of concentration 
time data will be plotted by treatment on linear and semi log scale. Individual participant 
concentration time profiles will be also presented. For summary statistics and summary plots
by sampling time, the nominal PK sampling time will be used, for individual participant plots 
by time, the actual PK sampling time will be used.
Relative Bioavailability (Periods 1-3): 
Natural log transformed encorafenib AUCinf (if data permit), AUClast and Cmax will be 
analyzed using a mixed effect model with sequence, period and treatment as fixed effects and 
participant within sequence as a random effect. Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% CIs will be obtained from the model. The adjusted 
mean differences and 90% CIs for the differences will be exponentiated to provide estimates 
of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. 
Treatment C (encorafenib CAP) is the Reference Treatment while Treatments A and B 
(
and 
tablet formulations) are the Test Treatments. This analysis will include 
only data from Treatments A, B and C.
PPI effect (Period 4) : 
Natural log transformed encorafenib AUCinf (if data permit), AUClast and Cmax will be 
analyzed using ANOVA with treatment and sequence as a fixed effect and subject within 
sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% CIs will be obtained from the model. The adjusted mean differences 
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CIs for the ratios. For the 
tablet
formulation, Treatment A (
tablet) is the Reference Treatment while Treatment D
(
tablet administered with rabeprazole) is the Test Treatment (this analysis will only 
include data from Treatments A and D). For the
tablet formulation, Treatment B 
(
tablet) is the Reference Treatment while Treatment E (
tablet administered 
with rabeprazole) is the Test Treatment (this analysis will only include data from Treatments 
B and E).
9.3.2. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BPs, pulse rates, and safety laboratory test data will be reviewed and 
summarized on an ongoing basis during the study to evaluate the safety of participants. Any 
clinical laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will 
be described. Safety data will be presented in tabular and/or graphical format and 
summarized descriptively, where appropriate.
Medical history and physical examination information, as applicable, collected during the 
course of the study, will be considered source data and will not be required to be reported, 
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unless otherwise noted. However, any untoward findings identified on physical examinations
conducted during the active collection period will be captured as AEs, if those findings meet 
the definition of an AE. Data collected at screening that are used for inclusion/exclusion 
criteria, such as laboratory test data, ECGs, and vital signs, will be considered source data, 
and will not be required to be reported, unless otherwise noted. Demographic data collected 
at screening will be reported.
9.3.3. Other Analyses
9.3.3.1. Retained Research Sample Analyses
Pharmacogenomic or biomarker data from Retained Research Samples may be collected 
during or after the trial and retained for future analyses; the results of such analyses are not 
planned to be included in the CSR.
9.4. Interim Analyses
No interim analysis will be conducted for this study. As this is an open-label study, the
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, and/or supporting clinical development.
9.5. Sample Size Determination
A sufficient number of participants will be screened to ensure that at least 18 participants are 
enrolled in the study.
The sample size is empirically selected and is not based on statistical power calculation.
For the comparison of the 2 new encorafenib tablet formulations to the commercially 
available CAP, a sample size of 18 PK evaluable participants will provide 90% CIs for the 
difference between treatments of ±0.1213 and ±0.1343 on the natural log scale for AUCinf
and Cmax, respectively, with 80% coverage probability. Table 8 presents the width of 90% CI 
for different estimated effects.
Table 8.
Confidence Interval Estimation of PK Endpoints for Bioavailability
Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
AUCinf
50%
70%
80%
90%
100%
110%
120%
130%
150%
0.4429, 0.5645
0.6200, 0.7903
0.7086, 0.9032
0.7972, 1.0161
0.8857, 1.1290
0.9743, 1.2419
1.0629, 1.3548
1.1515, 1.4677
1.3286, 1.6935
0.1216
0.1703
0.1946
0.2189
0.2433
0.2676
0.2919
0.3162
0.3649
Cmax
50%
70%
80%
90%
0.4371, 0.5719
0.6120, 0.8006
0.6994, 0.9150
0.7869, 1.0294
0.1347
0.1886
0.2156
0.2425
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Table 8.
Confidence Interval Estimation of PK Endpoints for Bioavailability
Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
100%
110%
120%
130%
150%
0.8743, 1.1438
0.9617, 1.2582
1.0492, 1.3725
1.1366, 1.4869
1.3114, 1.7157
0.2695
0.2964
0.3234
0.3503
0.4042
For the potential effect of PPI, a sample size of 9 PK evaluable participants will provide 90% 
CIs for the difference between treatments of ±0.2017 and ±0.2234 on the natural log scale for 
AUCinf and Cmax, respectively, with 80% coverage probability. Table 9 presents the width of 
90% CI for different estimated effects.
Table 9.
Confidence Interval Estimation of PK Endpoints for PPI Effect
Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
AUCinf
50%
70%
80%
90%
100%
110%
120%
130%
150%
0.4087, 0.6118
0.5721, 0.8565
0.6538, 0.9788
0.7356, 1.1012
0.8173, 1.2235
0.8990, 1.3459
0.9808, 1.4682
1.0625, 1.5906
1.2260, 1.8353
0.2031
0.2844
0.3250
0.3656
0.4062
0.4469
0.4875
0.5281
0.6093
Cmax
50%
70%
80%
90%
100%
110%
120%
130%
150%
0.3999, 0.6251
0.5599, 0.8752
0.6399, 1.0002
0.7198, 1.1252
0.7998, 1.2503
0.8798, 1.3753
0.9598, 1.5003
1.0398, 1.6254
1.1997, 1.8754
0.2252
0.3153
0.3604
0.4054
0.4504
0.4955
0.5405
0.5856
0.6757
These calculations are based on estimates of within-participant standard deviation of 0.196
and 0.217 encorafenib for loge AUCinf and loge Cmax respectively, based on the results from
crossover studies ARRAY-818-105 and ARRAY-162-105.
9.6. Data Monitoring Committee
This study will not use a data monitoring committee (DMC).
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
•
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;
•
Applicable ICH GCP guidelines;
•
Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:
•
Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;
•
Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;
•
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.  
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant should be given sufficient time and opportunity to ask questions and to 
decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each participant is fully informed about the nature and 
objectives of the study, the sharing of data related to the study, and possible risks associated 
with participation, including the risks associated with the processing of the participant’s 
personal data. 
The participant must be informed that their 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 participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about their
right to access and correct their personal data and to withdraw consent for the processing of 
their personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulations.
A copy of the ICD(s) must be provided to the participant.
Participants who are rescreened are required to sign a new ICD.
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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant -specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant -specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems.
10.1.4. Committees Structure
10.1.4.1. Data Monitoring Committee 
This study will not use an E-DMC.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
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Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Participant -level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
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.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
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The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR.
The investigator must permit study-related monitoring, audits, IRB/EC review, and
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, 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, virtual, or on-site monitoring), are provided in the data management plan and IQMP
maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 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 the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
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10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are 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.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor’s designee (Pfizer CRU).
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor’s designee (Pfizer CRU).
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor 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, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. 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 upon notification to the sponsor
if requested to do so by the responsible IRB/EC or if such termination is required to protect 
the health of study participants.
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Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:
•
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines;
•
Inadequate recruitment of participants by the investigator;
•
Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications, 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 30 
days before submission. This allows the sponsor to protect proprietary information and to 
provide comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results. 
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors. 
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
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If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Medically Qualified Individual
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the CTMS. 
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy healthcare professionals, participants are provided with 
an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol and 
study intervention identifiers, (b) participant’s study identification number, and (c) site 
emergency phone number active 24 hours/day, 7 days per week.
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. 
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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.
Table 10.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV 
MCH 
MCHC
Platelet count
WBC count
Neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen 
Urine bilirubin
Laboratory:
Microscopy a
•
COVID-19 PCR testing
•
Urine drug screeningc
•
Urine cotinine
•
eGFR (calculated using 
CKD-EPI equation)
At screening only:
•
FSHb
•
Hepatitis B surface 
antigen
•
Hepatitis B core antibody
•
Hepatitis C antibody
•
Human 
immunodeficiency virus
a.
Only if UTI is suspected and urine dipstick is positive for nitrites or leukocyte esterase or both.
b.
For confirmation of postmenopausal status only.
c.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific).
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition
•
An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal laboratory test results that meet any of the conditions below must be 
recorded as an AE:
•
Is associated with accompanying symptoms;
•
Requires additional diagnostic testing or medical/surgical intervention;
•
Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.
•
Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition.
•
New condition detected or diagnosed after study intervention administration,
even though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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Events NOT Meeting the AE Definition
•
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
•
The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
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d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic 
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:
•
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.
•
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
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It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must 
be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/SAEs associated 
with EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)**
Environmental or 
occupational exposure 
to the product under 
study to a 
nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
non-participant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to 
Pfizer Safety using the CT SAE Report Form and EDP Supplemental Form; if the EDP is 
associated with an SAE, then the SAE is reported to Pfizer Safety using the CT SAE Report 
Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, which would also include 
details of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form. 
•
When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.
•
The investigator will then record all relevant AE or SAE information in the CRF.
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•
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.
•
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
•
Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention.  The event does not generally interfere with 
usual ADL.
•
Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant.
•
Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.
•
A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.
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•
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.
•
The investigator will also consult the IB and/or product information, for 
marketed products, in their assessment.
•
For each AE or SAE, the investigator must document in the medical notes that 
they have reviewed the AE or SAE and have provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor.
•
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
•
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
•
If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
Follow-Up of AEs and SAEs
•
The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.
•
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.
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•
New or updated information will be recorded in the originally submitted 
documents.
•
The investigator will submit any updated SAE data to the sponsor within 24 
hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT
•
The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT.
•
If the electronic system is unavailable, then the site will use the paper SAE DCT
(see next section) to report the event within 24 hours.
•
The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.
•
After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic DCT has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via the CT SAE Report Form
•
Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.
•
In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 
•
Refrain from donating sperm.
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
OR
•
Must agree to use contraception/barrier as detailed below:
•
Agree to use a male condom, and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception (refer to the list 
of highly effective methods below in Section 10.4.4), as a condom may break or 
leak, when having sexual intercourse with a WOCBP who is not currently 
pregnant.
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she:
is not pregnant or breastfeeding and at least 1 of the following conditions applies:
•
Is not pregnant or breastfeeding
•
Is not a WOCBP (see definitions below in Section 10.4.3).
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:
•
Documented hysterectomy;
•
Documented bilateral salpingectomy;
•
Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied 
to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2. Postmenopausal female.
•
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:
•
A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 
•
A female on HRT and whose menopausal status is in doubt will be required to 
use one of the highly effective nonestrogen hormonal contraception methods 
if she wishes to continue her HRT during the study. Otherwise, she must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or female partners of male participants should be consistent with 
local availability/regulations regarding the use of contraceptive methods for those 
participating in clinical trials.
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The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner.
•
Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:
•
Oral + barrier*
•
Intravaginal + barrier*
•
Transdermal + barrier*
7. Progestogen-only hormone contraception associated with inhibition of ovulation:
•
Oral + barrier*
•
Injectable + barrier*
8. Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be evaluated 
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in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following:
•
Male or female condom with or without spermicide;
•
Cervical cap, diaphragm, or sponge with spermicide;
•
A combination of male condom with either cervical cap, diaphragm, or sponge 
with spermicide (double-barrier methods).
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10.5. Appendix 5: Genetics
Use/Analysis of DNA
•
Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.
•
The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.
•
The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to encorafenib or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.
•
The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.
•
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
•
The samples will be retained as indicated:
•
Retained samples will be stored indefinitely or for another period as per local 
requirements.  
•
Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed. Data already generated from the samples will be 
retained to protect the integrity of existing analyses.  
•
Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site.
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10.6. Appendix 6: 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 participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili 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 T bili 
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 
participant’s individual baseline values and underlying conditions. Participants 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:
•
Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value ≥2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available.
•
For participants with baseline AST OR ALT OR T bili 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 T bili above the normal range: T bili level increased from 
baseline value by an amount of  ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
Rises in AST/ALT and T bili 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 participant 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 T bili for suspected Hy’s law 
cases, 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. 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, or 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, liver imaging (eg, 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 
T bili 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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10.7. Appendix 7: Kidney Safety: Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine (Scr measurement to estimate glomerular filtration rate [Scr-based eGFR] or 
creatinine clearance [eCrCl]). Baseline and postbaseline serum Scys makes it feasible to 
distinguish AKI from other causes of Scr increase. If Scr increase is confirmed after baseline, 
then reflex measurement of Scys is indicated to estimate the combined Scr-Scys eGFR 
calculation (for adults only).
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.7.2. Age-Specific Kidney Function Calculation Recommendations
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations10
2021 CKD-
EPI            
Scr Only
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ō 0.7
N/A
eGFR = 143 × (Scr/0.7)-0.241  ×  (0.9938)Age
Female
if > 0.7
N/A
eGFR = 143 × (Scr/0.7)-1.200  ×  (0.9938)Age
Male
if ō 0.9
N/A
eGFR = 142 × (Scr/0.9)-0.302  ×  (0.9938)Age
Male
if > 0.9
N/A
eGFR = 142 × (Scr/0.9)-1.200  ×  (0.9938)Age
2021 CKD-
EPI           
Scr-Scys 
Combined
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ō 0.7
if ō 0.8
eGFR = 130 × (Scr/0.7)-0.219  ʹ (Scys/0.8)-0.323  ʹ (0.9961)Age
Female
if ō 0.7
if > 0.8
eGFR = 130 × (Scr/0.7)-0.219  ʹ (Scys/0.8)-0.778  ʹ (0.9961)Age
Female
if > 0.7
if ō 0.8
eGFR = 130 × (Scr/0.7)-0.544  ʹ (Scys/0.8)-0.323  ʹ (0.9961)Age
Female
if > 0.7
if > 0.8
eGFR = 130 × (Scr/0.7)-0.544  ʹ (Scys/0.8)-0.778  ʹ (0.9961)Age
Male
if ō 0.9
if ō 0.8
eGFR = 135 × (Scr/0.9)-0.144  ʹ (Scys/0.8)-0.323  ʹ (0.9961)Age
Male
if ō 0.9
if > 0.8
eGFR = 135 × (Scr/0.9)-0.144  ʹ (Scys/0.8)-0.778  ʹ (0.9961)Age
Male
if > 0.9
if ō 0.8
eGFR = 135 × (Scr/0.9)-0.544  ʹ  (Scys/0.8)-0.323  ʹ (0.9961)Age
Male
if > 0.9
if > 0.8
eGFR = 135 × (Scr/0.9)-0.544  ʹ  (Scys/0.8)-0.778  ʹ (0.9961)Age
10.7.3. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO
criteria.
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10.8. Appendix 8: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs
•
Marked sinus bradycardia (rate <40 bpm) lasting minutes.
•
New PR interval prolongation >280 ms.
•
New prolongation of QTcF to >480 ms (absolute) or by ≥60 ms from baseline.
•
New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.
•
New-onset type I second-degree (Wenckebach) AV block of >30 seconds’
duration.
•
Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs
•
QTcF prolongation >500 ms.
•
New ST-T changes suggestive of myocardial ischemia.
•
New-onset LBBB (QRS complex>120 ms).
•
New-onset right bundle branch block (QRS complex>120 ms).
•
Symptomatic bradycardia.
•
Asystole:
•
In awake, symptom -free participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node. 
•
In awake, symptom -free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 
•
Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.
•
Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).
•
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR
<40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 
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monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as
torsades de pointes]).
•
Type II second -degree (Mobitz II) AV block.
•
Complete (third -degree) heart block.
ECG Findings That Qualify as SAEs
•
Change in pattern suggestive of new myocardial infarction.
•
Sustained ventricular tachyarrhythmias (>30 seconds’ duration).
•
Second- or third-degree AV block requiring pacemaker placement.
•
Asystolic pauses requiring pacemaker placement.
•
Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.
•
Ventricular fibrillation/flutter.
•
At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all-inclusive of what to be reported as AEs/SAEs.
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10.9. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
ADL
activity/activities of daily living
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AKI
acute kidney injury
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the curve
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from 0 to time of last 
measurable concentration
AV
atrioventricular
BA
bioavailability
BE
bioequivalence
BLQ
below the limit of quantitation
BMI
body mass index
BP
blood pressure
BRAF
B-RAF proto-oncogene, serine/threonine kinase
BRAFmt
BRAF-mutated
CAP
encorafenib formulated capsule
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease - epidemiology
CL/F
apparent clearance of drug from eg, plasma
Cmax
maximum observed concentration
CNS
central nervous system
CO2
carbon dioxide (bicarbonate)
COT
cancer osaka thyroid
COVID-19
coronavirus disease 2019
CRAF
COT and RAF-1
CRC
colorectal cancer
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
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Abbreviation
Term
CTIS
Clinical Trial Information System
CTMS
Clinical Trial Management System
CV
cardiovascular
CYP
cytochrome P450
DCT
data collection tool
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DMC
data monitoring committee
DMID
dosage material identification
DU
dispensable unit
EC
ethics committee
EC50
half-maximal response concentration
ECC
emergency contact card
ECG
electrocardiogram or electrocardiography
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EOT
end of treatment
 
 
ERK
extracellular signal-regulated kinase
eSAE
electronic serious adverse event
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
F/U
follow-up
G1 to G5
Grade (KDIGO eGFR category standardization)
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GGT
gamma-glutamyl transferase
GLP
good laboratory practice
HBcAb
hepatitis B core antibody
HbsAb
hepatitis B surface antibody
HbsAg 
hepatitis B surface antigen
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Abbreviation
Term
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HME
hot-melt extrudate
HR
heart rate
HRT
hormone replacement therapy
Ht
height
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IPAL
Investigational Product Accountability Log
IPM
investigational product manual
IR
immediate release 
IRB
Institutional Review Board
IRC
internal review committee
IV
intravenous(ly)
K
Proportionality constant for Bedside and Modified Schwartz 
Equations (kidney function)
K2EDTA
dipotassium ethylenediaminetetraacetic acid
K3EDTA
tripotassium ethylenediaminetetraacetic acid
kel
first-order elimination rate constant
KDIGO
Kidney Disease Improving Global Outcomes
LBBB
left bundle branch block
LFT
liver function test
LLNA
local lymph node assay
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
mCRC
metastatic colorectal cancer
MCV
mean corpuscular volume
MEK
mitogen-activated protein kinase
MQI
medically qualified individual
MTD
maximum tolerated dose
N/A
not applicable
Nab
neutralizing antibodies
NRU
neutral red uptake
OAT
organic anion transporter
OATP
organic anion-transporting polypeptide
OCT
organic cation transporter
PCR
polymerase chain reaction
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Abbreviation
Term
PCRU
Pfizer Clinical Research Unit
PD
pharmacodynamic(s)
pERK
phosphorylated ERK
pMEK
phosphorylated MEK
P-gp
P-glycoprotein
PI
principal investigator
PK
pharmacokinetic(s)
PPI
proton-pump inhibitor
PSSA
Pfizer’s Serious Adverse Event Submission Assistant
PT
prothrombin time
PVC
premature ventricular contraction/complex
QD
once daily
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
QTL
quality tolerance limit
qual
qualitative
RAF
rapidly accelerated fibrosarcoma
rBA
relative bioavailability
RBC
red blood cell
RNA
ribonucleic acid
SADE
serious adverse device effect
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
SCL
supply chain lead
Scr
serum creatinine
Scys
serum cystatin C
SoA
schedule of activities
SOP
standard operating procedure
SRSD
Single Reference Safety Document
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal phase half-life
T3
total triiodothyronine
TB
tuberculosis 
T bili
total bilirubin
THC
tetrahydrocannabinol
Tlast
time of the last quantifiable concentration [time]
Tmax
time to reach Cmax
TOC
table of contents
UGT
uridine 5’-diphospho-glucuronosyltransferase-
glucuronosyltransferase
ULN
upper limit of normal
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Abbreviation
Term
US
United States
USADE
unanticipated serious adverse device effect
USPI
United States Prescribing Information
UTI
urinary tract infection
Vz/F
apparent volume of distribution for extravascular dosing
WBC
white blood cell
WOCBP
woman/women of childbearing potential
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11. REFERENCES
1. Japan Guideline for Bioequivalence Studies of Generic Products.
https://www.nihs.go.jp/drug/be-guide(e)/2020/GL1_BE_2020.pdf
2. Japan Guideline for Bioequivalence Studies for Formulation Changes of Oral Solid 
Dosage Forms
https://www.nihs.go.jp/drug/be-guide(e)/form/GL-E_120229_shohou.pdf 
3. Japan Guideline for Bioequivalence Studies for Different Oral Solid Dosage Forms
https://www.nihs.go.jp/drug/be-guide(e)/GL-E_120229_zaikei.pdf
4. Li, X.Q., et al., Comparison of inhibitory effects of the proton pump-inhibiting drugs 
omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human 
cytochrome P450 activities. Drug Metab Dispos, 2004. 32(8): p. 821-7.
5. Zvyaga, T., et al., Evaluation of six proton pump inhibitors as inhibitors of various 
human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos, 2012. 
40(9): p. 1698-711.
6. Marelli, S. and F. Pace, ParietÒ for the treatment of acid-related disorders. Expert Rev 
Gastroenterol Hepatol, 2012. 6(4): p. 423-35.
7. Shi, S. and U. Klotz, Proton pump inhibitors: an update of their clinical use and 
pharmacokinetics. Eur J Clin Pharmacol, 2008. 64(10): p. 935-51.
8. Williams, M.P., et al., A placebo-controlled Study to assess the effects of 7-day dosing 
with 10, 20 and 40 mg rabeprazole on 24-h intragastric acidity and plasma gastrin in 
healthy male subjects. Aliment Pharmacol Ther, 2000. 14(6): p. 691-9.
9. Hayato, S., et al., Dose-response relationships of rabeprazole 5, 10, 20, and 40 mg once 
daily on suppression of gastric acid secretion through the night in healthy Japanese 
individuals with different CYP2C19 genotypes. Eur J Clin Pharmacol, 2012. 68(5): p. 
579-88.
10. Inker LA et al. N Engl J Med. 2021;385:1737-49.
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Protocol C4221024
A Phase 1, Randomized, Open-Label Study in Healthy Participants to 
Estimate the Bioavailability of two new Encorafenib Formulations Relative to 
the Current Formulation and to Evaluate the Effect of a Proton-Pump 
Inhibitor on Encorafenib Plasma Pharmacokinetics
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
04 Jul 2022
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Modifications to the Analysis Plan Described in the Protocol..................................4
2.2. Study Objectives, Endpoints, and Estimands............................................................4
2.3. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoints.....................................................................................................7
3.2. Secondary Endpoints.................................................................................................8
3.3. Other Endpoint(s)......................................................................................................8
3.4. Baseline Variables.....................................................................................................8
3.5. Safety Endpoints .......................................................................................................8
3.5.1. Adverse Events.............................................................................................8
3.5.2. Laboratory Data............................................................................................8
3.5.3. Vital Signs ....................................................................................................9
3.5.4. Electrocardiograms.......................................................................................9
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.2.1. Analyses for Binary/Categorical Endpoints ...............................................10
5.2.2. Analyses for Continuous Endpoints ...........................................................10
5.3. Methods to Manage Missing Data ..........................................................................11
5.3.1. Pharmacokinetic Data.................................................................................11
5.3.2. Safety Data..................................................................................................11
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Primary Endpoints...................................................................................................12
6.2. Secondary Endpoints...............................................................................................12
6.3. Subset Analyses.......................................................................................................14
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6.4. Baseline and Other Summaries and Analyses.........................................................14
6.4.1. Demographic Summaries............................................................................14
6.4.2. Study Conduct and Participant Disposition................................................14
6.4.3. Study Treatment Exposure .........................................................................14
6.4.4. Concomitant Medications and Nondrug Treatments..................................14
6.5. Safety Summaries and Analyses .............................................................................14
6.5.1. Adverse Events...........................................................................................14
6.5.2. Laboratory Data..........................................................................................15
6.5.3. Vital Signs ..................................................................................................15
6.5.4. Electrocardiograms.....................................................................................15
7. INTERIM ANALYSES.......................................................................................................15
7.1. Introduction .............................................................................................................15
7.2. Interim Analyses and Summaries............................................................................15
APPENDICES .........................................................................................................................16
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................4
Table 2.
Trial Design ................................................................................................5
Table 3.
Definitions of PK Parameters.....................................................................7
Table 4.
PK Parameters to be Summarized Descriptively by Treatment ...............13
APPENDICES
Appendix 1. Summary of Analyses .........................................................................................16
Appendix 2. SAS Code for Analyses.......................................................................................17
Appendix 3. List of Abbreviations...........................................................................................19
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NOTE: Italicized text within this document has been taken verbatim from the Protocol.
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
04 Jul 2022
Original 
05 May 2022
N/A
N/A
2. INTRODUCTION
Encorafenib is a kinase inhibitor indicated, in combination with binimetinib, for the 
treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or 
V600K mutation, as detected by an FDA-approved test, or in combination with cetuximab, 
for the treatment of patients with mCRC with a BRAF V600E mutation, as detected by an 
FDA approved test, after prior therapy.
Formulated drug product containing encorafenib is currently available as a 75-mg size 
double zero capsule for commercial uses. At the approved dose for metastatic melanoma 
(450 mg QD), patients are required to swallow 6 capsules each day within a short period of 
time. The capsule burden and challenge for many patients to consistently ingest six double-
zero capsules has been noted during clinical development and subsequently post-
commercialization. Patients have often requested the option to open the capsules because 
they are too large to swallow. 
In order to decrease the size of the current formulated encorafenib capsule and improve the 
physical stability, 2 new encorafenib tablet formulations have been developed. This study is 
intended to select the optimal tablet formulation for commercialization based on the 
pharmacokinetics. In addition, the present dissolution data does not provide enough 
confidence to exclude the achlorhydric population (PPI effect) from the rBA study. Because 
of this difference, a preliminary assessment of the effect of a proton-pump inhibitor on the 
pharmacokinetics of the 2 encorafenib tablet formulations will also be conducted to assist in 
the formulation selection.
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C4221024.  
2.1. Modifications to the Analysis Plan Described in the Protocol
Not applicable.
2.2. Study Objectives, Endpoints, and Estimands
The following are the objectives and endpoints in this study. Estimand framework will not 
be applied to this Phase 1 study in healthy participants.
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Objectives
Endpoints
Primary: 
Primary: 
To estimate the relative BA of 2 new 
encorafenib 75-mg tablet formulations 
(eMCC and eMCCL) to the commercially 
available encorafenib formulated capsule 
(CAP) administered under fasted conditions 
to adult healthy participants.
Plasma AUCinf, AUClast and Cmax for 
encorafenib (alone and with 
rabeprazole).
Secondary: 
Secondary: 
To assess the safety and tolerability of the 3 
formulations (eMCC, eMCCL and CAP) 
encorafenib 75-mg, when given alone and 
in combination with rabeprazole in adult 
healthy participants.
To estimate the effect of rabeprazole on the 
PK of eMCC and eMCCL.
Overall safety profile as characterized 
by laboratory tests, vital signs, ECGs, 
and adverse events.
Other plasma PK parameters for 
encorafenib (alone and with 
rabeprazole): Tmax, t1/2, CL/F, and Vz/F, 
if possible.
2.3. Study Design
This study will be an open-label, randomized, 4-period, 6-sequence study in adult healthy 
participants.
Periods 1 through 3 will estimate the relative bioavailability of the 2 new encorafenib tablet 
formulations (eMCC and eMCCL) compared to the commercially available CAP formulation 
using a 75-mg encorafenib single dose administered under fasted condition. Period 4 will 
explore the potential effect of a PPI (rabeprazole) on the PK of encorafenib administered as
the eMCC and eMCCL tablet formulations. Participants will receive either the eMCC or 
eMCCL formulation with rabeprazole in Period 4.
Participants will be randomized into 1 of 6 treatment sequences as outlined in Table 2.
Approximately 18 participants will be enrolled into the study. The total duration of the study 
will be approximately 90 days including screening.
Table 2.
Trial Design 
Treatment 
Sequence
Period 1
Washout
Period 2
Washout
Period 3
Washout
Period 4
1 (N=3)
A
At least 
5 day 
washouta
B
At least 
5 day 
washouta
C
At least 
5 day 
washouta
D
2 (N=3)
A
C
B
E
3 (N=3)
B
C
A
D
4 (N=3)
B
A
C
E
5 (N=3)
C
A
B
D
6 (N=3)
C
B
A
E
a. between successive encorafenib doses.
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Treatments:

Treatment A (Test 1 for BA evaluation, Reference 1 for PPI effect): A single 75 mg 
encorafenib dose as the eMCC formulation will be administered on the morning of Day 1 
after an overnight fast of at least 10 hours.

Treatment B (Test 2 for BA evaluation, Reference 2 PPI effect): A single 75 mg 
encorafenib dose as the eMCCL formulation will be administered on the morning of Day 
1 after an overnight fast of at least 10 hours.

Treatment C (Reference for BA evaluation): A single 75 mg encorafenib dose as CAP 
formulation will be administered on the morning of Day 1 after an overnight fast of at 
least 10 hours.

Treatment D (Test 1 for PPI evaluation): 20 mg rabeprazole will be administered 
approximately 1 hour prior to dinner on Day -5 through Day -1 and staggered with a
single 75 mg encorafenib dose as eMCC formulation will be administered on the morning 
of Day 1 after an overnight fast of at least 10 hours.

Treatment E (Test 2 for PPI evaluation): 20 mg rabeprazole will be administered 
approximately 1 hour prior to dinner on Day -5 through Day -1 and staggered with a 
single 75 mg encorafenib dose as eMCCL formulation will be administered on the 
morning of Day 1 after an overnight fast of at least 10 hours.
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
The primary endpoints of the study are plasma AUCinf (if data permits), AUClast and Cmax for 
encorafenib (alone) under fasted conditions following administration of tablet (eMCC and 
eMCCL) and capsule (CAP) formulations. Ratios of AUCinf, AUClast and Cmax of encorafenib
administered as eMCC and eMCCL relative to CAP will be derived.
Encorafenib PK parameters following a single dose administration will be derived from the 
encorafenib plasma concentration versus time profiles using non-compartmental methods as 
data permit. The PK parameters to be assessed in this study, their definition, and method of 
determination are outlined in Table 3. Actual PK sampling times will be used in the 
derivation of PK parameters whenever possible. In the case that actual PK sampling times 
are not available, nominal PK sampling time will be used in the derivation of PK 
parameters.
Table 3.
Definitions of PK Parameters 
Parameter
Definition
Method of Determination
AUClast
Area under the plasma concentration-
time profile from time zero to the time of 
the last quantifiable concentration (Clast)
Linear-log trapezoidal method.
AUCinfa
Area under the plasma concentration-
time profile from time zero extrapolated 
to infinite time
AUClast + (Clast/kel),
where Clast is the predicted 
plasma concentration at the last 
quantifiable time point and kel is 
the elimination rate constant 
estimated from the log-linear 
regression analysis.
Cmax
Maximum plasma concentration
Observed directly from the data.
Tmax
Time for Cmax
Observed directly from the data 
as time of first occurrence.
t½a
Terminal plasma elimination half-life
Loge(2)/kel,
Only those data points judged to 
describe the terminal log-linear 
decline will be used in the 
regression.
CL/Fa
Apparent clearance after oral dose
Dose/AUCinf after oral dose.
Vz/Fa
Apparent volume of distribution after oral 
dosing
Dose/(AUCinf • kel) after oral 
dose.
Tlast
The time for Clast
Observed directly from the data.
a.  As data permits
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3.2. Secondary Endpoints
The secondary endpoint of the study is the overall safety profile of the 3 formulations 
(eMCC, eMCCL and CAP) of encorafenib when given alone and in combination with 
rabeprazole, as characterized by laboratory tests, vital signs, ECGs, and adverse events
(discussed in Section 3.5).
Other secondary endpoints include additional plasma PK parameters (including Tmax, t1/2, 
CL/F, and Vz/F, defined in Table 3) for encorafenib (alone and with rabeprazole) and the 
ratios of AUCinf, AUClast and Cmax of encorafenib (alone) relative to encorafenib (with 
rabeprazole) following administration of the eMCC and eMCCL formulations.
3.3. Other Endpoint(s)
None.
3.4. Baseline Variables
Baseline characteristics will be collected according to the schedule of activities (SoA) as 
specified in the protocol. 
3.5. Safety Endpoints
The following data will be considered in standard safety summaries (see protocol for 
collection days, baseline assessment, and list of parameters):

Adverse events (AE)

Laboratory data

Vital signs data

Electrocardiogram (ECG) results
3.5.1. Adverse Events
Any adverse events occurring following start of treatment will be considered as treatment 
emergent adverse event (TEAE). Events that occur during follow-up within the lag time of 
up to 28 days after the last encorafenib dose will be counted as treatment emergent and 
attributed to the last treatment taken. Events that occur during the washout period (up to 28 
days from the last treatment) between study periods will be counted as treatment emergent 
and attributed to the previous treatment taken. The time period for collecting AEs (“active 
collection period”) for each participant begins from the time the participant provides 
informed consent.
3.5.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol. To determine if there 
are any clinically significant laboratory abnormalities, the haematological, clinical chemistry 
(serum) and urinalysis safety tests will be assessed against the criteria specified in the 
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sponsor reporting standards. The assessment will not take into account whether each 
participants’s baseline test result is within or outside the laboratory reference range for the 
particular laboratory parameter.
For Periods 1 to 3, the baseline measurement is the predose measurement on Day -1 of each 
period. For Period 4, the baseline measurement is the predose measurement on Day -1 of 
Period 3.
3.5.3. Vital Signs
Supine blood pressure (BP) and pulse rate (PR) will be measured at times specified in the 
SoA given in the protocol.
For each period, the baseline measurement is the predose measurement on Day 1. Changes 
from baseline will be defined as the change between the postdose and baseline 
measurements.
3.5.4. Electrocardiograms
QT interval, QTcF, PR, QRS and heart rate (HR) will be recorded at each assessment time 
indicated in the SoA given in the protocol. If not supplied, QTcF will be derived using 
Fridericia’s heart rate correction formula:
QTcF = QT / (RR)^(1/3) where RR = 60/HR (if not provided)
For each period, the baseline value is the average of the triplicate ECG measurements 
collected before dose administration on Day 1. Changes from baseline will be defined as the 
change between the postdose ECG measurement and the derived baseline ECG.
The maximum absolute value (postdose) and the maximum increase from baseline for QTcF, 
PR and QRS, over all measurements taken postdose, will be determined.
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each postdose measurement to give the change from baseline. The maximum of 
these values over the respective period will then be selected, except in the case where a 
participant does not show an increase. In such an instance, the minimum decrease should be 
taken.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures.
Participant Analysis Set
Description
Enrolled 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
screening. A participant will be considered enrolled if the 
informed consent is not withdrawn prior to participating in 
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Participant Analysis Set
Description
any study activity after screening. Potential participants who 
are screened for the purpose of determining eligibility for the 
study, but do not participate in the study, are not considered 
enrolled, unless otherwise specified by the protocol.
Safety Analysis Set
All participants randomly assigned to a treatment sequence 
and who take at least 1 dose of encorafenib. Participants will 
be analyzed according to the formulation they actually 
received.
PK Concentration 
Population
The PK concentration population is defined as all 
participants randomized and treated who have at least 1 
encorafenib concentration in at least 1 period.
PK Parameter Analysis 
Population
The PK parameter analysis population is defined as all 
participants randomized and treated who have at least 1 of 
the encorafenib plasma PK parameters of primary interest in 
at least 1 treatment period.
5. GENERAL METHODOLOGY AND CONVENTIONS
Final analysis will be performed after study participant data set release following last 
participant last visit.
5.1. Hypotheses and Decision Rules
No statistical hypothesis will be tested in this study.
5.2. General Methods
5.2.1. Analyses for Binary/Categorical Endpoints
For binary or categorical variables, number of participants, numbers and percentages of 
participants meeting the categorical criteria will be presented in accordance with the Clinical 
Data Interchange Standards Consortium and Pfizer Standards (CaPS).
5.2.2. Analyses for Continuous Endpoints
For continuous variables, the data will be summarized using the number of participants, 
mean, median, standard deviation (SD), minimum, and maximum in accordance with the 
CaPS. For appropriate PK parameters, geometric mean and geometric coefficient of variation 
(%CV) will also be summarized.
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5.3. Methods to Manage Missing Data
5.3.1. Pharmacokinetic Data
Methods to handle missing PK data are described below. 
Concentrations Below the Limit of Quantification:
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.).
Deviations, Missing Concentrations and Anomalous Values:
In summary tables and plots of median profiles, statistics will be calculated having set
concentrations to missing if one of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample).
2. A deviation in sampling time is of sufficient concern or a concentration has been
flagged as anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 
participants. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst or pharmacokineticist.
PK Parameters:
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter 
cannot be derived from a participant’s concentration data, the parameter will be coded as NC 
(ie, not calculated). (Note that NC values will not be generated beyond the day that a 
participant discontinues). In summary tables, statistics will be calculated by setting NC 
values to missing; and statistics will be presented for a particular dose with ≥3 evaluable
measurements.
If an individual participant has a known biased estimate of a PK parameter (due for example 
to an unexpected event such as vomiting before all the compound is adequately absorbed 
from the gastrointestinal tract), this will be footnoted in summary tables and will not be 
included in the calculation of summary statistics or statistical analyses.
5.3.2. Safety Data
Missing values in standard summaries of AEs, laboratory data, vital signs, and ECGs will be 
imputed according to CaPS.
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6. ANALYSES AND SUMMARIES
6.1. Primary Endpoints
For assessment of the primary objectives of the study, natural log transformed encorafenib 
AUCinf (if data permit), AUClast and Cmax will be analyzed using a mixed effect model with 
sequence, period and treatment as fixed effects and participant within sequence as a random 
effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% 
CIs will be obtained from the model. The adjusted mean differences and 90% CIs for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% CIs for the ratios. Treatment C (encorafenib CAP) is the 
Reference Treatment while Treatments A and B (eMCC and eMCCL tablet formulations) are 
the Test Treatments. This analysis will include only data from Treatments A, B and C.
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the CSR. If there are major deviations from 
normality or outliers then the effect of these on the conclusions will be investigated through 
alternative transformations and/or analyses excluding outliers.  Justification for any 
alternative to the planned analysis will be provided in the clinical study report.
6.2. Secondary Endpoints
Safety data:
Safety data will be analyzed in accordance with the CaPS (see Section 6.5).
PK data for evaluation of the effect of rabeprazole:
For the assessment of the effect of rabeprazole on the PK of eMCC and eMCCL formulations 
of encorafenib, natural log transformed encorafenib AUCinf (if data permit), AUClast and Cmax
will be analyzed using ANOVA with treatment and sequence as a fixed effect and subject 
within sequence as a random effect. Estimates of the adjusted mean differences (Test-
Reference) and corresponding 90% CIs will be obtained from the model. The adjusted mean 
differences and 90% CIs for the differences will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. For the 
eMCC tablet formulation, Treatment A (eMCC tablet) is the Reference Treatment while 
Treatment D (eMCC tablet administered with rabeprazole) is the Test Treatment (this 
analysis will only include data from Treatments A and D). For the eMCCL tablet 
formulation, Treatment B (eMCCL tablet) is the Reference Treatment while Treatment E 
(eMCCL tablet administered with rabeprazole) is the Test Treatment (this analysis will only 
include data from Treatments B and E).
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the CSR. If there are major deviations from 
normality or outliers then the effect of these on the conclusions will be investigated through 
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alternative transformations and/or analyses excluding outliers.  Justification for any 
alternative to the planned analysis will be given in the report of the study.
PK summaries:
The encorafenib PK parameters will be summarized descriptively by treatment group in 
accordance with Pfizer data standards for the PK Parameter Analysis Population, as data 
permit. A listing of the individual participant ratios (Test-Reference) will be provided.
Missing values will be handled as detailed in Section 5.3.1. Each encorafenib PK parameter 
will be summarized by treatment group and will include the set of summary statistics as 
specified in Table 4.
Table 4.
PK Parameters to be Summarized Descriptively by Treatment 
Parameter
Summary Statistics
AUCinf, AUClast, 
Cmax, CL/F, Vz/F
N, arithmetic mean, median, SD, %CV, minimum, maximum, 
geometric mean and geometric %CV
Tmax
N, median, minimum, maximum
t½
N, arithmetic mean, median, SD, %CV, minimum, maximum
Box and whisker plots for individual participant parameters (AUCinf, AUClast and Cmax) will 
be presented by treatment and overlaid with geometric means.
The plasma concentrations of encorafenib will be listed and descriptively summarized by 
nominal PK sampling time and treatment for the PK Concentration Population. Individual 
participant and summary profiles (mean and median plots) of the plasma concentration-time 
data will be plotted by treatment using actual and nominal times, respectively. Mean and 
median encorafenib plasma concentration profiles will be presented on both linear and semi-
log scales. 
Presentations for encorafenib plasma concentrations will include:

A listing of all concentrations sorted by participant ID, treatment and nominal time
postdose. The concentration listing will also include the actual times. Deviations from the 
nominal time will be provided in a separate listing.

A summary of concentrations by treatment and nominal time postdose, where the set of 
statistics will include n, mean, median, SD, %CV, minimum, maximum and the number 
of concentrations above the LLQ.

Median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose).
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
Mean concentrations time plots (on both linear and semi-log scales) against nominal time 
postdose by treatment (all treatments on the same plot per scale, based on the summary of 
concentrations by treatment and time postdose).

Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment per 
scale).

Individual concentration time plots by participant (on both linear and semi-log scales)
against actual time postdose [there will be separate plots for each participant (containing
all treatments) per scale].
6.3. Subset Analyses
There are no planned subset analyses.
6.4. Baseline and Other Summaries and Analyses
6.4.1. Demographic Summaries
Demographic characteristics will be summarized for enrolled population in accordance with 
the CaPS.
6.4.2. Study Conduct and Participant Disposition
Participants evaluation groups will show end of study participant disposition. Frequency 
counts will be supplied for participant discontinuation(s) by treatment. Data will be reported 
in accordance with the CaPS.
6.4.3. Study Treatment Exposure
Study treatment exposure will be listed.
6.4.4. Concomitant Medications and Nondrug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be reported in the 
listings.
6.5. Safety Summaries and Analyses
All safety analyses will be performed on the Safety Analysis Set.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
6.5.1. Adverse Events
Adverse events will be reported in accordance with the CaPS.
Participant discontinuations due to adverse events will be detailed by treatment. Data will be 
reported in accordance with the CaPS.
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6.5.2. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the CaPS.
6.5.3. Vital Signs
Vital signs data will be listed and summarized by treatment in accordance with the CaPS.
6.5.4. Electrocardiograms
ECG data will be databased and available upon request.
7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study. As this is an open-label study,
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK modeling, and/or supporting clinical 
development.
7.1. Introduction
Not applicable.
7.2. Interim Analyses and Summaries
Available safety and PK data may be reviewed.
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APPENDICES
Appendix 1. Summary of Analyses
Endpoint
Population
Data Inclusion and Rules 
for Handling Intercurrent 
Events and Missing Data 
Analysis 
Method
Ratio of encorafenib 
AUCinf, AUClast, Cmax
PK Parameter 
Analysis 
Population
Observed data
Mixed effect 
ANOVA 
model
Encorafenib PK 
parameters
PK Parameter 
Analysis 
Population
Observed data
Descriptive 
statistics
Encorafenib PK 
concentrations
PK Concentration 
Population
Observed and imputed 
(Section 5.3.1) data
Descriptive 
statistics
Safety data
Safety analysis 
set
Observed and imputed 
(Section 5.3.2) data 
Descriptive 
statistics
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Appendix 2. SAS Code for Analyses
An example of the PROC MIXED code is provided below:
For primary objectives:

Treatment A (Test) vs Treatment C (Reference)

Treatment B (Test) vs Treatment C (Reference)
proc mixed data=tab.pk;
where trt in (“A”, “B”, “C”);
class seq period trt participant;
model l&var=seq period trt/ ddfm=KR;
random participant(seq) /participant=participant(seq);
lsmeans trt;
estimate 'A vs C' trt 1  0  -1  /cl alpha=0.1;
estimate 'B vs C' trt 0  1  -1 /cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows
A: 75 mg encorafenib dose as eMCC formulation, fasted condition.
B: 75 mg encorafenib dose as eMCCL formulation, fasted condition.
C: 75 mg encorafenib dose as CAP formulation, fasted condition.
*/
For secondary objectives:

Treatment A (Reference) vs Treatment D (Test)
proc mixed data=tab.pk;
where trt in (“A”, “D”);
class seq trt participant;
model l&var=seq trt / ddfm=KR;
random participant(seq) / subject=participant(seq);
lsmeans trt;
estimate 'D vs A' trt -1  1 / cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
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run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows
A: 75 mg encorafenib dose as eMCC formulation, fasted condition.
D: 20 mg rabeprazole with coadministered of 75 mg encorafenib dose as eMCC formulation, 
fasted condition.
*/

Treatment B (Reference) vs Treatment E (Test)
proc mixed data=tab.pk;
where trt in (“B”, “E”);
class seq trt participant;
model l&var=seq trt / ddfm=KR;
random participant(seq) / subject=participant(seq);
lsmeans trt;
estimate 'E vs B' trt -1  1 / cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows
B: 75 mg encorafenib dose as eMCCL formulation, fasted condition.
E: 20 mg rabeprazole with staggered coadministered of 75 mg encorafenib dose as eMCCL 
formulation, fasted condition.
*/
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Appendix 3. List of Abbreviations
Abbreviation
Term
AE
adverse event
ANOVA
analysis of variance
AUCinf
area under the plasma concentration-time profile from time zero 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time zero to 
the time of the last quantifiable concentration
BA
Bioavailability
BLQ
below the limit of quantitation
BP
blood pressure
CAP
capsule formulation
CaPS
Clinical Data Interchange Standards Consortium and Pfizer 
Standards
CI
confidence interval
CL/F
apparent clearance
Clast
predicted plasma concentration at the last quantifiable time point 
from the log-linear regression analysis
Cmax
maximum plasma concentration
CSR
clinical study report
%CV
coefficient of variation
ECG
Electrocardiogram
eMCC
Immediate-release tablet formulated with MCC as the single 
extragranular diluent
eMCCL
Immediate-release tablet formulated with both MCC and lactose as 
extragranular diluents
HR
Heart rate
kel
the terminal phase rate constant calculated by a linear regression of 
the loglinear concentration-time curve
LLQ
lower limit of quantitation
N/A
not applicable
NC
not calculated
ND
not done
NS
no sample
PK
pharmacokinetic(s)
PPI
proton-pump inhibitor
PR
pulse rate
QRS
Combination of Q-, R- and S- wave on an electrocardiogram 
representing ventricular depolarization
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
rBA
relative bioavailability
RR
respiratory rate
SAP
statistical analysis plan
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Abbreviation
Term
SD
standard deviation
SoA
schedule of activities
t1/2
terminal plasma elimination half-life
TEAE
treatment emergent adverse event
Tlast
the time for Clast
Tmax
time to Cmax
Vz/F
apparent volume of distribution for extravascular dosing
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