A Phase 3 Study of MK-4280A (Coformulated Favezelimab [MK-4280] Plus Pembrolizumab [MK-3475]) Versus Standard of Care in Previously Treated Metastatic PD-L1 Positive Colorectal Cancer (KEYFORM-007)
Phase: PHASE3
Conditions: Colorectal Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
NCT05064059
A Phase 3 study of MK-4280A (coformulated 
favezelimab [MK-4280] plus pembrolizumab 
[MK-3475]) Versus Standard of Care in 
Previously Treated Metastatic PD-L1 positive 
Colorectal Cancer (KEYFORM-007)
22-MAY-2023

PRODUCT: MK-4280A
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 study of MK-4280A (coformulated favezelimab [MK-4280] plus 
pembrolizumab [MK-3475]) Versus Standard of Care in Previously Treated Metastatic 
PD-L1 positive Colorectal Cancer (KEYFORM-007)
Protocol Number: 007-04
Compound Number: MK-4280A
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
Not applicable
EU CT
Not applicable
EudraCT
2021-001309-60
JRCT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
147726
Approval Date: 22 May 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 4
22-MAY-2023
This amendment was completed to address 
new data that emerged from external studies. 
 
 
 
 
 
Amendment 3
18-AUG-2022
This amendment was completed in response 
to Health Authority requests and to clarify 
information.
Amendment 2
17-SEP-2021
This amendment was completed to adjust 
inclusion and exclusion criteria.
Amendment 1
23-JUL-2021
This amendment was completed in response 
to FDA comments.
Original Protocol
14-JUN-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendment:
The main reason for amendment is to address new data that emerged from external studies. 
 
 
Summary of Changes Table
Section Number and 
Name
Description of Change
Brief Rationale
Primary Reason for Amendment
9 Statistical Analysis 
Plan
The SAP has been updated
 
 
This change was made to address new data 
that emerged from external studies. 
 
 
 
 
Section Number and 
Name
Description of Change
Brief Rationale
Other Changes in Amendment
Throughout Document
The structure of the protocol has been 
updated.
To comply with current industry regulations 
and guidelines. This restructuring does not 
affect the clinical or regulatory integrity of 
the protocol. All other relevant changes and 
their primary reasons are included for 
completeness.
Title Page
1.1 Synopsis
Added KEYFORM-007 to protocol title and 
acronym.
Revision to study branding.
2.3 Benefit/Risk 
Assessment
Language modified to explain that toxicity is 
caused by chemotherapy in previously 
treated mCRC.
To clarify the cause of toxicity.
4.2.1.1 Efficacy
Endpoints
Added a reference 
To incorporate recent study information
 
9.1 
 
 
 
.
 
 
  
 
 
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Section Number and 
Name
Description of Change
Brief Rationale
Throughout Document
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation 
of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities...........................................................................................21
1.3.1
Arm A (MK-4280A)....................................................................................21
1.3.2
Arm B (Regorafenib)...................................................................................29
1.3.3
Arm B (TAS-102)........................................................................................38
2
INTRODUCTION..........................................................................................................49
2.1
Study Rationale....................................................................................................50
2.2
Background ..........................................................................................................53
2.2.1
Pharmaceutical and Therapeutic Background .............................................54
2.2.1.1
Pembrolizumab Pharmaceutical and Therapeutic Background .........54
2.2.1.2
Favezelimab Pharmaceutical and Therapeutic Background..............55
2.2.2
Preclinical and Clinical Studies ...................................................................56
2.2.3
Ongoing Clinical Studies.............................................................................56
2.2.3.1
Ongoing Pembrolizumab Clinical Studies.........................................56
2.2.3.2
Ongoing Favezelimab Clinical Studies..............................................57
2.2.4
Information on Other Study-related Therapy ..............................................57
2.3
Benefit/Risk Assessment......................................................................................58
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................59
4
STUDY DESIGN............................................................................................................61
4.1
Overall Design......................................................................................................61
4.2
Scientific Rationale for Study Design.................................................................63
4.2.1
Rationale for Endpoints ...............................................................................64
4.2.1.1
Efficacy Endpoints.............................................................................64
4.2.1.2
Safety Endpoints................................................................................64
4.2.1.3
Patient-reported Outcomes.................................................................64
4.2.1.3.1
EORTC QLQ-C30 and EORTC QLQ-CR29 ..........................65
4.2.1.3.2
EuroQoL EQ-5D-5L ................................................................65
4.2.1.4
Pharmacokinetic Endpoints ...............................................................65
4.2.1.4.1
Serum Concentrations of MK-4280A......................................66
4.2.1.4.2
Anti-Pembrolizumab and Anti-Favezelimab...........................66
4.2.1.5
Pharmacodynamic Endpoints.............................................................66
4.2.1.6
Planned Exploratory Biomarker Research.........................................66
4.2.1.7
Future Biomedical Research..............................................................68
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4.2.2
Rationale for the Use of Comparator...........................................................68
4.3
Justification for Dose...........................................................................................68
4.3.1
Justification of Favezelimab Dose...............................................................68
4.3.2
Justification of Pembrolizumab Dose..........................................................69
4.3.3
Justification of the Coformulation MK-4280A............................................70
4.3.4
Justification of Regorafenib and TAS-102 Doses .......................................70
4.4
Beginning and End-of-Study Definition ............................................................70
4.4.1
Clinical Criteria for Early Study Termination .............................................70
5
STUDY POPULATION ................................................................................................71
5.1
Inclusion Criteria.................................................................................................71
5.2
Exclusion Criteria................................................................................................75
5.3
Lifestyle Considerations......................................................................................78
5.3.1
Meals and Dietary Restrictions....................................................................78
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................78
5.3.3
Activity Restrictions ....................................................................................78
5.4
Screen Failures.....................................................................................................78
5.5
Participant Replacement Strategy......................................................................78
6
STUDY INTERVENTION............................................................................................79
6.1
Study Intervention(s) Administered...................................................................79
6.2
Preparation/Handling/Storage/Accountability .................................................81
6.2.1
Dose Preparation..........................................................................................81
6.2.1.1
MK-4280A.........................................................................................81
6.2.1.2
Regorafenib........................................................................................81
6.2.1.3
TAS-102.............................................................................................81
6.2.2
Handling, Storage, and Accountability........................................................81
6.3
Measures to Minimize Bias: Randomization and Blinding..............................82
6.3.1
Intervention Assignment..............................................................................82
6.3.2
Stratification.................................................................................................82
6.3.3
Blinding........................................................................................................82
6.4
Study Intervention Compliance..........................................................................82
6.5
Concomitant Therapy..........................................................................................83
6.5.1
Rescue Medications and Supportive Care ...................................................85
6.6
Dose Modification (Escalation/Titration/Other)...............................................85
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................85
6.7
Intervention After the End of the Study............................................................93
6.8
Clinical Supplies Disclosure................................................................................94
6.9
Standard Policies..................................................................................................94
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DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................95
7.1
Discontinuation of Study Intervention...............................................................95
7.2
Participant Withdrawal From the Study...........................................................96
7.3
Lost to Follow-up .................................................................................................96
8
STUDY ASSESSMENTS AND PROCEDURES........................................................98
8.1
Administrative and General Procedures ...........................................................98
8.1.1
Informed Consent.........................................................................................98
8.1.1.1
General Informed Consent.................................................................99
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................99
8.1.2
Inclusion/Exclusion Criteria ........................................................................99
8.1.3
Participant Identification Card.....................................................................99
8.1.4
Medical History .........................................................................................100
8.1.4.1
Colorectal Cancer History................................................................100
8.1.5
Prior and Concomitant Medications Review.............................................100
8.1.5.1
Prior Medications.............................................................................100
8.1.5.1.1
Prior Colorectal Cancer Therapy Review..............................100
8.1.5.2
Concomitant Medications................................................................100
8.1.6
Assignment of Screening Number.............................................................101
8.1.6.1
Treatment Eligibility Assessment Form ..........................................101
8.1.7
Assignment of Treatment/Randomization Number...................................101
8.1.8
Study Intervention Administration ............................................................101
8.1.8.1
Timing of Dose Administration.......................................................102
8.1.8.1.1
MK-4280A Administration (Arm A).....................................102
8.1.8.1.2
Regorafenib Administration (Arm B)....................................102
8.1.8.1.3
TAS-102 Administration (Arm B).........................................102
8.1.9
Discontinuation and Withdrawal ...............................................................102
8.1.9.1
Withdrawal From Future Biomedical Research ..............................103
8.1.10
Participant Blinding/Unblinding................................................................103
8.1.11
Calibration of Equipment...........................................................................103
8.1.12
Tumor Tissue for Biomarker Status...........................................................103
8.2
Efficacy Assessments .........................................................................................104
8.2.1
Tumor Imaging and Assessment of Disease..............................................104
8.2.1.1
Initial Tumor Scans..........................................................................105
8.2.1.2
Tumor Scans During the Study........................................................105
8.2.1.3
End-of-treatment and Follow-up Tumor Scans ...............................106
8.2.1.4
RECIST 1.1 Assessment of Disease................................................106
8.2.2
Patient-reported Outcomes.........................................................................108
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8.3
Safety Assessments.............................................................................................109
8.3.1
Physical Examinations...............................................................................109
8.3.1.1
Full Physical Examination...............................................................109
8.3.1.2
Directed Physical Examination........................................................109
8.3.2
Vital Signs..................................................................................................109
8.3.3
Electrocardiograms ....................................................................................110
8.3.4
Performance Assessments..........................................................................110
8.3.4.1
Eastern Cooperative Oncology Group Performance Status.............110
8.3.5
Clinical Safety Laboratory Assessments ...................................................110
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)........................................................................................111
8.3.6
Pregnancy Testing......................................................................................111
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................111
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................112
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....114
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.114
8.4.4
Regulatory Reporting Requirements for SAE ...........................................114
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................115
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................115
8.4.7
Events of Clinical Interest..........................................................................115
8.5
Treatment of Overdose......................................................................................116
8.6
RAS and BRAF Status.......................................................................................116
8.7
Pharmacokinetics...............................................................................................116
8.7.1
Blood Collection for MK-4280A...............................................................117
8.7.1.1
Blood Collection for PK ..................................................................117
8.7.1.2
Blood Collection for Antidrug Antibodies ......................................117
8.8
Pharmacodynamics............................................................................................117
8.9
Biomarkers .........................................................................................................117
8.9.1
Planned Genetic Analysis Sample Collection............................................118
8.10
Future Biomedical Research Sample Collection.............................................118
8.11
Medical Resource Utilization and Health Economics.....................................118
8.12
Visit Requirements.............................................................................................118
8.12.1
Screening....................................................................................................118
8.12.2
Treatment Period........................................................................................119
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ........119
8.12.4
Posttreatment Visit.....................................................................................119
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8.12.4.1
Safety Follow-up Visit.....................................................................119
8.12.4.2
Efficacy Follow-up Visits................................................................120
8.12.4.3
Survival Follow-up Contacts ...........................................................120
8.12.5
Vital Status.................................................................................................120
9
STATISTICAL ANALYSIS PLAN ...........................................................................121
9.1
Statistical Analysis Plan Summary...................................................................121
9.2
Responsibility for Analyses/In-house Blinding ...............................................122
9.3
Hypotheses/Estimation ......................................................................................122
9.4
Analysis Endpoints.............................................................................................123
9.4.1
Efficacy Endpoints.....................................................................................123
9.4.2
Safety Endpoints........................................................................................123
9.4.3
PRO Endpoints...........................................................................................123
9.5
Analysis Populations..........................................................................................124
9.5.1
Efficacy Analysis Populations...................................................................124
9.5.2
Safety Analysis Populations ......................................................................124
9.5.3
PRO Analysis Populations.........................................................................124
9.6
Statistical Methods.............................................................................................124
9.6.1
Statistical Methods for Efficacy Analyses.................................................125
9.6.1.1
Overall Survival...............................................................................125
9.6.1.2
Progression-Free Survival................................................................125
9.6.1.3
Objective Response Rate .................................................................127
9.6.1.4
Analysis Strategy for Key Efficacy Variables.................................127
9.6.2
Statistical Methods for Safety Analyses ....................................................127
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses....................129
9.6.4
Demographic and Baseline Characteristics ...............................................130
9.7
Interim Analyses ................................................................................................130
9.7.1
Efficacy Interim Analysis ..........................................................................131
9.7.2
Safety Interim Analysis..............................................................................131
9.8
Multiplicity .........................................................................................................131
9.8.1
Overall Survival.........................................................................................132
9.8.2
Progression-free Survival...........................................................................134
9.8.3
Objective Response Rate ...........................................................................135
9.8.4
Safety Analysis ..........................................................................................135
9.9
Sample Size and Power Calculations ...............................................................135
9.10
Subgroup Analyses.............................................................................................136
9.11
Compliance (Medication Adherence)...............................................................137
9.12
Extent of Exposure.............................................................................................137
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SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................138
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......138
10.1.1
Code of Conduct for Clinical Trials...........................................................138
10.1.2
Financial Disclosure...................................................................................141
10.1.3
Data Protection...........................................................................................142
10.1.3.1
Confidentiality of Data ....................................................................142
10.1.3.2
Confidentiality of Participant Records.............................................142
10.1.3.3
Confidentiality of IRB/IEC Information..........................................142
10.1.4
Committees Structure.................................................................................143
10.1.4.1
External Data Monitoring Committee .............................................143
10.1.4.2
Executive Oversight Committee......................................................143
10.1.5
Publication Policy......................................................................................143
10.1.6
Compliance with Study Registration and Results Posting Requirements .144
10.1.7
Compliance with Law, Audit, and Debarment ..........................................144
10.1.8
Data Quality Assurance .............................................................................145
10.1.9
Source Documents .....................................................................................146
10.1.10
Study and Site Closure...............................................................................146
10.2
Appendix 2: Clinical Laboratory Tests............................................................147
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................149
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................149
10.3.2
Definition of AE ........................................................................................149
10.3.3
Definition of SAE ......................................................................................150
10.3.4
Additional Events Reported.......................................................................151
10.3.5
Recording AE and SAE .............................................................................151
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................155
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................156
10.5
Appendix 5: Contraceptive Guidance..............................................................157
10.5.1
Definitions..................................................................................................157
10.5.2
Contraceptive Requirements......................................................................158
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................159
10.7
Appendix 7: Country-specific Requirements..................................................163
10.7.1
China-specific Requirements.....................................................................163
10.7.2
Czech Republic-specific Requirements .....................................................163
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10.7.3
France-specific Requirements....................................................................164
10.7.4
Germany-specific Requirements................................................................165
10.7.5
Italy-specific Requirements .......................................................................166
10.7.6
Japan-specific Requirements .....................................................................167
10.7.7
Korea-specific Requirements.....................................................................168
10.7.8
South Africa-specific Requirements..........................................................168
10.7.9
Spain-specific Requirements .....................................................................168
10.7.10
Sweden-specific Requirements..................................................................169
10.7.11
United Kingdom-specific Requirements....................................................170
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................171
10.9
Appendix 9: Eastern Cooperative Oncology Group Performance Status....172
10.10 Appendix 10: Abbreviations .............................................................................173
11
REFERENCES.............................................................................................................179
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LIST OF TABLES
Table 1
Arm A (MK-4280A)........................................................................................21
Table 2
Arm B (Regorafenib).......................................................................................29
Table 3
Arm B (TAS-102)............................................................................................38
Table 4
Adequate Organ Function Laboratory Values .................................................73
Table 5
Study Interventions..........................................................................................80
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................87
Table 7
MK-4280A Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................92
Table 8
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...............................................................................113
Table 9
Censoring Rules for Primary and Sensitivity Analyses of PFS.....................126
Table 10
Analysis Strategy for Key Efficacy Variables...............................................127
Table 11
Analysis Strategy for Safety Parameters........................................................129
Table 12
Summary of Interim and Final Analyses Strategy.........................................131
Table 13
Efficacy Boundaries and Properties for Overall Survival Analyses..............133
Table 14
Efficacy Boundaries and Properties for Progression-Free Survival 
Analysis..........................................................................................................134
Table 15
Possible α Levels and Approximate Observed ORR Difference Required 
to Demonstrate Efficacy for Objective Response at IA.................................135
Table 16
Protocol-required Safety Laboratory Assessments........................................147
Table 17
Japan-specific Trial Flow Chart.....................................................................167
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LIST OF FIGURES
Figure 1
MK-4280A-007 Study Design.........................................................................20
Figure 2
Study Intervention Decision Making Process When Progression per 
RECIST 1.1 is Observed by Investigator (PFS Endpoint).............................108
Figure 3
Multiplicity Diagram for Type I Error Control..............................................132
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 study of MK-4280A (coformulated favezelimab [MK-4280] plus 
pembrolizumab [MK-3475]) Versus Standard of Care in Previously Treated Metastatic 
PD-L1 positive Colorectal Cancer (KEYFORM-007)
Short Title: MK-4280A (coformulation pembrolizumab plus favezelimab) Versus Standard 
of Care in Previously Treated Metastatic PD-L1 positive CRC
Acronym: KEYFORM-007
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Throughout this protocol, the term response evaluation criteria in solid tumors refers to the 
adjustment of RECIST 1.1 to include a maximum of 10 target lesions and a maximum of 
5 target lesions per organ. Refer to Section 4.2.1.1 for further details.
In males and females with mCRC whose tumors are positive for PD-L1 CPS≥1, have pMMR 
status
, and have progressed on or could not tolerate prior 
line(s) of therapy for mCRC:
Primary Objective
Primary Endpoint
•
To compare MK 4280A to standard 
of care (regorafenib or TAS-102) with 
respect to overall survival.
•
Hypothesis (H1): MK-4280A is 
superior to standard of care with respect to 
overall survival.
•
Overall survival: The time from 
randomization to death due to any cause.
Secondary Objectives
Secondary Endpoints
•
To compare MK 4280A to standard 
of care with respect to progression free 
survival per RECIST 1.1 as assessed by 
BICR.
•
Hypothesis (H2): MK-4280A is 
superior to standard of care with respect to 
progression free survival per RECIST 1.1 
by BICR.
•
Progression-free survival: The time 
from randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
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•
To compare MK 4280A to standard 
of care with respect to objective response 
rate per RECIST 1.1 as assessed by BICR
•
Hypothesis (H3): MK-4280A is 
superior to standard of care with respect to 
ORR per RECIST 1.1 by BICR.
•
Objective response: complete 
response or partial response.
•
To assess the efficacy of MK-4280A 
and standard of care with respect to duration 
of response per RECIST 1.1 by BICR.
•
Duration of response: the time from 
first response (complete response or partial 
response) to subsequent disease progression 
or death from any cause, whichever occurs 
first.
•
To determine the safety and 
tolerability of MK-4280A and standard of 
care.
•
Adverse event
•
Study intervention discontinuation 
due to AEs
•
To compare the change from 
baseline in global health status/QoL, 
physical functioning, appetite loss and 
bloating for MK-4280A versus standard of 
care.
•
Score for the following Patient-
Reported Outcomes scales/items: global 
health status/QoL (EORTC QLQ-C30 items 
29 and 30), physical functioning (EORTC 
QLQ-C30 items 1-5), appetite loss (EORTC 
QLQ-C30 item 13) and bloating (EORTC 
QLQ-CR29 item 37).
•
To compare the time to deterioration 
in global health status/QoL, physical 
functioning, appetite loss and bloating for 
MK-4280A versus standard of care.
•
Time-to-deterioration, defined as the 
time from baseline to the first onset of a 
≥10-point deterioration from baseline in 
global health status/QoL (EORTC QLQ-
C30 items 29 and 30), physical functioning 
(EORTC QLQ-C30 items 1-5), appetite loss 
(EORTC QLQ-C30 item 13) and bloating 
(EORTC QLQ-CR29 item 37).
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Colon cancer stage IV
Population
Participants with metastatic colorectal 
adenocarcinoma whose tumors are positive 
for PD-L1 CPS≥1, have pMMR status 
, and have 
progressed on or could not tolerate prior 
line(s) of therapy. Participants must have 
measurable disease per RECIST 1.1 with 
Eastern Cooperative Oncology Group 
Performance Status (ECOG PS) 0-1
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Unblinded open-label
Blinding Roles
Outcomes Assessor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 36 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact. See 
country-specific requirements in 
Appendix 7.
Number of Participants:
Approximately 432 participants will be randomized. After enrollment of the global portion of 
the study is complete, the study may remain open to enrollment in China alone until the 
target number of participants from China have been enrolled to meet local regulatory 
requirements.
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Intervention Groups and Duration:
Arm 
Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm A
MK-4280A
20 mg/mL 
favezelimab + 5 
mg/mL 
pembrolizumab for 
a total protein 
content of 25 
mg/mL
800 mg MK-
4280 + 200 
mg MK-3475
IV Infusion
Day 1, then 
Q3W, up to 35 
infusions
Test 
Product
Arm B
regorafenib
40 mg/tablet
160 mg
Oral
4-week cycle: 
QD Days 1-21, 
no dose Days 
22-28
Comparator
Arm B
TAS-102
15 mg 
trifluridine/6.14 mg 
tipiracil;
20 mg 
trifluridine/8.19 mg 
tipiracil
35 mg/m2
Oral
4-week cycle: 
BID Days 1 to 
5 and 8 to 12 
of each 28-day 
treatment cycle 
(no dose days 
6, 7, and 13-
28)
Comparator
BID=twice daily; Exp=experimental; IV=intravenously; PD=progressive disease; PO=orally; Q3W=every 3 
weeks; Q4W=every 4 weeks; QD=daily.
Other current or former name(s) or alias(es) for study intervention(s) are as follows: NA.
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Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study
from the time that the participant provides 
documented informed consent through the 
final protocol-specified contact. After a 
screening phase of 28 days, each participant 
will be assigned to receive study 
intervention until one of the conditions for 
discontinuation of study intervention is met.
After the end-of-treatment, each participant 
will be followed for the occurrence of 
adverse events and spontaneously reported 
pregnancy.
Participants who discontinue for reasons 
other than radiographic disease progression 
will have posttreatment follow-up imaging 
for disease status until any of the conditions 
for discontinuation of imaging are met.
All participants will be followed for overall 
survival until death, withdrawal of consent, 
or the end of the study.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 10.
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1.2
Schema
The study design is depicted in Figure 1
Figure 1
MK-4280A-007 Study Design
CPS=combined positive score; EMEA=Europe, Middle East, Africa; FOLFIRI=folinic acid, fluorouracil, and 
irinotecan; FOLFOX=fluoropyrimidine, oxaliplatin, and irinotecan; IHC=immunohistochemistry; 
IV=intravenous; mCRC=metastatic colorectal cancer; PO=orally; PD-L1=programmed cell death ligand 1; 
pMMR=proficient mismatch repair; Q3W=every 3 weeks; Q4W=every 4 weeks; QD=daily; RECIST=Response 
Evaluation Criteria In Solid Tumors; WK=week.
a
Capecitabine is acceptable as equivalent to IV fluoropyrimidine in prior therapy.
b
Strata are 1) Geographic region (Asia Pacific; EMEA/Americas), 2) Presence of liver metastasis (Yes, No), 
and 3) Time from initial diagnosis of metastatic disease to randomization (≥18 months, <18 months).
c
TAS-102 is a combination of trifluridine and tipiracil hydrochloride (tradename Lonsurf®).
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1.3
Schedule of Activities
1.3.1
Arm A (MK-4280A)
Table 1
Arm A (MK-4280A)
Study Period
Screening 
Phase
Intervention Phase
(3-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number/Title
Screening
C1 C2 C3 C4 C5 C6-
C35
Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up 
Survival 
Follow-
up
All assessments should be performed prior to 
treatment administration unless otherwise indicated.
If discontinuation visit occurs ≥30 days from last 
dose of study intervention, a separate Safety 
Follow-up Visit is not required, and all Safety 
Follow-up procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
1
1
1
1
1
At Discon
30 days 
from last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W ±7
Administrative Procedures
Informed Consent
X
If the investigator plans to treat beyond the initial 
radiologic disease progression per RECIST 1.1 
verified by BICR, additional consent will be 
required prior to post-progression treatment 
(Section 8.1.1.1).
Informed Consent 
for FBR
X
Not required to participate in the study.
To be obtained after consenting to the study.
Inclusion/Exclusion 
Criteria
X
Participant ID Card 
Issued
X
At the time of Visit 1, site personnel should add the 
randomization number to the Participant ID card.
Medical History and 
Demographics
X
CRC History
X
Prior/Concomitant 
Medication Review
X
X
X X
X
X
X
X
X
Prior CRC Therapy 
Review
X
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Study Period
Screening 
Phase
Intervention Phase
(3-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number/Title
Screening
C1 C2 C3 C4 C5 C6-
C35
Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up 
Survival 
Follow-
up
All assessments should be performed prior to 
treatment administration unless otherwise indicated.
If discontinuation visit occurs ≥30 days from last 
dose of study intervention, a separate Safety 
Follow-up Visit is not required, and all Safety 
Follow-up procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
1
1
1
1
1
At Discon
30 days 
from last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W ±7
Treatment 
Eligibility 
Assessment (TEA)
X
Prior to randomization, the investigator must 
provide rationale for participants to receive 
regorafenib or TAS-102.
Randomization
X
Poststudy 
Anticancer Therapy 
Status
X
Survival Status
X
Collect for participants who have entered Survival 
Follow-up. Upon Sponsor request, participants may 
be contacted for survival status at any time during 
the course of the study.
Efficacy Assessments
Tumor Scans (chest, 
abdomen, and 
pelvis; CT/MRI)
X
X
X
The tumor scan schedule follows calendar days; do 
not adjust for cycle delays. Tumor scans should be 
performed at 9 weeks from the date of 
randomization (63 days ±7 days), then Q9W 
(63 days ±7 days) or more frequently if clinically 
indicated, and at discontinuation ±28-day window.
Clinical Procedures/Assessments                                                                                                                                    
MK-4280A 
Administration
X
X X
X
X
X
AE/SAE Review
X
X
X X
X
X
X
X
X
X
Refer to Section 8.4.1 for details.
Full Physical 
Examination
X
X
Directed Physical 
Exam
X
X X
X
X
X
Height
X
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Study Period
Screening 
Phase
Intervention Phase
(3-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number/Title
Screening
C1 C2 C3 C4 C5 C6-
C35
Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up 
Survival 
Follow-
up
All assessments should be performed prior to 
treatment administration unless otherwise indicated.
If discontinuation visit occurs ≥30 days from last 
dose of study intervention, a separate Safety 
Follow-up Visit is not required, and all Safety 
Follow-up procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
1
1
1
1
1
At Discon
30 days 
from last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W ±7
Weight
X
X
X X
X
X
X
X
Vital Signs
X
X
X X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
ECG at screening, C2D1, D1 of every third cycle (9 
weeks) thereafter (eg, C5, C8, C11), EOT and 
Safety Follow-up Visits.
Timing of ECG may be subject to local 
requirements.
ECOG Performance 
Status
X
X
X X
X
X
X
X
Screening assessment must be within 10 days prior 
to first dose of study intervention. Subsequent 
assessments may be performed up to 72 hours prior 
to dosing.
LOCAL Laboratory Assessments
RAS and BRAF 
Status
X
Only for participants whose RAS and BRAF status 
is unknown at the time of obtaining consent. The 
site should submit required samples to their local 
laboratory for testing and must provide status prior 
to randomization.
Urine or Serum
Pregnancy Test 
(WOCBP only)
X
X
X X
X
X
X
X
X
WOCBP require a negative test prior to 
randomization. If more than 24/72 hours have 
elapsed since urine/serum testing prior to first dose 
of study intervention, another pregnancy test is 
required. 
Hematology
X
X
X X
X
X
X
X
X
Screening: perform within 10 days prior to the first 
dose of study intervention.
Perform up to 72 hours prior to dosing. If screening 
labs were within 72 hours of the first dose, repeat 
labs at Cycle 1 are not needed. 
Chemistry
X
X
X X
X
X
X
X
X
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Study Period
Screening 
Phase
Intervention Phase
(3-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number/Title
Screening
C1 C2 C3 C4 C5 C6-
C35
Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up 
Survival 
Follow-
up
All assessments should be performed prior to 
treatment administration unless otherwise indicated.
If discontinuation visit occurs ≥30 days from last 
dose of study intervention, a separate Safety 
Follow-up Visit is not required, and all Safety 
Follow-up procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
1
1
1
1
1
At Discon
30 days 
from last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W ±7
PT/INR and aPTT
X
Perform within 10 days prior to the first dose of 
study intervention.
Urinalysis
X
X
X X
X
X
X
X
At screening, perform within 10 days prior to the 
first dose of study intervention. Subsequent testing 
may be performed up to 72 hours prior to dosing.
If urinalysis is unable to be performed, urine 
dipstick is acceptable. Timing of urinalysis may be 
subject to local requirements.
T3/FT3, T4/FT4, 
and TSH
X
X
X
X*
X
X
Screening: perform within 10 days prior to the first 
dose of study intervention. 
For subsequent cycles after C1D1, testing may be 
performed up to 72 hours prior to dosing, 
Participants may be dosed while thyroid function 
test results are pending.
*After Cycle 6, perform testing on day 1 of every 
even number cycle. 
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Study Period
Screening 
Phase
Intervention Phase
(3-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number/Title
Screening
C1 C2 C3 C4 C5 C6-
C35
Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up 
Survival 
Follow-
up
All assessments should be performed prior to 
treatment administration unless otherwise indicated.
If discontinuation visit occurs ≥30 days from last 
dose of study intervention, a separate Safety 
Follow-up Visit is not required, and all Safety 
Follow-up procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
1
1
1
1
1
At Discon
30 days 
from last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W ±7
ACTH/Cortisol
X1
X
X2
X
X
May perform centrally if unable to perform locally.
1At C1D1, ACTH/cortisol must be collected prior 
to the first dose of study intervention. Testing may 
be performed up to 72 hours prior to dosing. 
Participants may be dosed while ACTH/cortisol test 
results are pending.
For subsequent cycles after C1D1, testing may be 
performed up to 72 hours prior to dosing. 
Participants may be dosed while ACTH/cortisol test
results are pending.
2After Cycle 6, perform testing on day 1 of every 
even number cycle.
Serum Tumor 
Marker (CEA)
X
X X
X
X
X
X
X
Perform within 72 hours prior to dosing at every 
cycle, Cycle 1 onwards.
HIV, Hepatitis B 
and C Testing
X
Not required unless mandated by local health 
authority. 
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Study Period
Screening 
Phase
Intervention Phase
(3-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number/Title
Screening
C1 C2 C3 C4 C5 C6-
C35
Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up 
Survival 
Follow-
up
All assessments should be performed prior to 
treatment administration unless otherwise indicated.
If discontinuation visit occurs ≥30 days from last 
dose of study intervention, a separate Safety 
Follow-up Visit is not required, and all Safety 
Follow-up procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
1
1
1
1
1
At Discon
30 days 
from last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W ±7
CENTRAL Laboratory Assessments
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Study Period
Screening 
Phase
Intervention Phase
(3-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number/Title
Screening
C1 C2 C3 C4 C5 C6-
C35
Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up 
Survival 
Follow-
up
All assessments should be performed prior to 
treatment administration unless otherwise indicated.
If discontinuation visit occurs ≥30 days from last 
dose of study intervention, a separate Safety 
Follow-up Visit is not required, and all Safety 
Follow-up procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
1
1
1
1
1
At Discon
30 days 
from last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W ±7
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Study Period
Screening 
Phase
Intervention Phase
(3-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number/Title
Screening
C1 C2 C3 C4 C5 C6-
C35
Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up 
Survival 
Follow-
up
All assessments should be performed prior to 
treatment administration unless otherwise indicated.
If discontinuation visit occurs ≥30 days from last 
dose of study intervention, a separate Safety 
Follow-up Visit is not required, and all Safety 
Follow-up procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
1
1
1
1
1
At Discon
30 days 
from last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W ±7
Health Related Quality of Life (HRQoL)
EQ-5D-5L
EORTC QLQ-C30
EORTC QLQ-CR29
X
X X
X
X
X*
X
X
ePROs should be done in the order in the table. It is 
strongly recommended that ePROs are completed 
prior to drug administration, adverse event 
evaluation and disease status notification.
Collect at C1, C2, C3, C4, C5, and then every 4 
cycles* thereafter (eg. C9, C13), until end of 
treatment or treatment discontinuation, whichever 
occurs first, and at the D30 posttreatment Safety 
Follow-up visit. A visit window of ±7 days will
apply to every PRO visit assessment after C1.
ACTH= adrenocorticotrophic hormone; AE=adverse event; aPTT=activated partial thromboplastin time;CxDx=Cycle #, Day #; CEA=carcinoembryonic antigen; CRC=colorectal 
cancer; ctDNA=circulating tumor deoxyribonucleic acid; Discon=discontinuation; DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology 
Group; EORTC=European Organisation for Research and Treatment of Cancer; EORTC QLQ-C30=EORTC Quality of Life Questionnaire – Core Questionnaire; EORTC QLQ-
CR29=EORTC Colorectal 29; EOT=end of treatment; ePRO= electronic patient-reported outcome; EQ-5D-5L=EuroQoL 5D-5L; FBR=future biomedical research; FT3= free 
triiodothyronine; FT4=free thyroxine; HIV=human immunodeficiency virus; HRQoL=health related quality of life; ID=identification; MMR=mismatch repair; PD-
L1=programmed cell death ligand 1;PK=pharmacokinetic; PT/INR=prothrombin time/international normalized ratio; Q9W=every 9 weeks; Q12W=every 12 weeks; QLQ=quality 
of life questionnaire; RECIST=response evaluation criteria in solid tumors; RNA=ribonucleic acid; SAE=serious adverse event; T3=triiodothyronine; T4=thyroxine; 
TEA=treatment eligibility assessment; TSH=thyroid-stimulating hormone; WOCBP=women of child bearing potential
See country-specific requirements in Appendix 7.
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1.3.2
Arm B (Regorafenib)
Table 2
Arm B (Regorafenib)
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening C1
C2
C3 C4 C5 C6 
Onward Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
prior to treatment administration 
unless otherwise indicated. If 
discontinuation visit occurs ≥30 days 
from last dose of study intervention, a
separate Safety Follow-up Visit is not 
required, and all Safety Follow-up
procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
15 1
15 1
1
1
1
At Discon
30 days 
from 
last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Administrative Procedures
Informed Consent
X
Informed Consent 
for FBR
X
Not required to participate in the 
study. 
To be obtained after consenting to the 
study.
Inclusion/Exclusion 
Criteria
X
Participant ID Card 
Issued
X
At the time of Visit 1, site personnel 
should add the randomization number 
to the Participant ID card.
Medical History 
and Demographics X
CRC History
X
Prior/Concomitant 
Medication Review X
X X X X X X X X
X
X
Prior CRC Therapy 
Review
X
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Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening C1
C2
C3 C4 C5 C6 
Onward Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
prior to treatment administration 
unless otherwise indicated. If 
discontinuation visit occurs ≥30 days 
from last dose of study intervention, a
separate Safety Follow-up Visit is not 
required, and all Safety Follow-up
procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
15 1
15 1
1
1
1
At Discon
30 days 
from 
last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Treatment 
Eligibility 
Assessment (TEA)
X
Prior to randomization, the 
investigator must provide rationale for 
participants to receive regorafenib or 
TAS-102.
Randomization
X
Poststudy 
Anticancer Therapy 
Status
X
Survival Status
X
Collect for participants who have 
entered Survival Follow-up. Upon 
Sponsor request, participants may be 
contacted for survival status at any 
time during the course of the study.
Efficacy Assessments
Tumor Scans 
(chest, abdomen, 
and pelvis; 
CT/MRI)
X
X
X
The tumor scan schedule follows 
calendar days; do not adjust for cycle 
delays. Tumor scans should be 
performed at 9 weeks from the date of 
randomization (63 days ±7 days), then 
Q9W (63 days ±7 days) or more 
frequently if clinically indicated, and 
at discontinuation ±28-day window.
089ZJJ
08VC4W

PRODUCT: MK-4280A
31
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening C1
C2
C3 C4 C5 C6 
Onward Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
prior to treatment administration 
unless otherwise indicated. If 
discontinuation visit occurs ≥30 days 
from last dose of study intervention, a
separate Safety Follow-up Visit is not 
required, and all Safety Follow-up
procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
15 1
15 1
1
1
1
At Discon
30 days 
from 
last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Clinical Procedures/Assessments
Regorafenib 
Administration
Q4W: QD Days 1-21 (Weeks 1, 2, and 
3), no dose Days 22-28 (Week 4).
The C1D1 dose must be given to the 
participant at the site.  
Regorafenib should be dispensed to 
participants on day 1 of every cycle. 
After day 1 of each cycle, collect and 
record the number of regorafenib 
capsules returned at each visit, when 
applicable, for accountability and 
compliance purposes.
AE/SAE Review 
X
X X X X X X X X
X
X
X
Refer to Section 8.4.1 for details.
Full Physical 
Examination 
X
X
Directed Physical 
Exam
X X X X X X X X
Height
X
Weight
X
X X X X X X X X
X
089ZJJ
08VC4W

PRODUCT: MK-4280A
32
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening C1
C2
C3 C4 C5 C6 
Onward Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
prior to treatment administration 
unless otherwise indicated. If 
discontinuation visit occurs ≥30 days 
from last dose of study intervention, a
separate Safety Follow-up Visit is not 
required, and all Safety Follow-up
procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
15 1
15 1
1
1
1
At Discon
30 days 
from 
last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Vital Signs 
X
X X X X X X X X
X
Weekly BP assessments are required 
from C1D1 through C2D15 and can 
be done at home.
Arrange to have a communication (eg, 
telephone call) with the participant 
each week to receive and assess the 
measurement.
12-Lead ECG
X
X
X X
X
X
ECG at screening, C2D1, D1 of every 
third cycle (12 weeks) thereafter (eg, 
C5, C8, C11), EOT and Safety 
Follow-up Visits.
Timing of ECG may be subject to 
local requirements.
ECOG 
Performance Status
X
X X X X X X X X
X
Screening assessment must be within 
10 days prior to first dose of study 
intervention. Subsequent assessments 
may be performed up to 72 hours prior 
to dosing.
089ZJJ
08VC4W

PRODUCT: MK-4280A
33
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening C1
C2
C3 C4 C5 C6 
Onward Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
prior to treatment administration 
unless otherwise indicated. If 
discontinuation visit occurs ≥30 days 
from last dose of study intervention, a
separate Safety Follow-up Visit is not 
required, and all Safety Follow-up
procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
15 1
15 1
1
1
1
At Discon
30 days 
from 
last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
LOCAL Laboratory Assessments
RAS and BRAF 
Status
X
Only for participants whose RAS and 
BRAF status is unknown at the time 
of obtaining consent. The site should 
submit required samples to their local 
laboratory for testing and must 
provide status prior to randomization.
Urine or Serum
Pregnancy Test 
(WOCBP only)
X
X
X
X X X X
X
X
WOCBP require a negative test prior 
to randomization. If more than 
24/72 hours have elapsed since 
urine/serum testing prior to first dose 
of study intervention, another 
pregnancy test is required.
Hematology
X
X X X X X X X X
X
X
Perform within 10 days prior to the 
first dose of study intervention.
Perform at C1 onwards: perform up to 
72 hours prior to dosing at every 
cycle. 
Perform up to 72 hours prior to 
dosing. If screening labs were within 
72 hours of the first dose, repeat labs 
at C1 are not needed.
Chemistry
X
X X X X X X X X
X
X
089ZJJ
08VC4W

PRODUCT: MK-4280A
34
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening C1
C2
C3 C4 C5 C6 
Onward Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
prior to treatment administration 
unless otherwise indicated. If 
discontinuation visit occurs ≥30 days 
from last dose of study intervention, a
separate Safety Follow-up Visit is not 
required, and all Safety Follow-up
procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
15 1
15 1
1
1
1
At Discon
30 days 
from 
last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
PT/INR and aPTT
X
Perform within 10 days prior to the 
first dose of study intervention. 
Urinalysis
X
X
X
X X X X
X
At screening, perform within 10 days 
prior to the first dose of study 
intervention. Subsequent testing may 
be performed up to 72 hours prior to 
dosing.
If urinalysis is unable to be performed, 
urine dipstick is acceptable. Timing of 
urinalysis may be subject to local 
requirements.
T3/FT3, T4/FT4, 
and TSH
X
X
X
X*
X
X
Screening: perform within 10 days 
prior to the first dose of study 
intervention.
For subsequent cycles after C1D1, 
testing may be performed up to 
72 hours prior to dosing, Participants 
may be dosed while thyroid function 
test results are pending.
*After Cycle 6, perform testing on day 
1 of every even number cycle.
089ZJJ
08VC4W

PRODUCT: MK-4280A
35
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening C1
C2
C3 C4 C5 C6 
Onward Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
prior to treatment administration 
unless otherwise indicated. If 
discontinuation visit occurs ≥30 days 
from last dose of study intervention, a
separate Safety Follow-up Visit is not 
required, and all Safety Follow-up
procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
15 1
15 1
1
1
1
At Discon
30 days 
from 
last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Serum Tumor 
Marker (CEA)
X
X
X X X X
X
X
Perform within 72 hours prior to 
dosing at every cycle, C1 onwards.
HIV, Hepatitis B 
and C Testing 
X
Not required unless mandated by local 
health authority.
CENTRAL Laboratory Assessments
089ZJJ
CCI
08VC4W

PRODUCT: MK-4280A
36
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening C1
C2
C3 C4 C5 C6 
Onward Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
prior to treatment administration 
unless otherwise indicated. If 
discontinuation visit occurs ≥30 days 
from last dose of study intervention, a
separate Safety Follow-up Visit is not 
required, and all Safety Follow-up
procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
15 1
15 1
1
1
1
At Discon
30 days 
from 
last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Health Related Quality of Life (HRQoL)
EQ-5D-5L
EORTC QLQ-C30
EORTC QLQ-
CR29
X
X
X X
X*
X
X
ePROs should be done in the order in 
the table. It is strongly recommended 
that ePROs are completed prior to 
drug administration, adverse event 
evaluation and disease status 
notification.
Collect at C1, C2, C3, C4, and then 
every 3 cycles* thereafter (eg, C7, 
C10), until end of treatment or 
treatment discontinuation, whichever 
occurs first, and at the D30 
posttreatment Safety Follow-up visit. 
A visit window of ± 7 days will apply 
to every PRO visit assessment after 
C1.
089ZJJ
08VC4W

PRODUCT: MK-4280A
37
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening C1
C2
C3 C4 C5 C6 
Onward Discon
Safety 
Follow-
up*
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
prior to treatment administration 
unless otherwise indicated. If 
discontinuation visit occurs ≥30 days 
from last dose of study intervention, a
separate Safety Follow-up Visit is not 
required, and all Safety Follow-up
procedures will be performed at the 
discontinuation visit.
*Refer to Section 8.12.4.1 for details.
Cycle Day
Up to 28 
days prior 
to first 
dose
1
15 1
15 1
1
1
1
At Discon
30 days 
from 
last 
dose
Scheduled Days
-28 to -1
+3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
AE=adverse event; aPTT=activated partial thromboplastin time; BP=blood pressure; CxDx=Cycle #, Day #; CEA=carcinoembryonic antigen; CRC=colorectal 
cancer; CT=computed tomography; ctDNA=circulating tumor deoxyribonucleic acid; Discon=discontinuation; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EORTC=European Organisation for Research and Treatment of Cancer; EORTC QLQ-
C30=EORTC Quality of Life Questionnaire – Core Questionnaire; EORTC QLQ-CR29=EORTC Colorectal 29; EOT=end of treatment; ePRO= electronic 
patient-reported outcome; EQ-5D-5L=EuroQoL 5D-5L; FBR=future biomedical research; FT3=free triiodothyronine; FT4=free thyroxine; HIV=human 
immunodeficiency virus; HRQoL=health related quality of life; ID=identification; MRI=magnetic resonance imaging; PD-L1=programmed cell death ligand 1; 
PRO=patient-reported outcome; PT/INR= prothrombin time/international normalized ratio; Q9W=every 9 weeks; Q12W=every 12 weeks; QD=one a day; 
QLQ=Quality of Life Questionnaire; RNA=ribonucleic acid; SAE=serious adverse event; T3=triiodothyronine; T4= thyroxine; TEA=treatment eligibility 
assessment; TSH=thyroid-stimulating hormone; WOCBP=women of child bearing potential
See country-specific requirements in Appendix 7.
089ZJJ
08VC4W

PRODUCT: MK-4280A
38
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
1.3.3
Arm B (TAS-102)
Table 3
Arm B (TAS-102)
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Administrative Procedures
Informed Consent
X
Informed Consent for 
FBR
X
Not required to participate in the 
study. 
To be obtained after consenting to 
the study.
Inclusion/Exclusion 
Criteria
X
Participant ID Card 
Issued
X
At the time of Visit 1, site 
personnel should add the 
randomization number to the 
Participant ID card.
Medical History and 
Demographics
X
CRC History
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
089ZJJ
08VC4W

PRODUCT: MK-4280A
39
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Prior CRC Therapy 
Review
X
Treatment Eligibility 
Assessment (TEA)
X
Prior to randomization, the 
investigator must provide rationale 
for participants to receive 
regorafenib or TAS-102.
Randomization
X
Poststudy Anticancer 
Therapy Status
X
Survival Status
X
Collect for participants who have 
entered Survival Follow-up. Upon 
Sponsor request, participants may 
be contacted for survival status at 
any time during the study.
089ZJJ
08VC4W

PRODUCT: MK-4280A
40
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Efficacy Assessments
Tumor Scans (chest, 
abdomen, and pelvis; 
CT/MRI) 
X
X
X
The tumor scan schedule follows 
calendar days; do not adjust for 
cycle delays. Scans should be 
performed at 9 weeks from the date 
of randomization (63 days ±7 
days), then Q9W (63 days ±7 days) 
or more frequently if clinically 
indicated, and at discontinuation 
±28-day window.
089ZJJ
08VC4W

PRODUCT: MK-4280A
41
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Clinical Procedures/Assessments
TAS-102 
Administration
Q4W: BID on Days 1-5 and on 
Days 8-12; no dose Days 6 and 7, 
and 13-28.
The C1D1 dose must be given to 
the participant at the site. At 
subsequent cycles, TAS-102 is 
dispensed to participants on day 1 
of every cycle. 
If for any reason both doses cannot 
be taken on Day 1 of each cycle 
(e.g., later morning or afternoon 
visit), the dosing schedule may be 
adjusted (ie, CxD1 one dose, CxD2 
- CxD5 BID dosing, CxD6 one 
dose).
After day 1 of each cycle, collect 
and record the number of TAS-102 
capsules returned at each visit, 
when applicable, for accountability 
and compliance purposes.
AE/SAE Review 
X
X X X X X X
X X
X X
X
X
X
X
X
Refer to Section 8.4.1 for details.
089ZJJ
08VC4W

PRODUCT: MK-4280A
42
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Full Physical 
Examination 
X
X
Directed Physical 
Exam
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
ECG at screening, C2D1, D1 of 
every third cycle (12 weeks) 
thereafter (eg, C5, C8, C11), EOT 
and Safety Follow-up Visits.
Timing of ECG may be subject to 
local requirements.
ECOG Performance 
Status
X
X
X
X
X
X
X
X
Screening assessment must be 
within 10 days prior to first dose of 
study intervention. Subsequent 
assessments may be performed up 
to 72 hours prior to dosing.
089ZJJ
08VC4W

PRODUCT: MK-4280A
43
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
LOCAL Laboratory Assessments
RAS and BRAF 
Status
X
Only for participants whose RAS 
and BRAF status is unknown at the 
time of obtaining consent. The site 
should submit required samples to 
their local laboratory for testing 
and must provide status prior to 
randomization.
Urine or Serum 
Pregnancy Test 
(WOCBP only)
X
X
X
X
X
X
X
X
X
WOCBP require a negative text 
prior to randomization. If more 
than 24/72 hours have elapsed 
since urine/serum testing prior to 
first dose of study intervention, 
another pregnancy test is required.
089ZJJ
08VC4W

PRODUCT: MK-4280A
44
PROTOCOL/AMENDMENT NO.: 007-04
MK-4280A-007-04 FINAL PROTOCOL
22-MAY-2023
Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Hematology
X
X X X Xc X X
X X
X X
X
X
X
X
Perform within 10 days prior to the 
first dose of study intervention. c 
C2D15 may be collected remotely. 
Perform at C1 onwards: perform up 
to 72 hours prior to dosing at every 
cycle.
If screening labs were within 
72 hours of the first dose, repeat 
labs at C1 are not needed.
Chemistry
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
X
Perform within 10 days prior to the 
first dose of study intervention. 
Urinalysis
X
X
X
X
X
X
X
X
At screening, perform within 
10 days prior to the first dose of 
study intervention. Subsequent 
testing may be performed up to 
72 hours prior to dosing.
If urinalysis is unable to be 
performed, urine dipstick is 
acceptable. Timing of urinalysis 
may be subject to local 
requirements.
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Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
T3/FT3, T4/FT4, and 
TSH
X
X
X
X*
X
X
Screening: perform within 10 days 
prior to the first dose of study 
intervention.
Participants may be dosed in 
subsequent cycles after C1D1 while 
thyroid function test results are 
pending. Testing may be performed 
up to 72 hours prior to dosing.
*After Cycle 6, perform testing on 
day 1 of every even number cycle.
Serum Tumor Marker 
(CEA)
X
X
X
X
X
X
X
X
Perform within 72 hours prior to 
dosing at every cycle, C1 onwards.
HIV, Hepatitis B and 
C Testing 
X
Not required unless mandated by 
local health authority.
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Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
CENTRAL Laboratory Assessments
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Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
Health Related Quality of Life (HRQoL)
EQ-5D-5L
EORTC QLQ-C30 
EORTC QLQ-CR29
X
X
X
X
X*
X
X
ePROs should be done in the order 
in the table. It is strongly 
recommended that ePROs are 
completed prior to drug 
administration, adverse event 
evaluation and disease status 
notification.
Collect at C1, C2, C3, C4, and then 
every 3 cycles* thereafter (eg, C7, 
C10), until end of treatment or 
treatment discontinuation, 
whichever occurs first, and at the 
D30 posttreatment Safety Follow-
up visit. A visit window of ± 7 days 
will apply to every PRO visit 
assessment after C1.
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Study Period
Screening 
Phase
Intervention Phase
(4-Week Cycles)
End of 
Treatment Posttreatment
Notes
Visit 
Number /Title
Screening
C1
C2
C3
C4
C5
C6 
Onward Discon
Safety 
Follow-
upa, b
Efficacy 
Follow-
up
Survival 
Follow-
up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose of 
study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-up 
procedures will be performed at the 
discontinuation visit.
a After Cycle 2, D15 visits are 
optional.
b Refer to Section 8.12.4.1 for 
details.
Cycle Day
Up to 28 
days prior 
to first dose
1
15 1
15 1
15a 1
15a 1
15a 1
15a At Discon
30 days 
from 
last dose
Scheduled Days
-28 to -1
+3 +3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
+7
+7
Q9W ±7 Q12W 
±7
AE=adverse event; aPTT=activated partial thromboplastin time; CxDx=Cycle #, Day #; BID=twice daily; CEA=carcinoembryonic antigen; CRC=colorectal cancer; 
CT=computed tomography; ctDNA=circulating tumor deoxyribonucleic acid; Discon=discontinuation; DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; EORTC=European Organisation for Research and Treatment of Cancer; EORTC QLQ-C30=EORTC Quality of Life Questionnaire – Core 
Questionnaire; EORTC QLQ-CR29=EORTC Colorectal 29; EOT=end of treatment; ePRO=electronic patient-reported outcome; EQ-5D-5L=EuroQoL 5D-5L; FBR=future 
biomedical research; FT3=free triiodothyronine; FT4=free thyroxine; HIV=human immunodeficiency virus; ID=identification; MMR=mismatch repair; MRI=magnetic 
resonance imaging; PD-L1=programmed cell death ligand 1; PRO=patient-reported outcome; PT/INR=prothrombin time/international normalized ratio; Q4W=every 4 weeks; 
Q9W=every 9 weeks; Q12W=every 12 weeks; QLQ=Quality of Life Questionnaire; RNA=ribonucleic acid; SAE=serious adverse event; T3=triiodothyronine; T4= thyroxine; 
TEA=treatment eligibility assessment; TSH=thyroid-stimulating hormone; WOCBP=women of child bearing potential.
See country-specific requirements in Appendix 7.
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2
INTRODUCTION
In the US, CRC is the third most common diagnosed cancer and the third leading cause of 
cancer death in both men and women [American Cancer Society 2014]. The American 
Cancer Society estimated that 149,500 adults would be diagnosed with CRC in 2021 in the 
US, with 52,980 deaths expect. The 5-year survival rate is 65% for all stages of CRC, but just 
14% for patients with metastatic disease [Siegel, R. L., et al 2021]. Approximately 4.5% of 
men and women will be diagnosed with colon and rectum cancer at some point during their 
lifetime [Surveillance Research Program, NCI. 2015]. Based on the SEER Program data 
from 2008 to 2012, the age-adjusted incidence rate was 42.4 per 100,000 population; the 
incidence was higher in men (48.9 per 100,000 men) than in women (37.1 per 100,000 
women). The incidence increased with age, from 0.1 per 100,000 in those between 10 and 14 
years of age to 311.9 per 100,000 among those above 85 years of age [Surveillance, 
Epidemiology, and End Results Program 2015].
Globally, CRC represents 11% of all cancer diagnoses and is responsible for approximately 
881,000 deaths worldwide [Rawla, P., et al 2019]. CRC death rates have increased in the EU 
from approximately 150,000 in 2015 to a projected 155,000 in 2021, in the UK alone, CRC 
deaths will have increased from about 20,000 to 21,000 in the same interval [Carioli, G., et al 
2021]. Across all stages of disease, 95% of mCRC patients have tumors that are non-MSI-
H/pMMR.
Similar to incidence patterns, mortality rates declined most rapidly in the past decade. The 
annual overall mortality for CRC was 15.5 per 100,000, and men had a higher mortality (18.6 
per 100,000 men) than women (13.1 per 100,000 women) [Surveillance, Epidemiology, and 
End Results Program 2015]. On average, the 5-year survival was 65%, and survival was 
highest among those with localized lesions (90.1%), followed by those with regional lesions 
(70.8%), and was the lowest among those with distant lesions (13.1%) [Surveillance 
Research Program, NCI. 2015].
Despite recent advances, the intent of therapy for most mCRC participants is palliative with 
few patients achieving long-term survival [American Cancer Society 2017]. Current standard 
of care therapies for mCRC in the early-line setting include chemotherapy based on 
fluoropyrimidine, oxaliplatin, and irinotecan used in combination or sequentially, with option 
for monoclonal antibodies targeting VEGF (eg, bevacizumab, ziv-aflibercept) or its receptors 
(eg, ramucirumab), and in patients with RAS WT tumors, monoclonal antibodies targeting 
the EGFR (eg, cetuximab, panitumumab). However, therapeutic options for heavily 
pretreated patients beyond the second-line setting are especially limited and associated 
toxicities can be severe. Although regorafenib and TAS-102 are the 2 commonly accepted 
standard of care therapies for patients who have been treated with fluoropyrimidine-, 
irinotecan-, oxaliplatin-containing chemotherapies, anti-VEGF and an anti-EGFR agent (if 
KRAS WT), they offer minimal benefit as ORR is ≤2% for both agents [Grothey, A., et al
2013] [U.S. Prescribing Information 2012]. Minimal durability of clinical benefit is 
evidenced by a 6-month PFS rate of ~15%. Clearly, there is a high unmet medical need in 
developing novel combination regimens to improve the clinical outcome for patients with 
mCRC, especially in the later line treatment setting.
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2.1
Study Rationale
Pembrolizumab and other anti-PD-1 agents produced durable clinical benefit in patients with 
mCRC with the deficient MMR/MSI-H phenotype [Le, D. T., et al 2015]. In the heavily 
treated mCRC setting, pembrolizumab produced high ORR, as well as evidence for durable 
clinical benefit [Le, D. T., et al 2015]. However, anticancer activity in CRC has been limited 
to cancers with the deficient MMR/MSI-H phenotype, which represents a minority (~5%) of 
the Stage IV mCRC population.
Because approximately 95% of mCRC patients have tumors that are neither dMMR nor 
MSI-H, there is a need to develop combination regimens that would provide durable clinical 
benefit. While high response rates from chemotherapy are reported in previously untreated 
mCRC population with current standard treatment, durability of clinical benefit is limited. 
Furthermore, therapy options for heavily pre-treated patients beyond the second-line setting 
are limited, and associated toxicities can be severe. Given that durable clinical benefit is the 
hallmark of pembrolizumab demonstrated in multiple tumor types with dMMR/MSI-H, 
addressing resistance to pembrolizumab in the patient population with neither dMMR nor 
MSI-H could improve the clinical outcome in this large segment of the population. As seen 
in the Phase 1 MK-4280-001 study (described below and refer to the MK-4280/MK-4280A 
IB for complete details), adding a LAG-3 inhibitor to pembrolizumab therapy may elicit 
responses in the pMMR/non-MSI-H population.
In this study, centralized testing by IHC of MMR proteins will be performed to separate the 
dMMR/MSI-H population from the pMMR/MSS population of colorectal cancer patients. 
Loss of MMR proteins correlate with abnormal microsatellite repeats [Cicek, M. S., et al 
2011]. A large case series (N=3,824) from the Colon Cancer Family Registry (supplemental 
table 2) showed that of all patients who were evaluable for both IHC and MSI (excluding 
those with no IHC or equivocal IHC data, n=3,240), loss of IHC expression of at least 1 
MMR protein occurred in 441 patients, of whom all but 1 met the definition of MSI-H 
disease (≥30% MSI markers). Conversely, 495 patients showed MSI-H genotype, but of 
these only 440 showed loss of IHC staining. Therefore, IHC may be more specific than PCR 
for selecting patients with pMMR/MSS colorectal cancer. Another study further showed
concordance between MSI testing by PCR and MMR testing by IHC [Loughrey, M. B., et al 
2021]. In this study, a cohort of 661 samples of Stage 2 and 3 colon cancers from a registry 
and biobank were tested for MMR proteins using the Ventana assay and by PCR. Of 593 
cases able to be assessed by both methods, 97.1% of MSI-H cases demonstrated aberrant 
IHC, while 97.8% of cases with abnormal IHC were also MSI-H by PCR.
Emerging data suggest that combining PD-1/PD-L1 inhibitors with other immune 
modulatory agents might sensitize tumors to immunotherapy and/or provide additive 
efficacy. LAG-3 may be an appropriate target for coinhibition with PD-1. In a mouse model, 
LAG-3 appears to play an immunosuppressive role, helping to prevent autoimmunity 
[Topalian, S. L., et al 2012].
CD8+ T cells expressing both LAG-3 and PD-1 are the dominant TIL population in mice 
transplanted with CT26 colon carcinoma cells, in which LAG-3 was shown to control T-cell 
proliferation/cell cycle progression, resulting in a state of hypofunction [Waugh, K. A., et al 
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2016]. Consistent with the landmark finding that immune cells within human colorectal 
tumors predict clinical outcome [Galon, J., et al 2006], both in vitro and in vivo data indicate 
that dual blockade of LAG-3 and PD-1 potentially can have a synergistic impact on reversing 
tumor-specific anergy [Andrews, L. P., et al 2017]. In one example, using the MC-38 mouse 
model of colon derived tumor cells, PD-1 inhibition resulted in expression of LAG-3 on T
cells [Beyrend, G., et al 2019]. In turn, combined PD-1 and LAG-3 blockade delayed tumor 
growth and enhanced survival.
In CRC patients, LAG-3 was overexpressed on colorectal immune cells, and correlated with 
poor differentiation, advanced stage, lymph node involvement, and invasion depth (T stage) 
[Chen, J. 2014]. Also, among MSI-H colon cancer patients, LAG-3 expression was 
associated with shorter relapse-free survival and correlated with tumor cell PD-L1 expression 
[Lee, S. J., et al 2017].
Favezelimab Alone and in Combination with Pembrolizumab in CRC
Clinical data in participants with MSS CRC treated with favezelimab alone and in 
combination with pembrolizumab in the first-in-human MK-4280-001 study is available 
(refer to the MK-4280/MK-4280A IB for complete details). Eligible participants with MSS 
PD-1/PD-L1-treatment-naïve mCRC that progressed on all prior therapies (3L+) were 
enrolled (Cohort A) to receive the recommended Phase 2 dose of 800 mg favezelimab alone, 
800 mg favezelimab + 200 mg pembrolizumab, or 800 mg favezelimab + 200 mg 
pembrolizumab (MK-4280A) coformulation, all Q3W. Treatment continued for 35 cycles or 
until progression, unacceptable toxicity, or investigator/participant decision to withdraw from 
study intervention. Participants with confirmed progression per iRECIST 1.1 on favezelimab 
alone could crossover to 800 mg favezelimab + pembrolizumab. 
A total of 20 participants received favezelimab monotherapy (Cohort A, Arm 1); 
89 (including 9 crossover) received favezelimab + pembrolizumab (either as separate agents 
or as a coformulation; Cohort A, Arms 2C and 5). At data cutoff, median follow-up was 
5.8 months in the favezelimab arm and 6.2 months in the favezelimab + 
pembrolizumab/MK-4280A arms. TRAEs were 65.0% with favezelimab and 65.2% with 
favezelimab + pembrolizumab/MK-4280A. Grade ≥3 TRAEs were 15.0% (favezelimab), and 
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20.2% favezelimab + pembrolizumab/MK-4280A). No Grade 5 TRAEs were reported. 
Common TRAEs (≥15.0%) included fatigue (20.0%) and nausea (15.0%) with favezelimab, 
and fatigue (16.9%) with favezelimab + pembrolizumab/MK-4280A [Garralda, E., et al 
2021]. 
The efficacy population included 20 participants who received favezelimab monotherapy and 
80 participants who received favezelimab + pembrolizumab, of which 12 and 36 participants, 
respectively, had PD-L1 CPS ≥1 tumors. Confirmed ORR was 0% in participants receiving 
favezelimab and 6.3% (4 PR, 1 CR) with favezelimab + pembrolizumab/MK-4280A. The 
ORR was 11.1%, 4 of 36 participants with tumors expressing PD-L1 CPS≥1 received 
favezelimab + pembrolizumab/MK-4280A. In the favezelimab + pembrolizumab/MK-4280A 
arms, median DOR was 10.6 months (range: 5.6-12.7 months). The median OS and 
12-month OS rate in participants who received favezelimab + pembrolizumab/MK-4280A 
was 8.3 months (range: 5.5-12.9 months) and 40.8% in the ITT population, and 12.7 months 
(range: 4.5 months-NR) and 50.6% in participants with tumors expressing PDL-1 CPS≥1. 
The median PFS and 6-month PFS rate in participants receiving favezelimab + 
pembrolizumab/MK-4280A was 2.1 months (range: 1.9-2.2 months) and 16.2% in the ITT 
population, and 2.2 months (range: 1.8-4.2 months) and 25.4% in participants with tumors 
expressing PD-L1 CPS≥1 [Garralda, E., et al 2021].
Overall, favezelimab alone or in combination with pembrolizumab had a manageable safety 
profile, with no treatment-related deaths. Promising antitumor activity was observed with 
favezelimab + pembrolizumab/MK-4280A therapy compared with monotherapy and was 
enhanced in participants with PD-L1 CPS ≥1 tumors [Garralda, E., et al 2021].
Additional evidence for PD-L1 as a prognostic and potentially predictive biomarker comes 
from the IMblaze 370 study [Eng, C., et al 2019], where 3L MSS CRC participants were 
treated with either regorafenib (control arm) or atezolizumab ± cobimetinib (experimental 
arms). In a subgroup analysis, atezolizumab-treated participants showed a trend towards 
improved median OS in PD-L1 positive participants (HR 0.90; 95% CI: 0.58-1.41, median 
OS ~8.5 vs. 6.5 months on the Kaplan-Meier chart). In PD-L1 negative participants, 
conversely, the trend in OS favored regorafenib with a HR of 1.42 (95% CI: 0.94-2.14, 
median OS from the Kaplan-Meier graph is roughly 9 months for regorafenib treated 
participants vs approximately 7 months for atezolizumab-treated participants).
The MK-4280-001 and IMblaze 370 studies, therefore, suggest that an immunotherapeutic 
approach may be appropriate for participants with PD-L1 positive tumors. For this reason, 
the current study is designed to demonstrate an overall improvement in survival with 
MK-4280A, as compared to standard available therapy (regorafenib or TAS-102), among 
patients with PD-L1 positive MSS tumors refractory to cytotoxic chemotherapy.
Favezelimab Alone and in Combination With Pembrolizumab in Solid Tumors or 
Hematologic Malignancies
Safety data from MK-4280-001 as of 23-OCT-2020 included 38 participants treated with 
favezelimab monotherapy and 340 participants treated with favezelimab and pembrolizumab 
(administered separately or as a coformulation). In the favezelimab arm, 94.7% of 
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participants experienced an AE, and 63.2% experienced a TRAE. 10.5% of participants had a 
Grade 3-5 TRAE and 2.6% had an SAE that was considered treatment related. 1 participant 
(2.6%) discontinued due to a serious TRAE. In the favezelimab + pembrolizumab arms, 
96.6% of participants experienced an AE, and 62.5% experienced a TRAE. 18.9% of 
participants had a Grade 3-5 TRAE and 6.6% had an SAE that was considered treatment
related. 10.9% of participants discontinued due to a TRAE, 2.9% discontinued due to a 
serious TRAE. There were no treatment-related deaths on either favezelimab or favezelimab 
+ pembrolizumab arms. The most common AEs for participants receiving favezelimab in 
combination with pembrolizumab (occurring in >20% of participants, excluding the 
chemotherapy arm) include fatigue (28.4%), nausea (23.8%), and decreased appetite 
(20.9%).
As of 23-OCT-2020, efficacy data are available for the participants treated in the dose 
escalation portion (Part A) of the study in participants with advanced solid tumors with no 
available therapy expected to benefit. These data include 18 participants treated with 
favezelimab monotherapy and 15 participants treated with favezelimab + pembrolizumab 
combination therapy at doses ranging from 7 mg to 700 mg. In participants treated on the 
combination arm at all favezelimab doses, the ORR was 26.7%, with 4 of 15 participants 
having confirmed partial responses. DCR was 40.0% (95% CI: 16.3, 67.7). By contrast, in 
participants treated on the monotherapy arm at all doses, the ORR was 5.6%, with 
1 participant having a confirmed partial response. DCR was 16.7% (95% CI: 3.6, 41.4). 
Moreover, these data show improved efficacy for favezelimab given in combination with 
pembrolizumab over favezelimab alone in this cohort of mixed solid tumors [Lakhani, N., et 
al 2018].
MK-4280-001 also included assessment of the safety and biocomparability of separately 
administered 800 mg favezelimab and pembrolizumab with coformulated MK-4280A. Based 
on a preliminary population PK analysis as of 23-OCT-2020, favezelimab serum 
concentrations after MK 4280A coformulation product dosing (800 mg favezelimab + 
200 mg pembrolizumab) overlapped predicted exposures from 800 mg favezelimab + 
pembrolizumab sequential dosing. The safety profile for participants receiving MK-4280A 
was consistent with the known safety profile of participants receiving sequential 
administration of 800 mg favezelimab and pembrolizumab. The efficacy was comparable 
between sequentially administered favezelimab + pembrolizumab (n=41) compared to 
coformulated MK-4280A (n=39) in participants with MSS CRC, ORR 7.3% (95% CI: 1.5, 
19.9) and 5.1% (95% CI: 0.6, 17.3), respectively, and DCR was 24.4% (95% CI: 12.4, 40.3) 
and 30.8% (95% CI: 17.0, 47.6), respectively. Therefore, data available to date support that 
favezelimab and pembrolizumab administered separately or as MK-4280A show comparable 
PK, safety, and efficacy.
2.2
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
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for the treatment of patients across several indications. For more details on specific 
indications refer to the IB.
Favezelimab binds to the immune checkpoint receptor LAG-3 and blocks the interaction of 
LAG-3 with MHC Class II ligands. Favezelimab has also been shown to have an acceptable 
preclinical safety profile and is in clinical development as an IV immunotherapy for 
advanced malignancies. For more details, refer to the MK-4280/MK-4280A IB.
Given the Sponsor’s observation of enhanced antitumor activity of anti-LAG-3 when 
combined with PD-1 blockade in nonclinical models, the Sponsor has developed a 
coformulated product of favezelimab and pembrolizumab (referred to as MK-4280A). 
MK-4280A is a fixed-dose combination of favezelimab and pembrolizumab antibodies. The 
single vial presentation could provide significant benefit to patients and providers, including 
simplified preparation and reduced infusion times compared with separate formulations. The 
Sponsor’s ongoing Phase 1 study (MK-4280-001) will evaluate the safety, efficacy, and 
biocomparability of this coformulated product with that of the sequential administration of 
favezelimab and pembrolizumab.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Pembrolizumab Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T cells and the ratio 
of CD8+ effector T cells/FoxP3+ regulatory T cells (Tregs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling on engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family
members are type I transmembrane glycoproteins containing an IgV-type domain responsible 
for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. 
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. After 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
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immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in colorectal cancer.
2.2.1.2
Favezelimab Pharmaceutical and Therapeutic Background
LAG-3 is an inhibitory immune modulatory receptor that regulates effector T-cell 
homeostasis, proliferation, and activation, and has a role in the suppressor activity of Tregs 
[Huang, C. T., et al 2004] [Baixeras, E., et al 1990] [Goldberg, M. V. 2011]. LAG-3 is 
expressed on activated CD8+ and CD4+ T cells, Tregs and the Tr1 regulatory T-cell 
population, as well as on natural killer cells and a subset of tolerogenic plasmacytoid 
dendritic cells [Huard, B., et al 1994] [Workman, C. J., et al 2009] [Gagliani, N., et al 2013]. 
Because of its proposed role on both effector T cells and Tregs, LAG-3 is one of several 
immune checkpoint molecules where simultaneous blockade of both cell populations has the 
potential to enhance antitumor immunity [Andrews, L. P., et al 2017]. 
LAG-3 is structurally related to CD4 and a member of the Ig superfamily. Like CD4, its 
ligand is MHC Class II molecules [Huard, B., et al 1995] [Triebel, F., et al 1990]. Interaction 
with its ligand leads to dimerization and signal transduction resulting in altered T-cell 
activation. Following T-cell activation, LAG-3 is transiently expressed on the cell surface. A 
large proportion of LAG-3 molecules are found in intracellular stores and can be rapidly 
translocated to the cell membrane upon T-cell activation [Woo, S. R., et al 2010]. LAG-3 
expression is regulated at the cell surface by extracellular cleavage to yield a soluble form of 
LAG-3 (sLAG-3), which can be detected in serum [Li, N., et al 2007]. Expression of LAG-3 
is tightly regulated and represents a self-limiting mechanism to counter uncontrolled T-cell 
activity.
LAG-3 is commonly coexpressed with PD-1 on anergic/exhausted T-cells, and both in vitro
and in vivo data indicate that dual blockade of LAG-3 and PD-1 can have a synergistic 
impact on reversing tumor-specific anergy [Camisaschi, C., et al 2010] [Matsuzaki, J., et al 
2010].
In samples collected from human patients, LAG-3 and PD-1 coexpression has been 
correlated with T-cell anergy/exhaustion. For example, tumor samples collected from 
patients with ovarian cancer contained NY ESO 1 specific CD8+ T cells that coexpressed 
high levels of PD-1 and LAG-3 [Matsuzaki, J., et al 2010]. In vitro dual blockade of these 2 
pathways was able to improve the T cells’ ability to produce IFN γ and proliferate, while 
blockade of either pathway on its own did not. Additionally, LAG-3 expression on Tregs has 
been shown to correlate with the production of cytokines traditionally thought to have an 
immunosuppressive role (eg, IL-10, TGF-β1) [Camisaschi, C., et al 2010]. LAG-3 expression 
has been identified on tumor-infiltrating Tregs in patients with head and neck squamous cell 
cancer and NSCLC as well as on tumor-infiltrating CD4+ Foxp3- (Tr1) cells in patients with 
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CRC [Jie, H. B., et al 2013] [Wei, T., et al 2015] [Chen, J. 2014]. In the patients with CRC, 
the presence of these LAG-3+ Tr1 cells expressing IL-10 was associated with disease 
progression [Scurr, M., et al 2014].
The use of favezelimab alone and in combination with other immune checkpoint inhibitors 
will be tested to potentially activate T-cells to enhance tumor killing in multiple human 
cancers that have not responded to other available therapies.
2.2.2
Preclinical and Clinical Studies
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other 
therapeutic modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses as a monotherapy in models of squamous cell carcinoma, pancreatic 
carcinoma, melanoma and CRC. Blockade of the PD-1 pathway effectively promoted CD8+ 
T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell function in vivo [Ropponen, K. M., et al 1997] [Dudley, M. E., et al 2005] [Hunder, N. 
N., et al 2008] [Pölcher, M., et al 2010] [Okazaki, T., et al 2001] [Greenwald, R. J., et al 
2005]. Experiments have confirmed the in vivo efficacy of PD-1 blockade as a monotherapy 
as well as in combination with chemotherapy in syngeneic mouse tumor models (see the 
pembrolizumab IB).
In the literature there are reports of co-blockade of PD-1 and LAG-3 with blocking 
antibodies in syngeneic mouse tumor models. Co-blockade was reported to result in greater 
tumor inhibition over either single agent in the Sal1N fibrosarcoma and MC38 colon 
adenocarcinoma tumor models [Woo, S. R., et al 2012]. However, co-blockade had little 
effect on the poorly immunogenic B16F10 melanoma model [Chen S, Lee LF, Fisher TS, 
Jessen B, 2015]. Blockade of LAG-3 alone had modest antitumor activity in the MBT-2 
bladder syngeneic mouse tumor model, whereas coblockade of LAG-3 and PD-1 (with 
28G10-mG1) resulted in greater numbers of animals with CRs and fewer numbers of animals 
with progressive disease compared to murinized anti-PD-1 alone in 2 independent studies. 
Loss of drug exposures over the course of therapy, preferentially in the combination therapy 
group, may underestimate the combination antitumor benefit. Curative murinized anti PD 1 
therapy or murinized anti-PD-1 and anti-LAG-3 combination therapy resulted in the 
establishment of long-term immune memory to MBT-2 tumor rechallenge.
2.2.3
Ongoing Clinical Studies
2.2.3.1
Ongoing Pembrolizumab Clinical Studies
Clinical trials have shown pembrolizumab monotherapy efficacy in participants with many 
different indications including advanced melanoma, NSCLC, head and neck cancer, bladder 
cancer, Hodgkin Lymphoma, triple negative breast cancer, gastric adenocarcinoma, and 
MSI-H cancers.
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In KEYNOTE-016, participants with progressive mCRC were treated with pembrolizumab at 
10 mg/kg every 2 weeks. As of JAN-2015, the primary endpoint, immune-related ORR in 
Cohort A with dMMR was 40% (4 of 10 participants), and the immune-related PFS rate at 
20 weeks was 78% (7 of 9 participants). In Cohort B, which included participants with 
non-MSI-H or MSS colorectal adenocarcinoma, the immune-related ORR was 0% (0 of 
18 participants), and the immune-related PFS rate at 20 weeks was 11% (2 of 18 participants) 
[Le, D. T., et al 2015]. KEYNOTE-028 screened a cohort of 137 participants with mCRC, 
including 33 (24%) with PD-L1-positive tumors, of which 23 participants were enrolled and 
treated with pembrolizumab. As of the data cutoff 20-JUN-2016, there was only one PR (4%) 
from the only participant who had MSI-H CRC. The ORR in MSS CRC was 0% (0 of 22) 
from this study [O'Neil, B. H., et al 2017]. In summary, pembrolizumab monotherapy had no 
activity in either MSS or pMMR mCRC. 
Ongoing clinical trials of pembrolizumab monotherapy or in combination are being 
conducted in advanced melanoma, nonsmall cell lung cancer, and a number of other 
advanced solid tumor indications and hematologic malignancies. For additional study details 
please refer to the pembrolizumab IB.
2.2.3.2
Ongoing Favezelimab Clinical Studies
Clinical studies for favezelimab or other mAb targeting LAG-3 are ongoing. Preliminary 
efficacy and safety data from the favezelimab first-in-human study (MK 4280-001) are 
provided in Section 2.1, as well as in the MK-4280/MK-4280A IB.
Several other ongoing clinical trials are examining pembrolizumab in combination with 
favezelimab in participants with various solid and hematologic malignancies. For details, 
please refer to the MK-4280/MK-4280A IB.
2.2.4
Information on Other Study-related Therapy
Regorafenib is a small molecule inhibitor with numerous targets, including VEGF receptors 
1-3, platelet-derived growth factor receptor, tyrosine receptor kinase 2, fibroblast growth 
factor receptors, BRAF, KIT, and RET [Loree, J. M. 2017]. The Phase 3 CORRECT study
has established regorafenib as a standard of care therapy for mCRC patients who are 
refractory to oxaliplatin and irinotecan-based therapy. In this study, median OS improved 
from 5.0 months with placebo to 6.4 months with regorafenib at a preplanned interim 
analysis (HR 0.77; 95% CI: 0.64–0.94; one-sided p=0.0052) [Grothey, A., et al 2013]. The 
CORRECT study results were confirmed in a broader Asian population in another Phase 3 
study, CONCUR. Regorafenib resulted in a significantly longer OS (primary endpoint) and 
PFS compared with placebo (HR 0.55; 95%, median 8.8 vs 6.3 months; p=0.00016 and HR 
0.31; median 3.2 vs 1.7 months; p<0.0001, respectively) [Li, J., et al 2015]. Regorafenib was 
approved by the FDA for patients with mCRC who have been previously treated with 
fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, with an anti-VEGF 
therapy, and, if KRAS WT, with an anti-EGFR therapy.
The recent REDOS study compared a dose-escalation strategy of regorafenib against 
standard dosing [Bekaii-Saab, T. S., et al 2019]. OS was 9.8 months with dose escalation, 
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compared to 6.0 months for standard dosing. However, the study was relatively small and 
consisted of only 123 participants randomized between the 2 groups. Thus, this study will 
allow investigators the option of either dosing strategy for participants treated with 
regorafenib.
TAS-102 is an orally administered combination of a thymidine-based nucleic acid analogue, 
trifluridine and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Trifluridine is 
the active cytotoxic component of TAS-102; its triphosphate form is incorporated into DNA, 
with such incorporation appearing to result in antitumor effects [Tanaka, N., et al 2014]. 
Tipiracil hydrochloride is a potent inhibitor of thymidine phosphorylase and, when combined 
with trifluridine to form TAS-102, prevents the rapid degradation of the trifluridine, resulting 
in the maintenance of adequate plasma levels of the active drug.
The Phase 3 RECOURSE study of TAS-102 plus best supportive care versus placebo plus 
best supportive care in participants with metastatic CRC refractory to standard 
chemotherapies increased OS from 5.3 months to 7.1 months compared with placebo 
(HR 0.68; 95% CI: 0.58–0.81, p<0.001) in treatment-refractory mCRC [Mayer, R. J., et al 
2015]. From these results, both regorafenib and TAS-102 have been recognized as standard 
treatments for refractory mCRC.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Extended duration of clinical benefit coupled with favorable tolerability and toxicity have 
been the hallmark of pembrolizumab monotherapy in many tumor types including 
MSI-H/dMMR mCRC. Based on the available preclinical and clinical information, including 
the unmet medical need for heavily pretreated patients, who have neither dMMR nor MSI-H 
tumors, the benefit/risk of the MK-4280A appear reasonable to evaluate in a Phase 3 clinical 
study.
Thus, the coformulation regimen being examined in the current trial has the potential to 
provide improvement of efficacy without toxicity of chemotherapy in previously treated 
mCRC.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Throughout this protocol, the term response evaluation criteria in solid tumors refers to the 
adjustment of RECIST 1.1 to include a maximum of 10 target lesions and a maximum of 
5 target lesions per organ. Refer to Section 4.2.1.1 for further details.
In males and females with mCRC whose tumors are positive for PD-L1 CPS≥1, have pMMR 
status based on IHC testing at screening, and have progressed on or could not tolerate prior 
line(s) of therapy for mCRC:
Primary Objective
Primary Endpoint
•
To compare MK 4280A to standard 
of care (regorafenib or TAS-102) with 
respect to overall survival.
•
Hypothesis (H1): MK-4280A is 
superior to standard of care with respect to 
overall survival.
•
Overall survival: The time from 
randomization to death due to any cause.
Secondary Objectives
Secondary Endpoints
•
To compare MK 4280A to standard 
of care with respect to progression free 
survival per RECIST 1.1 as assessed by 
BICR.
•
Hypothesis (H2): MK-4280A is 
superior to standard of care with respect to 
progression free survival per RECIST 1.1 
by BICR.
•
Progression-free survival: The time 
from randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
•
To compare MK 4280A to standard 
of care with respect to objective response 
rate per RECIST 1.1 as assessed by BICR
•
Hypothesis (H3): MK-4280A is 
superior to standard of care with respect to 
ORR per RECIST 1.1 by BICR.
•
Objective response: complete 
response or partial response.
•
To assess the efficacy of MK-4280A 
and standard of care with respect to duration 
of response per RECIST 1.1 by BICR.
•
Duration of response: the time from 
first response (complete response or partial 
response) to subsequent disease progression 
or death from any cause, whichever occurs 
first.
•
To determine the safety and 
tolerability of MK-4280A and standard of 
care.
•
Adverse event
•
Study intervention discontinuation 
due to AEs
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•
To compare the change from 
baseline in global health status/QoL, 
physical functioning, appetite loss and 
bloating for MK-4280A versus standard of 
care.
•
Score for the following Patient-
Reported Outcomes scales/items: global 
health status/QoL (EORTC QLQ-C30 items 
29 and 30), physical functioning (EORTC 
QLQ-C30 items 1-5), appetite loss (EORTC 
QLQ-C30 item 13) and bloating (EORTC 
QLQ-CR29 item 37).
•
To compare the time to deterioration 
in global health status/QoL, physical 
functioning, appetite loss and bloating for 
MK-4280A versus standard of care.
•
Time-to-deterioration, defined as the 
time from baseline to the first onset of a 
≥10-point deterioration from baseline in 
global health status/QoL (EORTC QLQ-
C30 items 29 and 30), physical functioning 
(EORTC QLQ-C30 items 1-5), appetite loss 
(EORTC QLQ-C30 item 13) and bloating 
(EORTC QLQ-CR29 item 37).
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, parallel-group, multi-site, open-label, safety 
and efficacy study of MK-4280A (Arm A) versus standard of care (Arm B) in approximately 
432 participants with metastatic (Stage IV as defined by AJCC, NCCN Guidelines 
Version 2.2018: Colon Cancer [National Comprehensive Cancer Network 2018]) colorectal 
adenocarcinoma whose tumors are positive for PD-L1 CPS≥1, have pMMR status based on 
IHC testing at screening, and have progressed on or could not tolerate previous treatment 
with fluoropyrimidine (or capecitabine), oxaliplatin, and irinotecan, ±VEGF agent, ±EGFR 
agent (if RAS WT left-sided tumor), and +RAF inhibitors (if BRAF V600E mutated). 
Participants must have measurable disease per RECIST 1.1, as determined by the 
investigator, and an ECOG PS of 0 to 1 at enrollment.
Participants may enroll regardless of RAS status; participants with no RAS mutations and 
left-sided tumors must have been treated with anti-EGFR agents as this subgroup is known to 
benefit from this therapy. Likewise, participants with and without BRAF mutations may 
enroll, though the efficacy of RAF inhibitors in patients with V600E mutations argues for the 
requirement that participants have progressed on this therapy before enrolling in this study.
After obtaining documented informed consent, candidate participants will be screened 
against all the eligibility criteria. Eligible participants will be randomly assigned to study 
intervention in a 1:1 ratio. 
Randomization will be stratified by geographic region of the enrolling site (Asia Pacific; 
EMEA/Americas), presence of liver metastasis (yes, no), and time from initial diagnosis of 
metastatic disease to randomization (≥18 months, <18 months). 
The study will be conducted in conformance with Good Clinical Practices (GCPs).
The primary endpoint of the study is OS. Secondary endpoints include PFS, OR, DOR per 
RECIST 1.1, safety and tolerability and PRO endpoints. On-study imaging assessments 
performed Q9W will be calculated from the date of randomization and independent of 
treatment delays for both treatment arms. 
For participants in the study, all disease assessments, including expedited verification of PD 
by BICR, will be made using RECIST 1.1. Tumor imaging showing site-assessed PD will be 
submitted for verification by BICR. In Arm A, treatment beyond centrally verified PD per 
RECIST 1.1 may be permitted at the discretion of the investigator (if, eg, no new symptoms, 
stable or decreasing tumor markers CEA) after consultation with the Sponsor. Updated 
documented informed consent for continuing treatment on Arm A must be obtained prior to 
receiving the next study treatment (Section 8.1.1.1). Participants in Arm B may not crossover 
to Arm A intervention.
Participants on Arm A may receive up to 35 cycles of MK-4280A (approximately 2 years) in 
the Intervention Phase.
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Participants receiving MK-4280A who attain locally confirmed CR per RECIST 1.1 by 
2 tumor scans at least 4 weeks apart and who have received at least 8 cycles (approximately 
6 months) with MK-4280A may discontinue intervention at the discretion of the investigator 
after receiving at least 2 cycles beyond the initial determination of a CR.
Adverse events will be monitored throughout the study and graded in severity according to 
the guidelines outlined in the NCI CTCAE v5.0 (Section 10.3.4). Each participant will be 
monitored for AEs and SAEs (refer to Section 8.4.1 for details). Because neither 
pembrolizumab monotherapy, nor favezelimab have activity as monotherapies in MSS CRC, 
if study intervention is discontinued for toxicity, single-agent therapy will not be offered.
Participants may undergo resection of the primary tumor and/or metastasectomy with 
curative intent after achieving a response to study intervention that converts previously 
unresectable disease to resectable disease, if deemed eligible per investigator’s discretion in a 
multidisciplinary approach according to his/her institutional standard, and with Sponsor 
consultation. After surgery, when clinically appropriate and after the surgical wound is fully 
healed participant may resume the same therapy they were receiving pre-operatively starting 
at least 4 weeks and no more than 12 week post-surgery, unless approved by the Sponsor. 
Post-operative therapy may continue until verified progression by BICR, intolerability, or for 
Arm A, have received up to 35 cycles of MK-4280A.
The first post-operative tumor scan should be performed at a minimum of no less than 4 
weeks after surgery and no more than 8 weeks after surgery and prior to the start of the next 
treatment cycle (Section 8.2.1.2). If treatment does not resume within 12 weeks after surgery, 
the investigator should consult with the Sponsor. In addition, participants who discontinue 
study intervention for reasons other than radiographic disease progression will have 
posttreatment follow-up for disease status Q9W (± 7 days) from date of randomization until 
disease progression (verified in an expedited manner by BICR per RECIST 1.1), start of a 
non-study anticancer therapy, consent withdrawal, becoming lost to follow-up, death, or end 
of the study. 
While off study intervention, participants who undergo surgical resection of visible disease 
may demonstrate disease progression in non-surgical sites. In this instance, disease 
progression might not necessarily reflect resistance to study intervention. Accordingly, 
participants from both study arms who develop isolated lesion/tumor growth postoperatively 
(eg, while off study intervention) may resume the previously assigned study intervention. 
The investigator must assess overall clinical benefit to the participant and consult the 
Sponsor prior to resuming study intervention.
The sample size is estimated based on the primary endpoint OS, and the required target 
events to detect the superiority of MK-4280A versus standard of care in the comparison of 
OS.
Details regarding IA are provided in Section 9.7. An eDMC will serve as the primary 
reviewer of the treatment-level results and will make recommendations for discontinuation or 
modification of the study. These recommendations will be made to an executive oversight 
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committee of the Sponsor. The eDMC responsibilities and review schedules will be outlined 
in the eDMC charter.
After enrollment of the global portion of the study is complete, the study may remain open to 
enrollment in China alone until the target number of participants in China has been enrolled 
to meet local regulatory requirements. This extension portion of the study will be identical to 
the global study, (eg, inclusion and exclusion criteria, study endpoints, primary and 
secondary objectives, and study procedures). 
Details regarding specific benefits and risks for participants participating in this clinical study 
may be found in the accompanying IB and ICF documents.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
MK-4280A is being developed to treat solid tumors and hematologic malignancies.
Randomization will be performed to avoid bias in the assignment of participants to study 
intervention, to increase the likelihood that known and unknown participant attributes 
(geographic region and presence of liver metastasis) are balanced across intervention arms, 
and to ensure the validity of statistical comparisons between intervention arms.
 
 
 
 
 
 
 
 
 
 
 
The study will be an open-label trial, as chemotherapy refractory patients have short overall 
survival and as OS is a concrete endpoint that will limit any bias. The paucity of alternative 
therapies will also serve to limit bias from lack of blinding. Moreover, the frequency of hand-
foot syndrome seen in regorafenib, and the frequency of cytopenias seen with TAS-102 
would render any attempt at blinding effectively futile.
In the landmark CORRECT study, subgroup analysis of OS significantly favored regorafenib 
versus placebo for participants from North America and Western Europe, but not Asia or 
Eastern Europe [Grothey, A., et al 2013]. In contrast, subgroup analysis of PFS significantly 
favored regorafenib compared with placebo, except for patients from Eastern Europe, for 
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whom the difference was not significant. Thus, it is important to investigate whether patients 
from different geographic region will respond differently to pembrolizumab plus favezelimab 
versus regorafenib.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
OS will serve as the primary endpoint for this study. OS has been recognized as the gold 
standard for the demonstration of superiority of a new antineoplastic therapy in randomized 
clinical studies. In 3L therapy of mCRC, OS is the most important endpoint, as standard of 
care regorafenib and TAS-102 are associated with median OS of only 6.4 and 7.1 months, 
respectively [Grothey, A., et al 2013] [Mayer, R. J., et al 2015]. A more recent estimate from 
the SUNLIGHT study [Tabernero, J., et al 2023] showed a median survival of 7.5 months.
The secondary efficacy endpoints will include PFS, OR, and DOR per RECIST 1.1 as 
assessed by BICR. These endpoints are commonly accepted endpoints by both regulatory 
authorities and the oncology community.
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures. 
Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 to allow a 
maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is 
needed to adequately represent the tumor burden. Refer to Section 8.2.1.4 for additional 
detail.
4.2.1.2
Safety Endpoints
The safety and tolerability of MK-4280A and of standard of care will be characterized in this 
study. See country-specific requirements in Appendix 7.
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 5.0.
4.2.1.3
Patient-reported Outcomes
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4.2.2
Rationale for the Use of Comparator
Regorafenib and TAS-102 are selected as the comparators included in this study since they 
are the globally accepted standard of care for mCRC that are refractory to fluoropyrimidine-, 
oxaliplatin-, and irinotecan-based chemotherapy, as recommended by formal guidelines 
(NCCN, ESMO, and JSCCR). Moreover, as both regorafenib and TAS-102 are not available 
in all regions and standard of care will be locally sourced, both options will be allowed in this 
study.
4.3
Justification for Dose
4.3.1
Justification of Favezelimab Dose
The planned dose of favezelimab in this study is 800 mg Q3W. Preliminary PK data from 
participants treated on MK-4280-001 in participants receiving favezelimab alone and in 
combination with pembrolizumab in advanced solid tumors at doses from 7 to 800 mg 
showed that serum favezelimab exposures increased in a dose-dependent manner. 
Preliminary PK profiles of favezelimab exposures suggest that target receptor-mediated 
clearance (reflecting target engagement of membrane LAG-3) of favezelimab was more 
likely to stay saturated at ≥700 mg dose compared with lower doses considering PK Ctrough
variability observed. Additionally, efficacy data from a randomized dose-finding study in 
participants with gastric cancer in MK-4280-001 suggested possible trend towards better 
efficacy at higher doses. Favezelimab given alone and in combination with pembrolizumab 
has been tolerable at all dose levels tested from 7 to 800 mg with no clear dose dependence in 
the type or frequency of AEs. For more detailed information, please refer to the 
MK-4280/MK-4280A IB. Therefore, based on the totality of preliminary data accumulated 
so far, the Sponsor has elected 800 mg dose of favezelimab in this Phase 3 study.
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4.3.2
Justification of Pembrolizumab Dose
The planned dose of pembrolizumab for this study is 200 mg Q3W. 
Based on the totality of data generated in the Keytruda development program, 200 mg Q3W 
is an appropriate dose of pembrolizumab for adults across all indications. As outlined below, 
this dose is justified by:
•
Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to the 
pembrolizumab IB)
•
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). All of these studies showed flat dose- and E-R relationships across the doses 
studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 
200 mg fixed dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-E-R relationships were also observed in other tumor types including 
head and neck cancer, bladder cancer, gastric cancer, and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These 
findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating TMDD conclusively showed saturation of PD-1 in systemic 
circulation at doses much lower than 200 mg Q3W. Second, a PBPK analysis was conducted 
to predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 
expression. This evaluation concluded that pembrolizumab at 200 mg Q3W achieves full 
PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
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in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics and given that fixed dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.3
Justification of the Coformulation MK-4280A
Given the Sponsor’s observation of limited favezelimab monotherapy activity and the 
observed efficacy and tolerability of favezelimab when used in combination with 
pembrolizumab in the ongoing Phase 1 clinical study of MK-4280-001, the Sponsor 
developed MK-4280A, a coformulated product of favezelimab in combination with 
pembrolizumab. PK, safety, and efficacy are comparable in MSS CRC participants treated 
with MK-4280A compared to separately administered favezelimab and pembrolizumab on 
MK-4280-001 (see MK-4280/MK-4280A IB for details). Compared with sequential 
administration of separate formulations, the single coformulation vial could provide 
significant benefit to patients and providers, including simplified preparation, reduced 
infusion times, and reduction of potential errors in drug administration.
4.3.4
Justification of Regorafenib and TAS-102 Doses
Doses and regimens for standard of care chemotherapy were selected based on standard 
clinical practice and should be prepared per local and institutional guidelines according to the 
approved product labels.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
Male/female participants with histologically confirmed diagnosis of PD-L1 CPS≥1 
metastatic colorectal adenocarcinoma who are pMMR by IHC and are at least 18 years of age 
will be enrolled in this study.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. The participant must have a histologically confirmed colorectal adenocarcinoma that is 
metastatic and unresectable (Stage IV as defined by AJCC eighth edition) [National 
Comprehensive Cancer Network 2018].
Note: upon providing documented informed consent, the participants tissue sample will 
be sent for central testing of PD-L1 expression and MMR status. Participants who test 
positive for PD-L1 (CPS≥1) and who have IHC consistent with pMMR tumors will 
qualify to participate in the study.
Note: RAS and RAF mutation status must be known.
2. Have measurable disease per RECIST 1.1 as assessed by the local site investigator. 
Lesions situated in a previously irradiated area are considered measurable if progression 
has been demonstrated in such lesions.
3. Has been previously treated for their disease and radiographically progressed on or after 
or could not tolerate standard treatment, which must include ALL of the following agents 
if approved and locally available in the country where the participant is randomized: 
Note: Adjuvant chemotherapy is regarded as prior systemic therapy if there is 
documented disease progression within 6 months of chemotherapy completion
Note: A participant who has withdrawn from standard treatment due to unacceptable 
toxicity warranting discontinuation of treatment and precluding retreatment with the same 
agent prior to progression of disease will also be eligible to enter the study. If a 
participant is determined to be intolerant to a prior line of therapy, the participant must 
have had a minimum of 2 cycles of that therapy.
a.
Fluoropyrimidine, irinotecan and oxaliplatin. 
Note: Capecitabine is acceptable as equivalent to fluorouracil in prior therapy 
(XELOX/CAPOX and XELIRI are considered equivalent to FOLFOX and FOLFIRI, 
respectively).
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Note: Participants who have previously received fluoropyrimidine, oxaliplatin, and 
irinotecan as part of the same and only chemotherapy regimen, eg, FOLFOXIRI or 
FOLFIRINOX, may participate the study.
b. With or without an anti-VEGF monoclonal antibody (eg, bevacizumab)
c.
At least one of the anti-EGFR monoclonal antibodies (cetuximab or panitumumab) 
for RAS WT participants with left sided tumors.
Note: For participants with ctDNA RAS mutant but RAS mutation negative in tissue, 
enrollment into the study before anti-EGFR administration is allowed.
d. Participants with BRAF v600E mutations must have been treated with a RAF 
inhibitor with or without binimetinib. Participants with BRAF mutations that are not 
v600E are not required to have received RAF inhibitor therapy.
4. Submit an archival (≤ 5 years) or newly obtained tumor tissue sample that has not been 
previously irradiated to enable central laboratory testing of PD-L1 and MMR status. 
FFPE blocks are preferred to slides.
5. Have an ECOG PS of 0 to 1 within 10 days prior to first dose of study intervention.
6. Have a life expectancy of at least 3 months, based on the investigator assessment.
7. Have the ability to swallow and retain oral medication and not have any clinically 
significant gastrointestinal abnormalities that might alter absorption.
8. Have adequate organ function as defined in the following table (Table 4). Specimens 
must be collected within 10 days prior to the start of study intervention.
Note: Participants may have their blood retested if they do not meet criteria greater than 
10 days prior to the anticipated first dose of study intervention.
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Table 4
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
ANC
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥60 mL/min for participant with creatinine 
levels >1.5 × institutional ULN
Urinalysis
Urine Protein <1g/24h or <2 (<100mg/dL) on 
a urine dipstick testc
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Coagulation
INR or PT
aPTT
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT 
is within therapeutic range of intended use of 
anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic-pyruvic transaminase); ANC=Absolute neutrophil 
count; aPTT=Activated partial thromboplastin time; AST (SGOT)=aspartate aminotransferase (serum 
glutamic-oxaloacetic transaminase); CrCl=creatinie clearance; GFR=glomerular filtration rate; 
INR=International normalized ratio; pRBC=packed red blood cell; PT=prothrombin time; ULN=upper 
limit of normal.
a
Criteria must be met without erythropoietin dependency and without pRBC transfusion within last 2 
weeks. 
b
CrCl should be calculated per institutional standard.
c
Participants with proteinuria ≥2+ (≥100 mg/dL) on urinalysis or urine dipstick testing will undergo 24-
hour urine collection for quantitative assessment of proteinuria
Note:
This table includes eligibility-defining laboratory value requirements for intervention; laboratory 
value requirements should be adapted according to local regulations and guidelines for the administration 
of specific chemotherapies.
Demographics
9. Is male or female, ≥18 years of age at the time of obtaining the documented informed 
consent.
10. Male or Female Participants
Male Participants
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least the time needed to eliminate each study intervention after 
the last dose of study intervention. The length of time required to continue contraception for 
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each study intervention is as follows: TAS-102 (90 days) and regorafenib (90 days). No 
contraception requirements are needed for males receiving MK-4280A.
•
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 unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause Appendix 5) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
•
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than 
the requirements above, the local label requirements are to be followed.
Female Participants
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least one of the following conditions applies:
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent 
basis), as described in Appendix 5 during the intervention period and for at least the time 
needed to eliminate each study intervention after the last dose of study intervention and 
agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the 
purpose of reproduction during this period. The length of time required to continue 
contraception for each study intervention is as follows: MK-4280A (120 days), TAS-102 
(180 days), and regorafenib (180 days).
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The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study intervention. 
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 or 72 hours, respectively, before the first dose 
of study intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
-
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.6.
-
Abstains from breastfeeding during the study intervention period and for at least 120 
days after study intervention.
-
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.
-
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the 
contraception requirements in the local label for any of the study interventions is 
more stringent than the requirements above, the local label requirements are to be 
followed.
Informed Consent
11. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Refer to Appendix 7 for country-specific requirements.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has previously been found to have dMMR/MSI-H tumor status determined by either IHC 
or PCR.
2. Has known active CNS metastases and/or carcinomatous meningitis or leptomeningeal 
disease. Participants with previously treated brain metastases may participate provided 
they are radiologically stable, ie, without evidence of progression for at least 28 days by 
repeat imaging (note that the repeat imaging should be performed during study 
screening), clinically stable and without requirement of steroid intervention for at least 
14 days prior to first dose of study intervention.
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3. Has a history of acute or chronic pancreatitis.
4. Has neuromuscular disorders associated with an elevated creatine kinase (eg, 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy).
5. Has clinically significant cardiovascular disease within 12 months from first dose of 
study intervention, including New York Heart Association Class III or IV congestive 
heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or 
cardiac arrhythmia associated with hemodynamic instability.
Note: Participants with cardiac failure NYHA Class II, III and IV are not permitted to 
receive treatment with regorafenib for Arm B.
Note: Medically controlled arrhythmia would be permitted.
6. Has urine protein ≥1 g/24h.
Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urinalysis or urine dipstick 
testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. 
7. A WOCBP who has a positive urine/serum pregnancy test within 24/72 hours prior to the 
first dose of study intervention (Appendix 5). If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.
Note: If 72 hours have elapsed between the screening pregnancy test and the first dose of 
study intervention, another pregnancy test (urine or serum) must be performed and must 
be negative in order for the participant to start receiving study intervention.
Prior/Concomitant Therapy
8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, 
anti-LAG-3 antibody, with a TKI (eg, lenvatinib) other than RAF inhibitors (binimetinib 
is permitted if combined with a RAF inhibitor), or with an agent directed to another 
stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
9. Has previously received regorafenib or TAS-102.
10. Has received prior systemic anticancer therapy including investigational agents within 
28 days before randomization.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
Note: If the participant had a major operation, the participant must have recovered 
adequately from the procedure and/or any complications from the operation before 
starting study intervention.
11. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
not have had radiation pneumonitis. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-CNS disease.
12. Has received a live or live-attenuated vaccine within 30 days before the first dose of 
study intervention. Administration of killed vaccines are allowed. 
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Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a given country 
is allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, or 
inactivated vaccines. These vaccines will be treated just as any other concomitant 
therapy. Refer to Section 6.5 for information on COVID-19 vaccines.
Note: Investigational vaccines (ie, those not licensed or approved for emergency use) are 
not allowed.
Prior/Concurrent Clinical Study Experience
13. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 28 days before the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 28 days after the last dose of the previous investigational 
agent.
Diagnostic Assessments
14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 10 days prior the first dose of study medication.
15. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, carcinoma in situ, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) 
that have undergone potentially curative therapy are not excluded.
16. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
17. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
18. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
19. Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or 
bacterial infections).
Note: No testing for active infections is required unless mandated by local health 
authority.
20. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority.
21. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
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22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
23. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
24. Has had an allogenic tissue/solid organ transplant.
Refer to Appendix 7 for country-specific requirements.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
5.3.3
Activity Restrictions
No restrictions regarding activity and exercise are required for this study.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Rescreening information is provided in Section 8.12.1.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies provided by the Sponsor will be packaged to support enrollment. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 5.
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Table 5
Study Interventions
Arm 
Name Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
IMP or 
NIMP/AxMP Sourcing
Arm 
A
Experimental MK-4280A
Drug
Solution
20 mg/mL 
favezelimab + 
5 mg/mL 
pembrolizumab 
for a total 
protein content 
of 25 mg/mL
800 mg 
MK-
4280 + 
200 mg 
MK-
3475
IV Infusion
Day 1, then Q3W, up 
to 35 infusions
Test 
Product
IMP
Sponsor
Arm 
B
Active 
Comparator
regorafenib
Drug
Tablet
40 mg/tablet
160 mg
Oral
4-week cycle: QD 
Days 1-21, no dose 
Days 22-28
Comparator IMP
Provided 
centrally 
by the 
Sponsor or 
locally by 
the trial 
site, 
subsidiary, 
or 
designee
Arm 
B
Active 
Comparator
TAS-102
Drug
Tablet
15 mg 
trifluridine/6.14 
mg tipiracil;
20 mg 
trifluridine/8.19 
mg tipiracil
35 
mg/m2
Oral
4-week cycle: BID 
Days 1 to 5 and 8 to 
12 of each 28-day 
treatment cycle (no 
dose days 6, 7, and 
13-28)
Comparator IMP
Provided 
centrally 
by the 
Sponsor or 
locally by 
the trial 
site, 
subsidiary, 
or 
designee
BID=twice daily; EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; IMP=investigational medicinal product; 
NIMP/AxMP=noninvestigational/auxiliary medicinal product; Q3W=every 3 weeks; QD=daily.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 5 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
6.2.1.1
MK-4280A
Details on preparation and administration of MK-4280A are provided in the Pharmacy 
Manual.
6.2.1.2
Regorafenib
Regorafenib will be prepared and administered as per the approved product label and should 
follow local therapeutic guidelines. It is recommended that participants start with 80 mg 
regorafenib QD on days 1 to 7, then 120 mg QD on days 8 to 14, followed by 160 mg QD on 
days 15 to 21, and 160 mg QD on subsequent cycles (days 1 to 21) [Bekaii-Saab, T. S., et al 
2018], although investigators are allowed to follow local/institutional guidelines for 
regorafenib.
6.2.1.3
TAS-102
TAS-102 will be prepared and administered as per the approved product label and should 
follow local therapeutic guidelines.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to MK-4280A study 
intervention and standard of care study intervention, respectively.
The SOC study intervention to be used, regorafenib or TAS-102, must be chosen by the 
investigator before randomization and reasons for selection of one or the other treatment will 
be documented (refer to Section 8.1.6.1).
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. Geographic region (Asia Pacific; EMEA/Americas)
2. Presence of liver metastasis (Yes, No)
3. Time from initial diagnosis of metastatic disease to randomization (≥18 months,
<18 months)
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the study intervention administered.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record.
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Refer to Section 6.6.1 for dose modification and toxicity management for irAEs associated 
with MK-4280A and for other allowed dose interruption of MK-4280A.
When participants are dosed MK-4280A 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 ID will be confirmed at the 
time of dosing by a member of the study-site staff other than the person administering the 
study intervention. 
For Arm B, the first dose of Cycle 1 of standard of care must be given to the participant at 
the site and will be witnessed by the investigator and/or study staff, and/or qualified designee 
per institutional guidelines and procedures. For medication taken at home, site staff will 
make tablet counts at regular intervals during the Intervention Phase. Compliance will be 
calculated by the Sponsor based on drug accountability documented by the site staff and 
monitored by the Sponsor/designee. The objective is 100% compliance, and investigators and 
their staff should evaluate compliance at each visit and take appropriate steps to optimize 
compliance.
6.5
Concomitant Therapy
The following medications and vaccinations are prohibited during the study:
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study. 
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-incompetent 
adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy.
•
Systemic glucocorticoids except when used for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology
-
For the prevention of emesis 
-
To premedicate for IV contrast allergies
-
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses >10 
mg/day prednisone equivalent)
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
•
Other glucocorticoid use except when used for the following purposes:
-
For topical use or ocular use
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-
Intraarticular joint use
-
For inhalation in the management of asthma or chronic obstructive pulmonary disease
If there is a clinical indication for any medications or vaccinations prohibited, the 
investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, and the Sponsor.
If the investigator determines that a participant requires any of the following prohibited 
medications and vaccinations for any reason during the study intervention period, study 
intervention (if combination, specify all) must be discontinued:
•
Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not 
specified in this protocol
•
Investigational agents other than those specified in the protocol
•
Radiation therapy
•
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion
•
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed
The investigator must refer to the up-to-date regorafenib or TAS-102 product label, for 
guidance on prescribing information for regorafenib or TAS-102, for Arm B. The 
investigator should be knowledgeable of prohibited medications or medications to be used 
with precaution. Specific to the use of regorafenib, avoid concomitant use of strong CYP3A4 
inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) and 
inhibitors of CYP3A4 activity (eg, clarithromycin, grapefruit juice, itraconazole, 
ketoconazole, posaconazole, telithromycin, and voriconazole). CYP3A4 inhibitors and 
inductors may impact mean exposure of regorafenib. UGT1A9 inhibitors (eg, phenytoin, 
fosphenytoin, diflunisal) should also be avoided.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
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All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
See country-specific requirements in Appendix 7.
6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of AEs with potential immunologic
etiology are outlined along with the dose modification guidelines in Section 6.6. See 
country-specific requirements in Appendix 7.
6.6
Dose Modification (Escalation/Titration/Other)
CTCAE v5.0 must be used to grade the severity of AEs (Section 10.3.4). If appropriate, the 
investigator may attribute each toxicity event for Arm A to MK-4280A and use dose 
modification table (Table 6). For Arm B, management of toxicity events attributed by the 
investigator to regorafenib or TAS-102 should be consistent with local dose modification 
guidelines and/or local regulations, if more stringent than FDA and/or SMPC guidelines.
All AEs should be followed as clinically appropriate until stabilization or resolution. The 
drug to which the investigator is attributing to the AE must be documented (ie, associated 
eCRFs, patient notes). Exceptional circumstances to following the dose modification tables 
below should be consulted with the Sponsor.
Dose modifications are always based on the previous cycle.
For Arm B, study intervention may be interrupted for situations other than treatment-related 
AEs such as medical or surgical events and/or unforeseen circumstances not related to study 
intervention. However, study intervention is to be restarted within 3 weeks (21 days) of the 
originally scheduled dose, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the participant's study record.
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
exposure may represent an immune-related response. These irAEs may occur shortly after 
the first dose or several months after the last dose of pembrolizumab monotherapy, 
coformulation, or IO combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab monotherapy, coformulation, or IO 
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combination administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of 
the evaluation. 
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult. Therefore, while the investigator may attribute a 
toxicity event to pembrolizumab monotherapy, coformulations, or IO combinations, 
pembrolizumab monotherapy, coformulations, or IO combinations must be held according to 
the criteria in the Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events.
Holding Study Interventions: 
When study interventions are administered in combination and if the AE is considered 
immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should 
be held according to recommended Dose Modification criteria.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO 
combinations.
Restarting Study Interventions: 
Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as 
described below:
If the toxicities do resolve and conditions are aligned with what is defined in the Dose 
Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, 
coformulations, or IO combinations may be restarted at the discretion of the investigator. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 6.
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Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive 
treatment should begin if the irAEs are not controlled by corticosteroids.
2. Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve 
or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4. If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE 
decreased to ≤Grade 1 after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
•   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
•   Add prophylactic 
antibiotics for opportunistic 
infections
•   Monitor participants for signs and 
symptoms of pneumonitis
•   Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
Diarrhea/Colitis 
Grade 2 or 3
Withhold
•   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
•   Monitor participants for signs and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in stool 
with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
•   Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis
•   Participants with diarrhea/colitis should 
be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid intake is 
not feasible, fluid and electrolytes should 
be substituted via IV infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 2a
Withhold
•   Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
•   Monitor with liver function tests 
(consider weekly or more frequently until 
liver enzyme value returned to baseline or 
is stable)
Grade 3b or 4c
Permanently 
discontinue
•   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of b-cell 
failure
Withholdd
•   Initiate insulin 
replacement therapy for 
participants with T1DM
•   Administer 
antihyperglycemic in
participants with 
hyperglycemia
•   Monitor participants for hyperglycemia 
or other signs and symptoms of diabetes
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
Hypophysitis
Grade 2
Withhold
•   Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
•   Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinued
Hyperthyroidism
Grade 2
Continue
•   Treat with nonselective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
•   Monitor for signs and symptoms of 
thyroid disorders
Grade 3 or 4
Withhold or 
permanently 
discontinued
Hypothyroidism
Grade 2, 3 or 4
Continue
•   Initiate thyroid 
replacement hormones (eg, 
levothyroxine or 
liothyronine) per standard of 
care
•   Monitor for signs and symptoms of 
thyroid disorders
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
•   Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper
•   Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
•   Based on severity of AE 
administer corticosteroids
•   Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
Myocarditis
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion 
of myocarditis 
(which was 
previously 
myocarditis Grade 
1 using CTCAE 
v4.0)
Withhold
•   Based on severity of AE 
administer corticosteroids
•   Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
•   Based on severity of AE 
administer corticosteroids
•   Ensure adequate evaluation to confirm 
etiology or exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
•   Based on severity of AE 
administer corticosteroids
•   Ensure adequate evaluation to confirm 
etiology or exclude other causes
Grade 3
Withhold or 
discontinue based on 
the evente
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
AE(s)=adverse event(s); ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-
Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a
AST/ALT: >3.0 to 5.0 ´ ULN if baseline normal; >3.0 to 5.0 ´ baseline, if baseline abnormal; 
bilirubin: >1.5 to 3.0 ´ ULN if baseline normal; >1.5 to 3.0 ´ baseline, if baseline abnormal.
b
AST/ALT: >5.0 to 20.0 ´ ULN if baseline normal; >5.0 to 20.0 ´ baseline, if baseline abnormal; 
bilirubin: >3.0 to 10.0 ´ ULN if baseline normal; >3.0 to 10.0 ´ baseline, if baseline abnormal.
c
AST/ALT: >20.0 ´ ULN if baseline normal; >20.0 ´ baseline, if baseline abnormal; 
bilirubin: >10.0 ´ ULN if baseline normal; >10.0 ´ baseline, if baseline abnormal.
d
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the 
investigator or treating physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to, encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing 
cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
MK-4280A
MK-4280A may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on MK-4280A associated infusion 
reaction are provided in Table 7.
Table 7
MK-4280A Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated
Increase monitoring of vital 
signs as medically indicated 
until the participant is deemed 
medically stable in the opinion 
of the investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications 
indicated for ≤24 hrs
Stop Infusion
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital 
signs as medically indicated 
until the participant is deemed 
medically stable in the opinion 
of the investigator.
If symptoms resolve within 1 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion 
rate (eg, from 100 mL/h to 
50 mL/h). Otherwise, dosing 
will be held until symptoms 
resolve and the participant 
should be premedicated for the 
next scheduled dose.
Participants who develop 
Grade 2 toxicity despite 
adequate premedication should 
be permanently discontinued 
from further study drug
intervention.
Participant may be premedicated 1.5 h 
(±30 min) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine).
Acetaminophen 500 to 1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms after 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital 
signs as medically indicated 
until the participant is deemed 
medically stable in the opinion 
of the investigator.
Hospitalization may be 
indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Participant is permanently 
discontinued from further study 
drug intervention.
No subsequent dosing
IV=intravenous; NSAID=nonsteroidal anti-inflammatory drug; PO=orally.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 
(CTCAE) at http://ctep.cancer.gov
Other Allowed Dose Interruption for MK-4280A
MK-4280A may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 9 weeks of the originally scheduled 
dose and within 12 weeks of the previously administered dose, unless otherwise discussed 
with the Sponsor. The reason for study intervention interruption is to be documented in the 
participant's study record.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
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6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled 
follow-up, even if the participant has discontinued study intervention. Therefore, all 
participants who discontinue study intervention before completion of the protocol-specified 
treatment period will still continue to be monitored in this study and participate in the study 
visits and procedures as specified in Section 1.3 and Section 8.12.4.3 unless the participant 
has withdrawn from the study Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1, require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Radiographic disease progression outlined in Section 8.2.1.5 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue 
treatment beyond disease progression).
•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.
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•
The participant requires any prohibited concomitant medications as described in Section 
6.5.
•
Arm A: Discontinuation of intervention may be considered for participants who have 
attained a confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), 
receiving 2 cycles of MK 4280A beyond the date when the initial CR was declared.
•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of study intervention.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed. 
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention. 
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. 
Refer to Section 8.12.4.3 for details regarding Survival Follow-up. See country-specific 
requirements in Appendix 7. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
•
Refer to Section 8.12.4.3 for details regarding Survival Follow-up.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
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.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within 
the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study can be found in the Laboratory Manual or Procedures Document.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
The participant may participate in the study without participating in FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
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telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.4.1
Colorectal Cancer History
The investigator or qualified designee (consistent with local requirements) will obtain prior 
and current details regarding the participant’s CRC. All prior historical information must be 
reviewed (eg, prior surgeries, radiation, other oncologic therapies).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.5.1.1
Prior Colorectal Cancer Therapy Review
The investigator or qualified designee (consistent with local requirements) will review all 
prior anticancer therapies including systemic therapies, radiation, and surgeries.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit.
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Concomitant medication review is to continue post the Safety Follow-up visit if related to an 
AE/SAE that is being followed.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.12.1.
8.1.6.1
Treatment Eligibility Assessment Form
A TEA form is included in this study to document the investigator assessment of participant 
suitability for potential treatment in Arm B with regorafenib or TAS-102 and the rationale. 
These data may be required to support reimbursement efforts for MK-4280A.
The investigator must complete this form and provide rationale to document the choice of 
regorafenib or TAS-102 before randomization.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy Manual.
It is strongly preferred that participants receive first dose of study intervention on day of 
randomization.
The first dose of Cycle 1 of oral study drug (regorafenib or TAS-102) must be taken by the 
participant while at the site.
Refer to the Pharmacy Manual for MK-4280A administration for Arm A. 
Refer to the regorafenib or TAS-102 product label, respectively, for guidance on 
administration procedures for regorafenib or TAS-102, for Arm B.
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Study intervention should begin within 3 days of randomization.
See country-specific requirements in Appendix 7.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
MK-4280A Administration (Arm A)
MK-4280A 800/200 mg will be administered as a 30-minute IV infusion Q3W. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 
minutes is permitted (ie, infusion time is 30 minutes: -5 min/+10 min). Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible.
All subsequent MK-4280A doses may be administered up to 3 days before or 3 days after the 
scheduled Day 1 of each cycle due to administrative reasons per the investigator’s judgment.
8.1.8.1.2
Regorafenib Administration (Arm B)
Participants are to take regorafenib at the same time each day on Days 1 to 21 of each cycle. 
Participants are advised to swallow the tablet whole with water following a low-fat meal. 
Any missed dose of regorafenib should be taken on the same day, as soon as the participant 
remembers, although 2 doses of regorafenib should not be taken on the same day to make up 
for a missed dose from the previous day. Participants are not to take any doses of regorafenib 
on Days 22 to 28 of each cycle. Refer to the regorafenib product label for current prescription
information.
8.1.8.1.3
TAS-102 Administration (Arm B)
Participants are to take TAS-102 twice daily on Days 1 through 5 and Days 8 through 12 of 
each 28-day cycle. Participants are to swallow the tablets whole with water after a meal. 
Participants are not to take 2 doses of TAS-102 at once to make up for a missed dose. 
Participants are not to take any doses of TAS-102 on Days 6 and 7 and 13 to 28 of each 
cycle. Refer to the TAS-102 package insert for current prescription information. For 
calculation of TAS-102 dosing based on weight/BSA, refer to the website 
https://www.lonsurfhcp.com/dosing.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.12.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the End-of-Treatment/Discontinuation visit at the time of withdrawal. 
Any AEs that are present at the time of withdrawal should be followed in accordance with 
the safety requirements outlined in Section 8.4.
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8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Tumor Tissue for Biomarker Status
During the screening period, a tumor sample for each participant is required and is to be:
•
A newly obtained tissue sample of a tumor lesion, which was not previously irradiated
Or
•
An archival tumor tissue sample if a new biopsy is unavailable (depending on protocol 
requirements)
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
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Details pertaining to tumor tissue submission can be found in the Procedures Manual.
The central laboratory will use the tissue sample to ascertain PD-L1 status using the PD-L1 
IHC 22C3 pharmDx (Investigational Use Only) diagnostic kit. The diagnostic test is identical 
to the US FDA-approved PD-L1 IHC 22C3 pharmDx diagnostic kit except it is labeled IUO. 
The PD-L1 IHC 22C3 pharmDx assay kit is currently approved to assess PD-L1 status.
The MMR status must be determined by central laboratory testing prior to randomization and 
the participant must have pMMR status based on IHC testing. Colorectal tumor MMR status 
is determined by IHC, while MSI status is determined by PCR. Tumors are classified as 
dMMR in the absence of at least 1 of 4 MMR proteins (MLH1/MSH2/MSH6/PMS2).
See country-specific requirements in Appendix 7.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for scan collection and transmission to the iCRO can be 
found in the SIM. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. The same scan technique should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the response assessment based on scans.
Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility.
Participant eligibility will be determined using investigator assessment based on RECIST 
1.1. While on study, scheduled imaging studies scans for each participant should be 
submitted for BICR. Unscheduled imaging studies scans obtained for assessment of disease 
progression or other reasons, but capturing radiologic progression or used in response 
assessments, should also be submitted for BICR.
If brain scans are performed, magnetic resonance imaging is preferred; however, CT imaging 
will be acceptable, if MRI is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain x-rays acquired for 
correlation, should also be submitted to the iCRO.
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Other imaging modalities that may be collected, submitted to the iCRO, and included in the 
response assessment include chest X-rays, PET-CT, etc . Other types of medical imaging 
(such as ultrasound) should not be submitted to the iCRO and will not be included in 
response assessment.
8.2.1.1
Initial Tumor Scans
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
randomization. Any scans obtained after Cycle 1 Day 1 cannot be included in the screening 
assessment. The site must review screening scans to confirm the participant has measurable 
disease per RECIST 1.1.
8.2.1.2
Tumor Scans During the Study
The first on-study scan should be performed at 9 weeks (63 days ±7 days) from the date of 
randomization. Subsequent tumor scans should be performed every 9 weeks (63 days 
±7 days) or more frequently if clinically indicated. After 9 weeks (63 days ±7 days),
participants who remain on treatment will have scans performed every 9 weeks (63 days 
±7 days). Scan timing should follow calendar days and should not be adjusted for delays in 
cycle starts. Scans are to be performed until disease progression is identified by the 
investigator and verified by the BICR, or until the start of new anticancer treatment, 
withdrawal of consent, or death, whichever occurs first.
Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to the regular scan 
schedule, starting with the next scheduled time point. Participants who receive additional 
scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 
weeks later; scans may resume at the subsequent scheduled time point.
On-study brain or bone scans should be performed if clinically indicated or to confirm CR 
(if other lesions indicate CR and brain or bone lesions existed at baseline).
Treatment beyond centrally verified PD per RECIST 1.1 may be permitted at the discretion 
of the investigator after consultation with the Sponsor and receiving documented informed 
consent. Participants who continue treatment beyond centrally verified PD must continue 
tumor assessments as described in the SoA (Section 1.3). Investigator assessments are to be 
documents on the eCRF, but scans are not to be submitted to the iCRO. Further progression 
and discontinuation of study intervention are to be determined by the investigator.
When the investigator identifies radiographic progression per RECIST 1.1, the iCRO will 
perform expedited verification of radiologic disease progression and communicate the results 
to the study site and Sponsor via email. In clinically stable participants, scans should 
continue until disease progression has been verified by BICR (if initial site-assessed disease 
progression was not verified by BICR, each subsequent scan must be submitted to iCRO with 
verification of disease progression request until disease progression has been verified by 
BICR). Once disease progression is verified centrally, subsequent scans (if acquired) should 
not be submitted to the iCRO.
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For participants who have surgery with curative intent during the study, scans must be 
performed at a minimum of no less than 4 weeks after surgery and no more than 8 weeks 
prior to the next treatment cycle. The last set of scans prior to restart of treatment will be 
used to establish a new baseline of tumor burden. Subsequent scans will be compared to this 
new baseline and the visit responses will be limited to PD, non-PD, or NE (not evaluable); 
these new postoperative images will be assessed every 9 weeks (63 days ± 7 days) for 
12 months and every 12 weeks (84 days ± 7 days) thereafter.
For those participants who did not achieve a confirmed curative outcome, a new baseline is 
not required. Participants will continue on study as planned using RECIST 1.1 (refer to data 
entry guidelines).
8.2.1.3
End-of-treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of randomization, refer to Section 8.2.1.2.
Scans are to be continued until one of the following conditions are met:
•
disease progression as defined by RECIST 1.1 verified by BICR 
•
the start of a new anticancer treatment
•
pregnancy
•
death
•
withdrawal of consent
•
the end of the study
8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
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Upon investigator-assessed disease progression, the indicative scan(s) are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
-
resume imaging per protocol schedule (≥4 weeks to next scan)
-
send scans to iCRO
-
continue local assessment
-
do not change investigator assessment of progression 
-
if subsequent scan(s) indicate progression, submit scan(s) to iCRO to request 
verification
•
If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or imaging or starting new anti-cancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
If disease progression is verified, the process continues as follows:
•
investigator judgement will determine action
•
if the participant is clinically stable and study intervention is to continue, communication 
with the sponsor is required and a reconsent addendum must be signed
•
obtain scans locally per original protocol schedule
•
do not send scans to iCRO
Figure 2 illustrates the study intervention decision process involving verification of disease 
progression for participants.
•
For the purpose of this decision process, lack of clinical stability is defined as:
-
unacceptable toxicity
-
clinical signs or symptoms indicating clinically significant disease progression
-
decline in performance status
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-
rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention
Figure 2
Study Intervention Decision Making Process When Progression per RECIST 
1.1 is Observed by Investigator (PFS Endpoint)
RECIST= response evaluation criteria in solid tumors ; PFS= progression-free survival
8.2.2
Patient-reported Outcomes
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Laboratory 
or Study Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee (consistent with local requirements) will perform a 
complete physical examination during the Screening period per institutional standard. Height 
and weight will also be measured and recorded. Clinically significant abnormal findings 
should be recorded as medical history.
Time points for full physical examinations are described in Section 1.3. After the first dose of 
study intervention, new clinically significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical exam as defined in Section 1.3, the investigator 
or qualified designee (consistent with local requirements) will perform a brief directed 
physical examination (per institutional standard) as clinically indicated prior to study 
intervention administration. Weight will also be measured and recorded. New clinically 
significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
•
Temperature, pulse rate, RR, and BP will be assessed by institutional standard.
•
BP and pulse measurements will be assessed per institutional standard with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.
•
Note: Participants in Arm B receiving regorafenib treatment are required to measure BP 
weekly. Weekly BP assessments can be done at home.
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•
BP and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions.
•
Vital Signs will be measured in a semisupine or sitting position after 5 minutes rest and 
will include temperature, systolic and diastolic BP, and pulse and RR.
8.3.3
Electrocardiograms
Single 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA (Section 1.3) using an 
ECG machine that automatically calculates the HR and measures pulse rate, QRS, QT, and 
QTc intervals.
8.3.4
Performance Assessments
8.3.4.1
Eastern Cooperative Oncology Group Performance Status
The ECOG PS is standardized criteria to measure how cancer impacts level of functioning 
(performance status) in terms of ability to care for oneself, daily activity, and physical ability 
(walking, working, etc) with Grades 0 to 5.
The investigator or qualified designee (consistent with local requirements) will assess ECOG 
status (Appendix 9) at screening, before the administration of each dose of study 
intervention, at the End-of-Treatment Visit, and at the 30 day Safety Follow-up Visit, as 
specified in the SoA (Section 1.3).
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
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. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual or Procedures Document and the
SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
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•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 90 days for Arm A and 30 days for Arm B after the 
last dose of study intervention, every attempt should be made to perform repeat 
assessments until the values return to normal or baseline or if a new baseline is 
established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Laboratory 
Manual or Procedures Document. Refer to the SoAs (Section 1.3) for the timing of laboratory 
assessments.
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.6
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at every cycle during intervention and safety follow-up (Section 1.3 SoA).
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
See country-specific requirements in Appendix 7.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention randomization through 30 days after cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days after cessation of study intervention or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
randomization through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.5, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 8.
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Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 8
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
-  participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout or 
run-in treatment 
including placebo run-
in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously reported –
Follow to completion/
termination; report 
outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of 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 and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as an AE.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
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2. An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing*.
*Note: These criteria are based on available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. The study-site guidance for assessment and follow up 
of these criteria can be found in the Investigator Study File Binder (or equivalent).
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
MK-4280A
For this study, an overdose of MK-4280A will be defined as exceeding the prescribed dose 
by ≥100%.
No specific information is available on the treatment of overdose of MK 4280A. In the event 
of overdose, the participant should be observed closely for signs of toxicity. Appropriate 
supportive intervention should be provided if clinically indicated.
Regorafenib and TAS-102
For this study, refer to the regorafenib and TAS-102 product labels for current overdose 
information, frequently observed adverse drug reactions, and guidelines.
8.6
RAS and BRAF Status
All participants in the trial must be tested for RAS and BRAF status, unless at the time of 
obtaining consent the participant already has a documented RAS and BRAF status.
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8.11
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data, associated with medical encounters, 
will be collected in the CRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
All-cause hospitalizations and emergency department visits must be reported in the eCRF, 
from the time of treatment randomization through 90 days following cessation of study 
intervention, or 30 days following cessation of study intervention if the participant initiates 
new anticancer therapy, whichever is earlier.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.
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Screening procedures are to be completed within 28 days before the first dose of study 
intervention. Except for the following:
•
Archival tumor tissue sample should be from ≤5 years prior to screening. Newly obtained 
tumor tissue may be obtained within 28 days of treatment initiation.
•
Laboratory tests are to be performed within 10 days prior to the first dose of study 
intervention.
•
Evaluation of ECOG is to be performed within 10 days prior to the first dose of study 
intervention.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 24 or 72 hours, respectively, prior to the first dose of study intervention. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study-site laboratory).
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.12.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.12.3
Discontinued Participants Continuing to be Monitored in the Study
When a participant discontinues study intervention in the Intervention Phase, procedures for 
discontinuation will be performed.
The discontinuation visit should occur at the time study intervention is discontinued for any 
reason. If the discontinuation visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up visit, the discontinuation visit procedures and 
any additional safety follow-up procedures should be performed. Visit requirements are 
outlined in Section 1.3. Additional details regarding participant withdrawal and 
discontinuation are presented in Section 7.
8.12.4
Posttreatment Visit
8.12.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first. The Safety Follow-up Visit should occur before initiation of a new anticancer 
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treatment if the new treatment occurs before 30 days post last dose and may be conducted by 
telephone.
8.12.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin Efficacy 
Follow-up. Follow-up visits after treatment discontinuation must coincide with the imaging 
schedule until disease progression, death, or end-of-study. Participants who completed all 
efficacy assessments and/or will not have further efficacy assessments must enter Survival 
Follow-up.
Every effort should be made to collect information regarding disease status until the start of 
new anticancer therapy, disease progression, death, end-of-study. Information regarding 
poststudy anticancer treatment will be collected if new treatment is initiated.
8.12.4.3
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below:
•
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
•
For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
8.12.5
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes made to primary 
and/or key secondary hypotheses, or the statistical methods related to those hypotheses, then 
the protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding/final database lock, will be documented in a sSAP and referenced in the CSR for 
the study. Post hoc exploratory analyses will be clearly identified in the CSR. The PRO 
analysis plan will be included in the sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
Study Design Overview
A Phase 3 study of MK-4280A Versus Standard of Care in Previously 
Treated Metastatic Colorectal Cancer.
Treatment Assignment
Approximately 432 participants will be randomized in a 1:1 ratio between 
2 treatment groups: (1) the MK-4280A arm (Arm A) and (2) the standard 
of care (regorafenib or TAS-102) arm (Arm B). Stratification factors are: 
Geographic region (Asia Pacific; EMEA/Americas), presence of liver 
metastasis (Yes, No) and time from initial diagnosis of metastatic disease 
to randomization (≥18 months, <18 months). This is an open-label study.
Analysis Populations
Efficacy: ITT
Safety: APaT
Primary Endpoint(s)
Overall survival
Key Secondary Endpoints
Progression-free survival per RECIST 1.1 as assessed by BICR.
Objective response rate per RECIST 1.1 as assessed by BICR.
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary hypothesis testing for OS and secondary hypothesis testing 
for PFS will be evaluated by comparing the experimental group to the 
control group using a stratified log-rank test. The HR will be estimated 
using a stratified Cox regression model. Event rates over time will be 
estimated within each treatment group using the Kaplan-Meier method. 
The stratified M&N method with strata weighted by sample size will be 
used for secondary hypothesis testing of ORR [Miettinen, O. and 
Nurminen, M. 1985]
Statistical Methods for Key 
Safety Analyses
For analyses in which 95% CIs will be provided for between-treatment 
differences in the percentage of participants with events, these analyses 
will be performed using the M&N method [Miettinen, O. and 
Nurminen, M. 1985].
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Interim Analyses
Efficacy
One interim analysis is planned in this study. Results will be reviewed
by an eDMC. Details are provided in Section 9.7.

Interim Analysis:
o
Timing: to be performed after both ~309 OS events have been 
observed and ~ 10 months after last participant randomized
o
Primary purpose: interim efficacy analysis for OS, final 
analysis for PFS and ORR

Final Analysis:
o
Timing: to be performed after both ~386 OS events have been 
observed and ~12 months after interim analysis
o
Primary purpose: final analysis for OS
Safety
An interim safety analysis will be performed and reviewed by the
eDMC 6 months after first participant is randomized or 2 months after 
60th participant is randomized, whichever comes first. Afterwards, the 
eDMC will review safety data periodically in the study. Details will be 
specified in the DMC charter.
Multiplicity
The overall type I error over the primary and secondary hypotheses is 
strongly controlled at 2.5% (1-sided), with 2.5% initially allocated to 
OS (H1), 0% to PFS (H2), and 0% to ORR (H3).
By using the graphical approach of Maurer and Bretz [Maurer, W. and 
Bretz, F. 2013], if one hypothesis is rejected, the alpha will be shifted to 
other hypotheses.
Sample Size and Power 
The planned sample size is approximately 432 participants. It is 
estimated that there will be ~ 386 OS events at the final analysis. With 
386 OS events, the study has 93.5% power for detecting a HR of 0.7 at 
an initially assigned 0.025 (1-sided) significance level.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment as appropriate in this protocol, and the allocation will be implemented in IRT.
Although the study is open-label, analyses or summaries generated by randomized 
intervention assignment, or actual intervention received will be limited and documented.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
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9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
9.4.1
Efficacy Endpoints
Primary
•
Overall Survival
OS is defined as the time from randomization to death due to any cause.
Secondary
•
Progression-free survival
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. 
•
Objective Response Rate
The ORR is defined as the percentage of participants who achieve a confirmed CR or PR per 
RECIST 1.1 as assessed by BICR.
•
Duration of Response
For participants who demonstrate confirmed CR or PR, duration of response is defined as the 
time from the first documented evidence of CR or PR until disease progression or death due 
to any cause, whichever occurs first.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, SAEs, fatal AEs, laboratory tests. Furthermore, specific events will be 
collected and designated as ECIs as described in Section 8.4.7.
9.4.3
PRO Endpoints
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9.5
Analysis Populations
See country-specific requirements in Appendix 7.
9.5.1
Efficacy Analysis Populations
The ITT population will serve as the primary population for the analysis of efficacy data in 
this study. The ITT population consists of all randomized participants. Participants will be 
analyzed in the treatment arm to which they are randomized. Details of the approach to 
handling missing data are provided in Section 9.6.1.4.
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one dose of study treatment. Participants will be included 
in the treatment group corresponding to the study treatment they actually received for the 
analysis of safety data using the APaT population. This will be the treatment group to which 
they are randomized except for participants who take incorrect study treatment for the entire 
treatment period; such participants will be included in the treatment group corresponding to 
the study treatment actually received.  
At least one laboratory or vital sign measurement obtained after at least one dose of study 
treatment is required for inclusion in the analysis of the respective safety parameter. To 
assess change from baseline, a baseline measurement is also required.
9.5.3
PRO Analysis Populations
The PRO analyses are based on the PRO FAS population, defined as all randomized 
participants who have at least one PRO assessment available for the specific endpoint and 
have received at least one dose of the study intervention. Participants will be analyzed in the 
treatment group to which they are randomized.
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8, Multiplicity. Nominal p-values may be 
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity, sample size, etc.
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9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
The stratification factors used for randomization (Section 6.3.2) will be applied to all 
stratified analyses, in particular, the stratified log-rank test, stratified Cox model, and 
stratified M&N method [Miettinen, O. and Nurminen, M. 1985]. In the event, that there are 
small strata, for the purpose of analysis, strata will be combined to ensure sufficient number 
of participants, responses and events in each stratum. Details regarding the pooling strategy 
will be prespecified in the sSAP prior to the database lock for the first analysis when each 
applicable endpoint will be analyzed, and decisions regarding the pooling will be based on a 
blinded review of response and event counts by stratum. 
9.6.1.1
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, the HR). The HR and its 95% CI from the stratified 
Cox model with a single treatment covariate will be reported. The stratification factors used 
for randomization (Section 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model. Participants without documented death at the time of analysis will be 
censored at the date the participant was last known to be alive.
9.6.1.2
Progression-Free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, HR) between the treatment arms. 
The HR and its 95% CI from the stratified Cox model with a single treatment covariate will 
be reported. The stratification factors used for randomization (Section 6.3.2) will be applied 
to both the stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the earlier of the 
date of the first assessment at which PD is objectively documented per RECIST 1.1 by BICR 
and the date of death. Death is always considered a PD event.
For the primary analysis, any participant who experiences an event (PD or death) 
immediately after 2 or more missed disease assessments will be censored at the last disease 
assessment prior to the missed visits. In addition, any participant who initiates new 
anticancer therapy prior to documented progression will be censored at the last disease 
assessment prior to the initiation of new anticancer therapy. Participants who do not start new 
anticancer therapy and who do not experience an event will be censored at the last disease 
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assessment. If a participant meets multiple criteria for censoring, the censoring criterion that 
occurs earliest will be applied.  
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 2 
sensitivity analyses with different sets of censoring rules will be performed. The first 
sensitivity analysis follows the intention-to-treat principle. That is, PDs/deaths are counted as 
events regardless of missed study visits or initiation of new anticancer therapy. The second 
sensitivity analysis considers initiation of new anticancer treatment or discontinuation of 
treatment due to reasons other than complete response, whichever occurs later, to be a PD 
event for participants without documented PD or death. If a participant meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied. The 
censoring rules for the primary and sensitivity analyses are summarized in Table 9. Details 
regarding PFS analysis for surgical participants will be provided in the sSAP.
Table 9
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity 
Analysis 1
Sensitivity 
Analysis 2
PD or death 
documented after ≤1 
missed disease 
assessment, and 
before new anticancer 
therapy, if any
Progressed at date of 
documented PD or 
death 
Progressed at 
date of 
documented PD 
or death
Progressed at date of 
documented PD or death
PD or death 
documented 
immediately after ≥2 
consecutive missed 
disease assessments, 
or after new 
anticancer therapy
Censored at last 
disease assessment 
prior to the earlier date 
of ≥2 consecutive 
missed disease 
assessment and new 
anticancer therapy, if 
any
Progressed at 
date of 
documented PD 
or death
Progressed at date of 
documented PD or death
No PD and no death; 
and new anticancer 
treatment is not 
initiated
Censored at last 
disease assessment 
Censored at last 
disease 
assessment 
Progressed at treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at last 
disease assessment if still 
on-study treatment or 
completed study 
treatment
No PD and no death;
new anticancer 
treatment is initiated
Censored at last 
disease assessment 
before new anticancer 
treatment 
Censored at last 
disease 
assessment
Progressed at date of new 
anticancer treatment
PD=progressive disease; PFS=progression-free survival.
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9.6.1.3
Objective Response Rate
The stratified M&N method will be used for the comparison of ORR between 2 treatment 
groups [Miettinen, O. and Nurminen, M. 1985]. The difference in ORR and its 95% CI from 
the stratified M&N method with strata weighting by sample size will be reported. The 
stratification factors used for randomization (Section 6.3.2) will be applied to the analysis.  
The point estimate of ORR will be provided by treatment group, together with 95% CI using 
exact binomial method proposed by Clopper and Pearson [Clopper, C. J. and Pearson, E. S. 
1934].
9.6.1.4
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 10.
Table 10
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Analyses
OS
Testing: stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at the date 
participant last known 
to be alive
Key Secondary Analyses
PFS per RECIST 
1.1 by BICR
Testing: stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method 
ITT
Censored according to 
rules in Table 9
ORR per RECIST 
1.1 by BICR
Testing and estimation:
stratified M&N method
ITT
Participants with 
missing data are 
considered non-
responders
BICR=blinded independent central review; ITT=intent-to-treat; M&N=Miettinen & Nurminen; ORR=objective 
response rate; OS=overall survival; PFS=progression-free survival; RECIST 1.1=Response Evaluation Criteria in 
Solid Tumors.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory tests.
The analysis of safety results will follow a tiered approach (Table 11). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
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system organ class terms) and events that meet predefined limits of change in laboratory and 
vital signs are either prespecified as “Tier 1” endpoints or will be classified as belonging to 
“Tier 2” or “Tier 3” based on the observed proportion of participants with events. 
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance. There are 
no Tier 1 events for this protocol. Adverse events that are immune-mediated or potentially 
immune-mediated are well documented and will be evaluated separately; however, these 
events have been characterized consistently throughout the pembrolizumab clinical 
development program, and determination of statistical significance is not expected to add 
value to the safety evaluation. The coformulated MK-4280A has not been found to be 
associated with any new safety signals. Finally, there are no known AEs associated with 
participants with CRC for which determination of a p-value is expected to impact the safety 
assessment. 
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the M&N method, an unconditional, 
asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 10% of participants was chosen for Tier 2 events because the population enrolled 
in this study is in critical condition and usually experiences various AEs of similar types 
regardless of treatment; events reported less frequently than 10% of participants would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of 
participants in 1 of the treatment groups) and SAEs (≥5% of participants in 1 of the treatment 
groups) will be considered Tier 2 endpoints. Because many 95% CIs may be provided 
without adjustment for multiplicity, the CIs should be regarded as a helpful descriptive 
measure to be used in safety review, not as a formal method for assessing the statistical 
significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad AE 
categories consisting of the proportion of participants with any AE, a drug-related AE, a 
serious AE, an AE which is both drug-related and serious, a Grade 3-5 AE, a drug-related 
Grade 3-5 AE, and discontinuation due to an AE will be considered Tier 3 endpoints. Only 
point estimates by treatment group are provided for Tier 3 safety parameters.
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Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory parameters, summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group in table format.
Table 11
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Grade 3-5 AE (incidence ≥5% of participants in one 
of the treatment groups)
X
X
Serious AE (incidence ≥5% of participants in one of 
the treatment groups)
X
X
AEs (incidence ≥10% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade 3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, system organ class (incidence 
<10% of participants in all of the treatment groups)
X
Change from Baseline Results (laboratory toxicity 
shift)
X
AE=adverse events; CI=confidence interval.
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses
This section describes the planned analyses for the PRO endpoints. 
Change from Baseline
The time point for the change from baseline will be determined based on blinded data review 
prior to the database lock for any PRO analysis and documented in the sSAP. 
To assess the treatment effects on the PRO score change from baseline in the global health 
status/QoL, physical, appetite loss and bloating, a constrained longitudinal data analysis 
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model proposed by Liang and Zeger [Liang, Kung-Yee and Zeger, Scott L. 2000] will be 
applied, with the PRO score as the response variable, and treatment, time, the treatment by 
time interaction, and the stratification factors used for randomization (Section 6.3.2) as 
covariates. The treatment difference in terms of least square mean change from baseline will 
be estimated from this model together with 95% CI. Model-based least square mean with 
95% CI will be provided by treatment group for PRO scores at baseline and post-baseline 
time point. 
Time-to-Deterioration
The Kaplan-Meier method will be used to estimate the TTD curve for each treatment group. 
The estimate of median time-to-deterioration and its 95% confidence interval will be 
obtained from the Kaplan-Meier estimates. The treatment difference in TTD will be assessed 
by the stratified log-rank test. A stratified Cox proportional hazard model with Efron's 
method of tie handling and with a single treatment covariate will be used to assess the 
magnitude of the treatment difference (ie, HR). The HR and its 95% CI will be reported. The 
stratification factors used for randomization (Section 6.3.2) will be used as the stratification 
factors in both the stratified log-rank test and the stratified Cox model.
Details of PRO analyses will be described in the sSAP.
9.6.4
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
The eDMC will serve as the primary reviewer of the results of the IAs and will make 
recommendations for discontinuation of the study or modification to the executive oversight 
committee of the Sponsor. If the eDMC recommends modifications to the design of the 
protocol or discontinuation of the study, this executive oversight committee and potentially 
other limited Sponsor personnel may be unblinded to the treatment-level results in order to 
act on these recommendations. The extent to which individuals are unblinded with respect to 
results of IAs will be documented by the unblinded statistician. Additional logistic details 
will be provided in the eDMC Charter.
Treatment-level results of the interim analysis will be provided by the unblinded statistician 
to the eDMC. Prior to final study unblinding, the unblinded statistician will not be involved 
in any discussions regarding modifications to the protocol or statistical methods, 
identification of protocol deviations, or data validation efforts after the IAs.
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9.7.1
Efficacy Interim Analysis
One IA is planned in addition to the FA for this study. For the IA and FA, all randomized 
participants will be included. Results of the IA will be reviewed by the eDMC. Details of the 
boundaries for establishing statistical significance with regard to efficacy are discussed 
further in Section 9.8.
The analyses planned, endpoints evaluated, and drivers of timing are summarized in 
Table 12.
Table 12
Summary of Interim and Final Analyses Strategy
Analyses
Key 
Endpoints
Timing
Estimated Time 
after First 
Participant 
Randomized
Primary Purpose 
of Analysis
IA
OS
(PFS and 
ORR if OS 
is rejected) 
Both ~309 OS events 
have been observed and 
~ 10 months after last 
participant randomized
~ 21 months
Interim OS 
analysis
Final PFS and 
ORR analysis
FA
OS
Both ~386 OS events 
have been observed and 
~12 months after IA
~ 33 months
Final OS 
analysis
FA=final analysis; IA=interim analysis; ORR=objective response rate; OS=overall survival; 
PFS=progression-free survival.
Note that for FA, if the OS events accrue slower than expected and the final targeted OS events cannot be 
reached by ~33 months after the first participant randomized, the Sponsor may conduct the analysis with 
up to additional ~4 months of follow-up, or the specified number of events is observed, whichever occurs 
first.
9.7.2
Safety Interim Analysis
The eDMC will be responsible for periodic interim safety reviews as specified in the eDMC 
charter. An interim safety analysis will be performed 6 months since first participant is 
randomized or 2 months after 60th participant is randomized, whichever comes first. 
Afterwards, the eDMC will review safety data periodically in the study. Interim safety 
analyses will also be performed at the time of interim efficacy analyses. Details will be 
specified in the eDMC charter.
9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to 
provide strong multiplicity control for multiple hypotheses as well as interim analyses. 
According to this approach, study hypotheses may be tested more than once, and when a 
particular null hypothesis is rejected, the α allocated to that hypothesis can be reallocated to 
other hypothesis tests. Note that if the OS null hypothesis is rejected at FA of the study, the 
previously computed PFS and ORR test statistics at IA may be used for inferential testing 
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with its updated bounds considering the α reallocation from the OS hypothesis. Figure 3
shows the initial 1-sided α allocation for each hypothesis in the ellipse representing the 
hypothesis. The weights for reallocation from each hypothesis to the others are shown in the 
boxes on the lines connecting hypotheses.
The initial α assigned to OS, PFS and ORR will be 0.025, 0 and 0, respectively. If OS 
hypothesis is rejected, the corresponding alpha can be reallocated equally to PFS and ORR. If 
the PFS hypothesis is rejected, the corresponding alpha can be reallocated to ORR. If the 
ORR hypothesis is rejected, the corresponding α can be reallocated to PFS.
Figure 3
Multiplicity Diagram for Type I Error Control
ORR=objective response rate; OS=overall survival; PFS=progression-free survival.
Note: If OS null hypothesis is rejected, the allocation strategy allows testing of PFS and ORR at 
α = 0.0125, separately.
9.8.1
Overall Survival
The study will test OS at IA and FA. Following the multiplicity strategy as outlined in 
Figure 3, the OS hypothesis will be tested at α=0.025. Table 13 shows the bounds and 
boundary properties for OS hypothesis testing derived using a Lan-DeMets spending 
function approximating O’Brien-Fleming bounds.
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Table 13
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
=0.025
IA: 80%*
N: 432
Events: 309
Month: 21
Z 
2.2504
p (1-sided)a
0.0122
HR at boundb
0.7738
P(Cross) if HR=1c
0.0122
P(Cross) if HR=0.7d
0.8123
FA 
N: 432
Events: 386
Month: 33
Z 
2.0249
p (1-sided)a
0.0214
HR at boundb
0.8135
P(Cross) if HR=1c
0.0250
P(Cross) if HR=0.7d
0.9350
HR=hazard ratio; IA=interim analysis, FA=final analysis.
The number of events and timings are estimated.
* Percentage of total planned events at the interim analysis.
a
p (1-sided) is the nominal α for group sequential testing.
b
HR at bound is the approximate HR required to reach an efficacy bound.
c
P (Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
d
P (Cross if HR=0.7) is the probability of crossing a bound under the alternative hypothesis.
The bounds provided in the table above are based on the assumptions that the expected 
number of events at IA and FA are 309 and 386, respectively. At the time of an analysis, the 
observed number of events may differ substantially from the expected. To avoid 
overspending at an IA and leave reasonable α for the FA, the minimum α spending strategy 
will be adopted. At an IA, the information fraction used in Lan-DeMets spending function to 
determine the alpha spending at the IA will be based on the minimum of the expected 
information fraction and the actual information fraction at each analysis. Specifically,
•
In the scenario that the events accrue slower than expected and the observed number of 
events is less than the expected number of events at a given analysis, the information 
fraction will be calculated as the observed number of events at the IA over the target 
number of events at FA.
•
In the scenario that the events accrue faster than expected and the observed number of 
events exceeds the expected number of events at a given analysis, then the information 
fraction will be calculated as the expected number of events at the IA over the target 
number of events at FA.
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The final analysis will use the remaining Type I error that has not been spent at the earlier 
analysis.
Of note, while the information fraction used for alpha spending calculation will be the 
minimum of the actual information fraction and the expected information fraction, the 
correlations required for deriving the bounds will still be computed using the actual 
information fraction based on the observed number of events at each analysis over the target 
number of events at FA.
The minimum spending approach assumes timing is not based on any observed Z-value and 
thus the Z test statistics used for testing conditioned on timing are multivariate normal. Given 
the probabilities derived with the proposed spending method, the correlations based on actual 
event counts are used to compute bounds that control the Type I error at the specified alpha 
level for a given hypothesis conditioned on the interim analysis timing. Since this is true 
regardless of what is conditioned on, the overall Type I error for a given hypothesis 
unconditionally is controlled at the specified level. By using more conservative spending 
early in the study, power can be retained to detect situations where the treatment effect may 
be delayed.
9.8.2
Progression-free Survival  
The study will test PFS at IA only if the OS null hypothesis is rejected. Following the 
multiplicity strategy as outlined in Figure 3, the PFS hypothesis may be tested at α=0.0125 
(if the OS null hypothesis is rejected, but not the ORR hypothesis) or at α= 0.025 (if both the 
OS and ORR null hypotheses are rejected). Table 14 shows the boundary properties for each 
of these α levels for the PFS analysis. Note that the final row indicates the total power to 
reject the null hypothesis for PFS at each α level. 
Table 14
Efficacy Boundaries and Properties for Progression-Free Survival Analysis
Analysis
Value
=0.0125
=0.025
IA
N = 432 
Events*: 419
Month: 21
Z
2.2414
1.9600
p (1-sided) a
0.0125
0.025
HR at boundb
0.8032
0.8256
P(Cross) if HR=1c
0.0125
0.025
P(Cross) if HR=0.65d
0.9850
0.9929
HR=hazard ratio; IA=interim analysis.
*The number of events and timing are estimated.
a
p (1-sided) is the nominal α for group sequential testing. 
b
HR at bound is the approximate HR required to reach an efficacy bound.
c
P (Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
d
P(Cross if HR=0.65) is the probability of crossing a bound under the alternative hypothesis.
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Note that if the OS null hypothesis is rejected, the PFS test statistics computed at IA will be 
used for inferential testing with its corresponding alpha levels.
9.8.3
Objective Response Rate
The study will test ORR only once at the IA if the OS null hypothesis is rejected. Following 
the multiplicity strategy as outlined in Figure 3, the ORR hypothesis may be tested at 
α=0.0125 (if the OS null hypothesis is rejected, but not the PFS hypothesis) or at α= 0.025 (if 
both the OS and PFS null hypothesis is rejected). Power at the possible α-levels as well as 
the approximate treatment difference required to reach the bound (ΔORR) are shown in 
Table 15, assuming underlying 2% and 12% response rates in the control and experimental 
groups, respectively.
Table 15
Possible α Levels and Approximate Observed ORR Difference Required to 
Demonstrate Efficacy for Objective Response at IA
α
~Δ ORR
Power (ΔORR=0.1)
0.0125
0.0550
0.970
0.025
0.0481
0.984
IA=interim analysis; ORR=Objective Response Rate.
Note that if the OS null hypothesis is rejected, the ORR test statistics computed at IA will be 
used for inferential testing with its corresponding alpha levels.
9.8.4
Safety Analysis
The eDMC has responsibility for assessment of overall risk/benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. eDMC review of 
efficacy data to assess the overall risk/benefit to study participants will not require a 
multiplicity adjustment typically associated with a planned efficacy IA. However, to account 
for any multiplicity concerns raised by the eDMC review of unplanned efficacy data 
prompted by safety concerns, a sensitivity analysis for ORR, PFS, and OS adopting a 
conservative multiplicity adjustment will be prespecified in the sSAP.
9.9
Sample Size and Power Calculations
The study will randomize 432 participants in a 1:1 ratio into the MK-4280A arm (Arm A) 
and the standard of care arm (Arm B). OS is the primary endpoint for the study, with PFS 
and ORR as the key secondary endpoints.
For the OS endpoint, based on a target number of 386 events and 1 IA at approximately 80% 
of the target number of events, the study has approximately 93.5% power to detect a HR of 
0.7 at the initially allocated α=0.025 (1-sided).
For the PFS endpoint, based on a target number of 419 events at the IA (final PFS analysis), 
the study has approximately 99% power to detect a HR of 0.65 at the reallocated α=0.0125 
(1-sided) if only OS hypothesis is rejected. 
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Based on the 432 participants with at least approximately 10 months of follow-up, the power 
of the ORR testing at the reallocated α=0.0125 (1-sided) if only OS hypothesis rejected is 
approximately 97% to detect a 10-percentage point difference between an underlying 2% 
ORR in the control arm (Arm B) and a 12% ORR in the experimental arm (Arm A).
Note that the above OS and PFS power calculations are based on a constant HR assumption. 
Based on CORRECT, RECOURSE, and SUNLIGHT studies, the above sample size and 
power calculations for OS and PFS assume the following:
•
OS follows an exponential distribution with a median of 7.5 months for the control group.
•
PFS follows an exponential distribution with a median of 2 months for the control group.
•
Enrollment period of 12 months with enrollment ramp-up over first 2 months.
•
An annual dropout rate of 2% and 5% for OS and PFS, respectively
•
A follow-up period of 22 and 10 months and for OS and PFS, respectively, after the last 
participant is randomized.
The sample size and power calculations were performed using R (“gsDesign” package).
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS (with a nominal 95% CI) will be estimated and 
plotted by treatment group within each category of the following subgroup variables:
•
Geographic region (Asia Pacific; EMEA/Americas)
•
Geographic region (Western Europe/North America, Asia, Rest of the World)  
•
Time from initial diagnosis of metastatic disease to randomization (≥18 months, 
<18 months)
•
ECOG PS (0, 1)
•
Age category (<65 years, ≥65 years)
•
Sex (female, male)
•
Race (white, all others)
•
Primary tumor sidedness (left-sided, right-sided)
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•
Number of prior treatments (0-3, ≥4)
•
Presence of liver metastasis (Yes, No)
•
RAS (WT, mutant)
•
Investigators’ choice of standard of care chemotherapy prior to randomization 
(regorafenib versus TAS-102)
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is less than 10% of the ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable, and this subgroup variable will not be 
displayed in the forest plot. The subgroup analyses for OS will be conducted using an 
unstratified Cox model.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of Exposure for a participant is defined as the number of cycles and number of days 
for which the participant receives the study intervention. Summary statistics will be provided 
on the extent of exposure for the overall study intervention for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the 
safety and effectiveness of our products. As such, we are committed to designing, 
implementing, conducting, analyzing, and reporting these trials in compliance with 
the highest ethical and scientific standards. Protection of participants in clinical trials 
is the overriding concern in the design and conduct of clinical trials. In all cases, 
MSD clinical trials will be conducted in compliance with local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also 
in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
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protection rights of all participants, trial site staff and, where applicable, third 
parties. All trial protocols are and will be assessed for the need and capability to 
enroll underrepresented groups. Participants must meet protocol entry criteria to 
be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis-generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
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authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations. Changes to the protocol that are required urgently to eliminate 
an immediate hazard and to protect participant safety may be enacted in anticipation 
of ethics committee approval. MSD will inform regulatory authorities of such new 
measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an MSD trial at 
any time, without any influence on their access to, or receipt of, medical care that 
may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on chart review and medical evaluation to identify 
potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc.) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial 
protocol, and in signing the protocol, agree to support these ethical and scientific standards.
See country-specific requirements in Appendix 7.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
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the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
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regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally 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.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
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10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
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 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification 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, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, 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.
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10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 16 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
See country-specific requirements in Appendix 7.
Table 16
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indicesa
MCV
MCH
% Reticulocytesb
WBC count with 
Differentialb:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNc
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
above the ULN)
Albumin
CO2 or Bicarbonatea
Chloride
Phosphorous
Creatinined
Sodium
ALT/SGPT
Total Protein
Glucose 
nonfasting
Calcium
Alkaline 
phosphatase
Magnesium
Amylase/Lipasee
LDH
Routine 
Urinalysisf
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick. Dry chemical method may be used to evaluate 
leukocyte esterase as per institutional standard. See country-specific 
requirements in Appendix 7.
•
Microscopic examination (if blood or protein is abnormal)
Pregnancy 
Testing
•
Highly sensitive serum or urine pregnancy test (as needed for WOCBP)g
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Laboratory 
Assessments
Parameters
Screening 
Only Tests
•
PT/INR and aPTT/PTTh
•
FSH (as needed in WONCBP only)i
•
Serology (HIV antibody, HBsAg, and Hepatitis C Virus antibody). NOTE: 
certain ex-US sites require testing for HIV and Hepatitis B and C during 
screening. Consult with regional health authorities and institutional standards 
to confirm if such testing is applicablej.
•
See country-specific requirements in Appendix 7
Other Tests
•
Thyroid panel: TSH, T3/FT3, and T4/FT4k
•
ACTH/Cortisol
•
Serum Tumor Marker (CEA)
ACTH=adrenocorticotrophic hormone; ALT=alanine aminotransferase; aPTT/PTT=activated partial 
thromboplastin time; AST=aspartate aminotransferase; BUN=blood urea nitrogen; C1D1=Cycle 1 Day 1; 
CEA=Carcinoembryonic antigen; CO2=carbon dioxide; EOT=end of treatment; FSH=follicle-stimulating 
hormone; FT3=free triiodothyronine; FT4=free thyroxine; GFR=glomerular filtration rate; HBsAg=Hepatitis 
B surface antigen; HBV DNA=Hepatitis B virus deoxyribonucleic acid; HCV=Hepatitis C virus; HCV 
RNA=Hepatitis C virus ribonucleic acid; HIV=human immunodeficiency virus; INR=international 
normalization ratio; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; MCV=mean 
corpuscular volume; PT=prothrombin time; RBC=red blood cell; SGOT=serum glutamic-oxaloacetic 
transaminase; SGPT=serum glutamic-pyruvic transaminase; T3=triiodothyronine; T4thyroxine; 
TSH=thyroid-stimulating hormone; ULN=upper limit of normal; US=United States; WBC=white blood 
cells; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential.
a.
Performed only if considered local standard of care.
b.
Absolute or % acceptable per institutional standard.
c.
Urea is acceptable if BUN is not available as per institutional standard.
d.
GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
e.
Obtain lipase and amylase test for screening, EOT and 30-day follow-up.
f.
If urine dipstick is abnormal, urinalysis must be performed. Perform on WOCBP only 24 hours before 
first dose. 
g.
Pregnancy tests must be repeated before every cycle.
h.
Performed as part of the screening assessment and as clinically indicated for participants taking 
anticoagulants.
i.
If necessary, to check menopausal status.
j.
HBsAg or HBV DNA. HCV RNA (qualitative) or HCV antibody.
k.
Participants may be dosed in subsequent cycles after C1D1 while thyroid function tests are pending. Free 
T3/T4 is acceptable when total T3/T4 cannot be determined.
The investigator or medically qualified designee (consistent with local requirements) must 
document their review of each laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a 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 a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions 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.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Events NOT meeting the AE definition
•
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.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
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, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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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
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
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.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not the cancer under study) as noted in Section 8.4.1.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
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.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; 
(2) the AE resolved/improved despite continuation of the Sponsor’s product; (3) the study is 
a single-dose drug study; or (4) Sponsor’s product(s) is/are only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s product(s) is/are used 
only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
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•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has 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 his/her 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 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 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 health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool 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 EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
See country-specific requirements in Appendix 7.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male 
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. A spermatogenesis 
cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or medical 
history interview.
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 in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
a    Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive 
implants are limited to those which inhibit ovulation.
c    IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
China-specific Requirements
Biomarker sample collection and analysis for participants enrolled in China will be 
dependent on approval by the HGRAC. Please see Section 5.1 Inclusion Criteria for 
eligibility.
Section 8.1.12 Tumor Tissue for Biomarker Status
In China, the below samples, including tumor tissue or slides, will be collected for the 
participants who enrolled after HGRAC approval of the biomarker testing:
•
Tumor tissue blocks or slides for PD-L1 
•
Tumor tissue blocks or slides for MMR 
Section 9.5 Analysis Populations: 
The Chinese participants randomized after the enrollment of the global portion is closed if 
any will not be included in the primary analysis population which is based on the global 
portion. The China portion will also be analyzed separately per local regulatory requirement.
Appendix 2: Clinical Laboratory Tests
For the urinalysis, Leucocytes Esterase may be substituted using Leucocyte, as per 
institutional standard.
10.7.2
Czech Republic-specific Requirements
Section 1.3 Schedule of Activities
HBV, HCV, HIV, and tuberculosis (if applicable) testing at screening is mandatory.
Section 5.1 Inclusion Criteria
Inclusion Criterion: Male participants are eligible to participate if they agree to the following 
during the intervention period and for at least the time needed to eliminate each study 
intervention after the last dose of study intervention. The length of time required to continue 
contraception for each study intervention is as follows: TAS-102 (180 days) and regorafenib 
(90 days). No contraception requirements are needed for males receiving MK-4280A.
Section 5.2 Exclusion Criteria
•
Exclusion Criterion: Has a known history of HIV infection. Testing for HIV is required 
at screening.
•
Exclusion Criterion: has active tuberculosis (if applicable).
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•
Exclusion Criterion: Has a known history of Hepatitis B (defined as Hepatitis B surface 
antigen reactive) or known active Hepatitis C virus (defined as Hepatitis C virus RNA 
[qualitative] is detected) infection.
Note: Testing for Hepatitis B and Hepatitis C is required at screening.
Section 6.5 Concomitant Therapy
Investigators must refer to the up-to-date SmPCs of registered products used in this study, 
regarding forbidden medications or medications to be used with precaution. Specific to the 
use of regorafenib, avoid concomitant use of strong CYP3A4 inducers (eg, rifampin, 
phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) and inhibitors of CYP3A4 
activity (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, 
telithromycin, and voriconazole). CYP3A4 inhibitors and inductors may impact mean 
exposure of regorafenib. UGT1A9 inhibitors (eg, phenytoin, fosphenytoin, diflunisal) should 
also be avoided.
Section 6.5.1 Rescue Medications and Supportive Care
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):
•
Live vaccines must not be administered within 30 days prior to the first dose of study 
intervention, while participating in the study, and for 120 days after the last dose of study 
intervention.
Section 10.5 Appendix 5: Contraceptive Guidance
Ovulation-blocking oral hormonal contraception to be included as a highly reliable 
contraception method.
10.7.3
France-specific Requirements
Section 1.3 Schedule of Activities
Pregnancy testing must be performed at each cycle during study intervention as well as at the 
end-of-study intervention and at Safety FU.
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Section 5.1 Inclusion Criteria
Inclusion Criteria: Patients will be included according to the renal function requirement 
below:
Renal
Creatinine AND/OR
Measured or calculateda creatinine 
clearance (GFR can also be used in place of 
creatinine or CrCl)
aCrCl should be calculated per institutional 
standard.
≤1.5 × ULN AND/OR
≥60 mL/min for participant with creatinine 
levels >1.5 × institutional ULN
Inclusion Criteria: Male participants to use contraception for 180 days (6 months) after 
completing TAS-102 treatment.
Section 8.1.8 Study Intervention Administration
Investigators should refer to http://base-donnees-publique.medicaments.gouv.fr for updated 
SmPC of the marketing authorization of commercially available products used during the 
study for patient management, particularly regarding safety monitoring, product 
contraindications, and precautions.
Section 8.3.6 Pregnancy Testing
Monthly urine pregnancy testing is required during treatment as well as up to 120 days (4 
months) for WOCBP in Arm A (MK-4280A) and 180 days (6 months) for WOCBP in Arm 
B (TAS-102 plus regorafenib).
Section 10.5 Appendix 5: Contraceptive Guidance
Pregnancy testing must be performed at each cycle during study intervention as well as at the 
end-of-study intervention and at Safety FU.
10.7.4
Germany-specific Requirements
Legally Acceptable Representative
Persons of legal age, who are incapable of comprehending the nature, significance and 
implications of the clinical trial and of determining their will, are excluded from the trial at 
German sites; therefore, all references to a participant’s “legally acceptable representative” in 
the protocol are not applicable for participants in Germany.
Section 1.3 Schedule of Activities
Monthly urine pregnancy testing is required during study intervention as well as at the end-
of-study intervention and at Safety FU.
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Section 5.2 Exclusion Criteria
Exclusion Criterion: HIV testing is required for participants.
Exclusion Criterion: Hepatitis B and C testing is required for participants.
Section 10.5 Appendix 5: Contraceptive Guidance
Monthly urine pregnancy testing after randomization is required during study intervention as 
well as at the end-of-study intervention and at Safety FU.
10.7.5
Italy-specific Requirements
Section 1.3 Schedule of Activities
•
Monthly urine pregnancy testing is required during treatment as well as up to 120 days 
for WOCBP in Arm A (MK-4280A) and 180 days for WOCBP in Arm B (TAS-102 plus 
regorafenib)
•
HBV, HCV, HIV and tuberculosis testing at Screening is mandatory.
Section 5.2: Exclusion Criteria
•
Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or 
bacterial infections).
Note: Testing for tuberculosis is requested at screening.
•
Has a known history of HIV infection. HIV testing is required at screening.
•
Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: Testing for Hepatitis B and Hepatitis C is required for screening.
Section 8.3.6 Pregnancy Testing
•
Monthly urine pregnancy testing is required during treatment as well as up to 120 days 
for WOCBP in Arm A (MK-4280A) and 180 days for WOCBP in Arm B (TAS-102 plus 
regorafenib).
Section 10.5 Appendix 5: Contraceptive Guidance
•
Monthly urine pregnancy testing is required during treatment as well as up to 120 days 
for WOCBP in Arm A (MK-4280A) and 180 days for WOCBP in Arm B (TAS-102 plus 
regorafenib).
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10.7.6
Japan-specific Requirements
Section 1.3 Schedule of Activities
Hepatitis B virus test (HBs antigen, HBc antibody, and HBs antibody) at screening is 
mandatory.
1.3.1 Arm A (MK-4280A)
In addition to all study procedures and assessments listed, the following procedure should be 
performed as indicated for subjects in Japan.
Table 17
Japan-specific Trial Flow Chart
Study 
Period
Screeni
ng 
Phase
Intervention Phase
(3-Week Cycles)
End of 
Treat
ment
Posttreatment
Notes
Visit 
Number
/Title
Screeni
ng
C
1
C
2
C
3
C
4
C
5
C6-
C35 Discon
Safety 
Follow
-up*
Effic
acy 
Follo
w-up 
Survi
val 
Follo
w-up
All assessments should be 
performed prior to treatment 
administration unless otherwise 
indicated. If discontinuation visit 
occurs ≥30 days from last dose 
of study intervention, a separate
Safety Follow-up Visit is not 
required, and all Safety Follow-
up procedures will be performed 
at the discontinuation visit.
*Refer to Section 8.12.4.1 for 
details.
Cycle 
Day
Up to 
28 days 
prior to 
first 
dose
1 1 1 1 1 1
At 
Discon
30 
days 
from 
last 
dose
Schedul
ed Days
-28 to -
1
+
3
±
3
±
3
±
3
±
3 ±3
+7
+7
Q9W 
±7
Q12
W ±7
Clinical Procedures/Assessments
Pulse 
Oximetr
y 
(SpO2)
X X X X X X
X
X
At C1D1, collect prior to first 
dose of study intervention.
C1D1=Cycle 1, Day 1; Discon=discontinuation; Q9W=every 9 weeks; Q12W=every 12 
weeks
For subjects in Japan only, pulse oximetry will be performed using local standard procedures 
by the investigator or qualified designee at the time points outlined in Table 17 above.
Section 5.2 Exclusion Criteria
•
Exclusion Criterion: Has a known history of Hepatitis B (defined as HBsAg) or known 
active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: Testing for Hepatitis B and Hepatitis C is required at screening.
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Patients who are HBc antibody positive or HBs antibody positive will be excluded from the 
study.
Subjects who are positive for HBs antibody but negative for HBc antibody and HBs antigen 
and have a known history of HBV vaccination are eligible.
10.7.7
Korea-specific Requirements
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
Section 5.2 Exclusion Criteria
•
Exclusion Criterion: Has a known history of HIV infection. Testing for HIV is required at 
screening.
•
Exclusion Criterion: Has a known history of Hepatitis B (defined as HBsAg reactive) or 
known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: Testing for Hepatitis B and Hepatitis C is required at screening.
10.7.8
South Africa-specific Requirements
Section 5.2 Exclusion Criteria
•
Exclusion Criterion: Has a known history of HIV infection. Testing for HIV is required at 
screening.
•
Exclusion Criterion: Has a known history of Hepatitis B (defined as HBsAg reactive) or 
known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: Testing for Hepatitis B and Hepatitis C is required at screening.
10.7.9
Spain-specific Requirements
Section 1.3 Schedule of Activities
Pregnancy testing must be performed at each cycle during study intervention as well as at the 
end-of-study intervention and at Safety FU.
Section 5.2 Exclusion Criteria
•
Exclusion Criterion: Has a known history of HIV infection. Testing for HIV is required at 
screening.
•
Exclusion Criterion: has active tuberculosis (if applicable).
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•
Exclusion Criterion: Has a known history of Hepatitis B (defined as HBsAg reactive) or 
known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: Testing for Hepatitis B and Hepatitis C is required at screening.
Section 6.5 Concomitant Therapy
Investigators must refer to the up-to-date SmPCs of registered products used in this study, 
regarding forbidden medications or medications to be used with precaution.
Section 10.5 Appendix 5: Contraceptive Guidance
Pregnancy testing must be performed at each cycle during study intervention as well as at the 
end-of-study intervention and at Safety FU.
10.7.10
Sweden-specific Requirements
Section 4.2.1.2 Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs; and changes in vital signs and laboratory values. 
Adverse events will be assessed as defined by CTCAE,v5.0.
Section 10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1 Code of Conduct for Clinical Trials
III. Participant Protection
A. Ethics Committee Review (IRB/IEC) and Health Authorities
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents must be submitted to and approved by the applicable Competent Authority and 
IRB/IEC before the study is initiated in accordance with EU Directive 2001/20/EC, Article 
10 (a) and/or local requirements. Any amendments to the protocol will require IRB/IEC and 
Competent Authority approval before implementation of changes made to the study design, 
except for changes necessary to eliminate an immediate hazard to study participants 
[2001/20/EC, Article 10 (c)].
•
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws,
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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In the EU [CT-1 (2010/C 82/01)], the Sponsor must send immediate end-of-study 
notification to the national competent authority and the Ethics Committee of the Member 
State concerned. The end-of-study notification must be sent within 15 days after the study is 
halted to clearly describe the reasons and follow-up measures, if any, taken for safety 
reasons. The 15-day notification applies only for early termination of the study. Otherwise 
the time window to send end-of-study notification is 90 days in the EU.
10.7.11
United Kingdom-specific Requirements
Section 5.1 Inclusion Criteria
Inclusion Criterion: Male participants are eligible to participate if they agree to the following 
during the intervention period and for at least the time needed to eliminate each study 
intervention after the last dose of study intervention. The length of time required to continue 
contraception for each study intervention is as follows: TAS-102 (180 days) and regorafenib 
(90 days). No contraception requirements are needed for males receiving MK-4280A.
Section 6.5.1 Rescue Medications and Supportive Care
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):
•
Live vaccines must not be administered for 90 days after the last dose of study 
intervention.
•
Males are to be advised to seek counseling on sperm storage before starting treatment 
with pemetrexed, etoposide, and/or platinum-based therapy as per respective SmPCs.
•
Monthly urine pregnancy testing is required during treatment as well as at the end-of-
study treatment.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Not applicable.
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10.9
Appendix 9: Eastern Cooperative Oncology Group Performance Status
Grade
Performance Status
0
Normal activity. Fully active, able to carry on all predisease performance without 
restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
5
Dead. 
[ECOG ACRIN Cancer Research Group 2016]
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
3L
third-line
3L+
third-line or beyond
ACTH
adrenocorticotrophic hormone
ADA
antidrug antibodies
ADL
activities of daily living  
AE
adverse event 
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APaT
All-Participants-as-Treated
aPTT/PTT
activated partial thromboplastin time
AR
adverse reaction
ART
antiretroviral therapy
AST
aspartate aminotransferase
BICR
blinded independent central review
BID
twice daily
BP
blood pressure
BUN
blood urea nitrogen
C
cycle
CAPOX
capecitabine and oxaliplatin
C30
cancer-specific 30 items
CD
cluster of differentiation
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CEA
carcinoembryonic antigen
CF
compact flash
CG
Cockcroft-Gault
CI
confidence interval
CL
clearance
Cmax
maximum concentration
Cmin
minimum concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CPS
combined positive score
CR
complete response
CR29
colorectal cancer-specific 29 items
CRC
colorectal cancer
CrCl
creatinine clearance
CRF
case report form 
CSR
clinical study report
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Abbreviation
Expanded Term
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
minimum concentration
D
day
DCR
disease control rate
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
dMMR
mismatch repair deficient
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
ECOG PS
ECOG performance status
eCRF
electronic Case Report Form
EDC
electronic data collection 
eDMC
external data monitoring committee 
EEA
European Economic Area
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EMEA
Europe, Middle East, Africa
EOC
Executive Oversight Committee 
EORTC
European Organisation for Research and Treatment of Cancer
EOT
end of treatment
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQoL 5D-5L
ESMO
European Society for Medical Oncology
EU
European Union
FA
final analysis
FAS
full analysis set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed paraffin-embedded
FOLFIRI
folinic acid, fluorouracil, and irinotecan
FOLFIRINOX
folinic acid, fluorouracil, irinotecan, and oxaliplatin
FOLFOX
fluoropyrimidine, oxaliplatin, and irinotecan
FOLFOXIRI
folinic acid, fluorouracil, irinotecan, and oxaliplatin
FSH
follicle-stimulating hormone
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Abbreviation
Expanded Term
FT3
free triiodothyronine
FT4
free thyroxine
FU
follow-up
GFR
glomerular filtration rate
GI
gastrointestinal
H1
Hypothesis 1
H2
Hypothesis 2
H3
Hypothesis 3
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HGRAC
Human Genetic Resources Administration of China
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HR
hazard ratio
HRQoL
health related quality of life
HRT
hormone replacement therapy
IA
interim analysis
IB
investigator’s brochure 
ICF
informed consent form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCRO
imaging contract research organization
ID
identification
IEC
independent ethics committee
Ig
immunoglobulin
IgG4
humanized immunoglobulin G4
IgV-type
Ig-variable–type
IHC
Immunohistochemistry
IMP
investigational medicinal product
IND
investigational new drug 
INR
international normalized ratio
IO
immuno-oncology
irAE
immune-related AE
IRB
institutional review board 
iRECIST
response evaluation criteria in solid tumors 1.1 for immune-based 
therapeutics
IRT
interactive response technology
ITT
intention-to-treat
IUD
intrauterine device
IUO
investigational use only
IUS
intrauterine hormone-releasing system
IV
intravenous
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Abbreviation
Expanded Term
IVD
in vitro diagnostic
JSCCR
Japanese Society for Cancer of the Colon and Rectum
LAG-3
lymphocyte activation gene 3
LAM
lactational amenorrhea method
M&N
Miettinen and Nurminen
mAb
monoclonal antibody
MCH
mean corpuscular hemoglobin
mCRC
metastatic colorectal cancer
MCV
mean corpuscular volume
MHC
major histocompatibility complex
MMR
mismatch repair
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MSI-H
microsatellite instability-high
MSS
microsatellite stable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
not evaluable
NIMP
non-investigational medicinal product
non-MSI-H
non-microsatellite instability-high
NSAE
nonserious adverse event
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
nonsmall cell lung cancer
NYHA
New York Heart Association
OR
objective response 
ORR
objective response rate
OS
overall survival
PBPK
physiologically based pharmacokinetic 
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PFS
progression-free survival
PK
pharmacokinetic
PKCθ
protein kinase C-theta
pMMR
proficient mismatch repair
PO
orally 
PR
partial response
pRBC
packed red blood cell
PRO
patient-reported outcome
PT
prothrombin time
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Abbreviation
Expanded Term
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
Q8W
every 8 weeks
Q9W
every 9 weeks
QD
daily 
QLQ
Quality of Life Questionnaire
QoL
quality of life
RBC
red blood cells
RECIST
response evaluation criteria in solid tumors
RNA
ribonucleic acid
ROW
rest of world
SAE
serious adverse event 
SEER
Surveillance, Epidemiology, and End Results
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SIM
Site Imaging Manual
sLAG-3
soluble Lymphocyte activation gene-3
SmPC
Summary of Product Characteristics
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus
T3
triiodothyronine
T4
thyroxine
TB
tuberculosis
TEA
treatment eligibility assessment
TIL
tumor-infiltrating lymphocyte
TKI
tyrosine kinase inhibitor
TMDD
target-mediated drug disposition
TRAE
treatment-related adverse event
Tregs
regulatory T cells
TSH
thyroid-stimulating hormone
TTD
time to deterioration
UK
United Kingdom
ULN
upper limit of normal
US
United States
V
volume of distribution
VEGF
vascular endothelial growth factor
WBC
white blood cells
WOCBP
woman/women of childbearing potential 
WT
wild type
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Abbreviation
Expanded Term
XELIRI
capecitabine plus irinotecan
XELOX
capecitabine plus oxaliplatin
ZAP70
zeta-chain-associated protein kinase
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11
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