A Phase 2 Study to Evaluate Patient Reported Preference for Subcutaneous Pembrolizumab Coformulated With Hyaluronidase (MK-3475A) Over Intravenous Pembrolizumab Formulation in Participants With Multiple Tumor Types (MK-3475A-F11)
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer, Renal Cell Carcinoma, Melanoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT06099782 
Document Date: 
05-Feb-2024 
A Phase 2 Study to Evaluate Patient Reported Preference for 
Subcutaneous Pembrolizumab Coformulated with 
Hyaluronidase (MK-3475A) Over Intravenous Pembrolizumab 
Formulation in Participants With Multiple Tumor Types 
(MK-3475A-F11)

PRODUCT: MK-3475A
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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 2 Study to Evaluate Patient Reported Preference for Subcutaneous 
Pembrolizumab Coformulated with Hyaluronidase (MK-3475A) Over Intravenous 
Pembrolizumab Formulation in Participants With Multiple Tumor Types (MK-3475A-F11)
Protocol Number: F11-02
Compound Number: MK-3475A
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
NCT06099782
EU CT
2023-506017-22
EudraCT
Not applicable
jRCT
jRCT2051230147
WHO
Not applicable
UTN
U1111-1293-0814
IND
161465
Approval Date: 05 February 2024
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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 02
05-FEB-2024
To address Health Authority/Agency feedback to 
update country-specific requirements for France
and Poland with mandatory HBV, HCV, and 
HIV testing at screening.
Amendment 01
05-SEP-2023
To address Health Authority/Agency request to 
ensure that biases deriving from the potential 
differences in mental and cognitive condition of 
participants are mitigated at enrollment and 
participants are competent to judge presented 
options.
Original Protocol
19-JUL-2023
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendment:
To address Health Authority/Agency feedback to update country-specific requirements for 
France and Poland with mandatory HBV, HCV, and HIV testing at screening.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 10.7.3
Country-specific 
Requirements: 
France and 
Section 10.7.5
Country-specific 
Requirements: 
Poland
Added country-specific requirements for HBV, 
HCV, and HIV testing at screening.
This change was made to address Health 
Authority/Agency feedback to add mandatory 
HBV, HCV, and HIV testing at screening to the 
country-specific appendices for France and 
Poland.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Title Page
Added NCT and jRCT numbers.
NCT and jRCT numbers became available.
Section 1.3, 
Schedule of 
Activities
Added an X to the screening column for 
imaging assessments.
This change was made to clarify that imaging 
assessments are required during the screening 
period.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 10.1.1 
Code of Conduct 
for Interventional 
Clinical Trials
Added statement that the clinical trial will be 
conducted in compliance with Regulation (EU) 
536/2014.
This change was made to comply with 
Regulation (EU) 536/2014.
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...............................................3
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities...........................................................................................17
2
INTRODUCTION..........................................................................................................22
2.1
Study Rationale....................................................................................................22
2.2
Background ..........................................................................................................22
2.2.1
Subcutaneous Formulation...........................................................................23
2.2.2
Preclinical and Clinical Studies ...................................................................24
2.2.3
Ongoing Clinical Studies.............................................................................25
2.2.4
Information on Other Study-related Therapy ..............................................25
2.3
Benefit/Risk Assessment......................................................................................25
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................27
4
STUDY DESIGN............................................................................................................28
4.1
Overall Design......................................................................................................28
4.2
Scientific Rationale for Study Design.................................................................29
4.2.1
Description of Endpoints .............................................................................30
4.2.1.1
Patient Preference Measures..............................................................30
4.2.1.1.1
PPQ ..........................................................................................30
4.2.1.1.2
TASQ.......................................................................................31
4.2.1.1.3
Participant Choice Questionnaire ............................................31
4.2.1.2
Health Care Professional Questionnaire............................................31
4.2.1.3
Safety Endpoints................................................................................31
4.3
Justification for Dose...........................................................................................31
4.3.1
MK-3475A Subcutaneous Dose ..................................................................31
4.3.2
Pembrolizumab Intravenous Dose...............................................................32
4.4
Beginning and End-of-Study Definition ............................................................32
4.4.1
Clinical Criteria for Early Study Termination .............................................32
5
STUDY POPULATION ................................................................................................34
5.1
Inclusion Criteria.................................................................................................34
5.2
Exclusion Criteria................................................................................................38
5.3
Lifestyle Considerations......................................................................................41
5.3.1
Meals and Dietary Restrictions....................................................................41
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................41
5.3.3
Activity Restrictions ....................................................................................41
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5.4
Screen Failures.....................................................................................................41
5.5
Participant Replacement Strategy......................................................................41
6
STUDY INTERVENTION............................................................................................42
6.1
Study Intervention(s) Administered...................................................................42
6.1.1
Treatment .....................................................................................................45
6.2
Preparation/Handling/Storage/Accountability .................................................45
6.2.1
Dose Preparation..........................................................................................45
6.2.2
Handling, Storage, and Accountability........................................................45
6.3
Measures to Minimize Bias: Randomization and Blinding..............................46
6.3.1
Intervention Assignment..............................................................................46
6.3.2
Stratification.................................................................................................46
6.3.3
Blinding........................................................................................................46
6.4
Study Intervention Compliance..........................................................................46
6.5
Concomitant Therapy..........................................................................................47
6.5.1
Rescue Medications and Supportive Care ...................................................48
6.6
Dose Modification (Escalation/Titration/Other)...............................................48
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................48
6.7
Intervention After the End of the Study............................................................55
6.8
Clinical Supplies Disclosure................................................................................55
6.9
Standard Policies..................................................................................................55
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................56
7.1
Discontinuation of Study Intervention...............................................................56
7.2
Participant Withdrawal From the Study...........................................................57
7.3
Lost to Follow-up .................................................................................................57
8
STUDY ASSESSMENTS AND PROCEDURES........................................................58
8.1
Administrative and General Procedures ...........................................................58
8.1.1
Informed Consent.........................................................................................58
8.1.1.1
General Informed Consent.................................................................59
8.1.2
Inclusion/Exclusion Criteria ........................................................................59
8.1.3
Participant Identification Card.....................................................................59
8.1.4
Medical History ...........................................................................................59
8.1.4.1
Tobacco Use Assessment...................................................................60
8.1.5
Prior and Concomitant Medications Review...............................................60
8.1.5.1
Prior Medications...............................................................................60
8.1.5.2
Concomitant Medications..................................................................60
8.1.6
Assignment of Screening Number...............................................................60
8.1.7
Assignment of Randomization Number.......................................................60
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8.1.8
Study Intervention Administration ..............................................................61
8.1.8.1
Timing of Dose Administration.........................................................61
8.1.9
Discontinuation and Withdrawal .................................................................61
8.1.10
Participant Blinding/Unblinding..................................................................61
8.1.11
Calibration of Equipment.............................................................................61
8.1.12
Tumor Tissue for Biomarker Status.............................................................61
8.2
Questionnaires......................................................................................................61
8.3
Imaging Assessments ...........................................................................................62
8.3.1
Tumor Imaging and Assessment of Disease................................................62
8.4
Safety Assessments...............................................................................................62
8.4.1
Physical Examinations.................................................................................62
8.4.1.1
Full Physical Examination.................................................................63
8.4.1.2
Directed Physical Examination..........................................................63
8.4.1.3
Injection Site Reactions .....................................................................63
8.4.2
Vital Signs....................................................................................................64
8.4.3
Electrocardiograms ......................................................................................64
8.4.4
Clinical Safety Laboratory Assessments .....................................................64
8.4.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................65
8.4.5
Pregnancy Testing........................................................................................65
8.4.6
Performance Assessments............................................................................65
8.4.6.1
Eastern Cooperative Oncology Group Performance Status...............65
8.5
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................65
8.5.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................66
8.5.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......68
8.5.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...68
8.5.4
Regulatory Reporting Requirements for SAE .............................................69
8.5.5
Pregnancy and Exposure During Breastfeeding ..........................................69
8.5.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................69
8.5.7
Events of Clinical Interest............................................................................70
8.6
Treatment of Overdose........................................................................................70
8.7
Pharmacokinetics.................................................................................................70
8.8
Pharmacodynamics..............................................................................................70
8.9
Biomarkers ...........................................................................................................70
8.10
Future Biomedical Research Sample Collection...............................................70
8.11
Medical Resource Utilization and Health Economics.......................................70
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8.12
Visit Requirements...............................................................................................71
8.12.1
Screening......................................................................................................71
8.12.2
Treatment Period..........................................................................................71
8.12.3
Posttreatment Visit.......................................................................................71
8.12.4
Vital Status...................................................................................................71
9
KEY STATISTICAL CONSIDERATIONS ...............................................................72
9.1
Responsibility for Analyses/In-house Blinding .................................................72
9.2
Hypotheses/Estimation ........................................................................................72
9.3
Analysis Endpoints...............................................................................................72
9.3.1
Participant Preference and Satisfaction Measure Endpoints .......................72
9.3.2
Safety Endpoints..........................................................................................73
9.4
Analysis Populations............................................................................................73
9.4.1
Participant Preference and Satisfaction Measure Analysis Populations......73
9.4.2
Safety Analysis Populations ........................................................................73
9.5
Statistical Methods...............................................................................................73
9.5.1
Statistical Methods for Participant Preference and Satisfaction Measure 
Analyses.......................................................................................................73
9.5.2
Statistical Methods for Safety Analyses ......................................................74
9.6
Interim Analyses ..................................................................................................75
9.7
Multiplicity ...........................................................................................................75
9.8
Sample Size and Power Calculations .................................................................75
9.9
Subgroup Analyses...............................................................................................75
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................76
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........76
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................76
10.1.2
Financial Disclosure.....................................................................................79
10.1.3
Data Protection.............................................................................................80
10.1.3.1
Confidentiality of Data ......................................................................80
10.1.3.2
Confidentiality of Participant Records...............................................80
10.1.3.3
Confidentiality of IRB/IEC Information............................................81
10.1.4
Committees Structure...................................................................................81
10.1.4.1
Executive Oversight Committee........................................................81
10.1.5
Publication Policy........................................................................................81
10.1.6
Compliance with Study Registration and Results Posting Requirements ...81
10.1.7
Compliance with Law, Audit, and Debarment ............................................82
10.1.8
Data Quality Assurance ...............................................................................82
10.1.9
Source Documents .......................................................................................83
10.1.10
Study and Site Closure.................................................................................84
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10.2
Appendix 2: Clinical Laboratory Tests..............................................................85
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................87
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................87
10.3.2
Definition of AE ..........................................................................................87
10.3.3
Definition of SAE ........................................................................................88
10.3.4
Additional Events Reported.........................................................................89
10.3.5
Recording AE and SAE ...............................................................................89
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................93
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................94
10.5
Appendix 5: Contraceptive Guidance................................................................95
10.5.1
Definitions....................................................................................................95
10.5.2
Contraceptive Requirements........................................................................96
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................97
10.7
Appendix 7: Country-specific Requirements....................................................98
10.7.1
Argentina......................................................................................................98
10.7.2
Chile.............................................................................................................98
10.7.3
France...........................................................................................................98
10.7.4
South Africa.................................................................................................98
10.7.5
Poland ..........................................................................................................99
10.8
Appendix 8: Melanoma Staging .......................................................................100
10.9
Appendix 9: Surgical Considerations (Melanoma).........................................105
10.10 Appendix 10: Eastern Cooperative Oncology Group Performance Status..107
10.11 Appendix 11: Abbreviations .............................................................................108
11
REFERENCES.............................................................................................................113
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LIST OF TABLES
Table 1
Study Schedule of Activities........................................................................17
Table 2
Adequate Organ Function Laboratory Values .............................................38
Table 3
Study Interventions......................................................................................43
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated With Pembrolizumab Monotherapy, 
Coformulations, or IO Combinations ..........................................................................49
Table 5
Pembrolizumab Monotherapy, Coformulations, or IO Combinations 
Infusion/Injection Reaction Dose Modification and Treatment Guidelines................53
Table 6
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................................67
Table 7
Analysis Strategy for Key participant preference and satisfaction 
measure Variables........................................................................................................74
Table 8
Protocol-required Clinical Laboratory Assessments ...................................85
Table 9
Melanoma T Category Definition..............................................................100
Table 10
Melanoma N Category Definition .............................................................101
Table 11
Melanoma M Category Definition.............................................................102
Table 12
AJCC Pathological (pTNM) Staging Groups ............................................103
Table 13
AJCC Clinical Prognostic (cTNM) Staging Groups..................................104
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LIST OF FIGURES
Figure 1
Study Design................................................................................................16
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2 Study to Evaluate Patient Reported Preference for Subcutaneous 
Pembrolizumab Coformulated with Hyaluronidase (MK-3475A) Over Intravenous 
Pembrolizumab Formulation in Participants With Multiple Tumor Types (MK-3475A-F11)
Short Title: Patient Reported Preference for Subcutaneous MK-3475A Over Intravenous 
Pembrolizumab Formulation in Multiple Tumor Types
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
In participants at least 18 years of age with early-stage or advanced/ metastatic solid tumors.
Primary Objective
Primary Endpoint
To evaluate participant preference for 
MK-3475A SC
Participant preference assessed by response 
of MK-3475A SC on PPQ question 1
Secondary Objectives
Secondary Endpoints
To evaluate the reasons for preference for 
MK-3475A SC
Participant responses to PPQ question 3
To evaluate participant satisfaction with 
route of administration of MK-3475A SC 
and pembrolizumab IV
Participant responses to the TASQ SC and 
TASQ IV
To evaluate participants choice of 
administration for the study Treatment 
Continuation Period
Participant choice of MK-3475A SC for the 
study Treatment Continuation Period
To evaluate the safety and tolerability of 
MK-3475A SC and pembrolizumab IV
AE
Discontinuation of study intervention due to 
AEs
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Solid tumour
Population
Participants with early-stage or 
advanced/metastatic solid tumors
Study Type
Interventional
Intervention Model
Cross-Over
This is a multi site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 3 years from the time 
the first participant provides documented 
informed consent until the last participant’s 
last study-related contact.
Number of Participants:
Approximately 144 participants will be randomized to the study as described in Section 9.
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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-3475A
165 mg/mL
395 mg
SC
Day 1 of each 
cycle (Q3W) 
for C1-C3. On 
completion of 
C3, participant 
will be 
switched to IV 
infusion.
Test Product
Arm A
Pembrolizumab 25 mg/mL
200 mg
IV Infusion
Day 1 of each 
cycle (Q3W) 
for C4-C6. On 
completion of 
C6, participant 
will receive 
preferred IMP 
for up to 17 
cycles 
(melanoma and 
RCC) or 35 
cycles 
(NSCLC).
Comparator
Arm B
Pembrolizumab 25 mg/mL
200 mg
IV Infusion
Day 1 of each 
cycle (Q3W) 
for C1-C3. On 
completion of 
C3, participant 
will be 
switched to SC.
Comparator
Arm B
MK-3475A
165 mg/mL
395 mg
SC
Day 1 of each 
cycle (Q3W) 
for C4-C6. On 
completion of 
C6, participant 
will receive 
preferred IMP 
for up to 17 
cycles 
(melanoma and 
RCC) or 35 
cycles 
(NSCLC).
Test Product
C=cycle; IMP= investigational medicinal product; IV=intravenous; NSCLC= non–small cell lung cancer; Q3W=every 3 
weeks; RCC=renal cell carcinoma; SC=subcutaneous.
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Other current or former name(s) or alias(es) for study intervention(s) are as follows: 
pembrolizumab (KEYTRUDA®, MK-3475, or SCH 900475).
Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study 
for approximately 1 year for adjuvant RCC 
and melanoma and 2 years for metastatic 
NSCLC from the time the participant 
provides documented informed consent 
through the final protocol-specified contact. 
After a screening phase of up to 28 days, 
each participant will be receiving assigned 
intervention for approximately 1 year for 
adjuvant RCC and melanoma and 2 years 
for metastatic NSCLC. After the end of
treatment each participant will be followed 
for up to 90 days.
After a screening phase of up to 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 AEs 
and spontaneously reported pregnancy.
Study Governance Committees:
Executive Oversight Committee
Yes
External Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 11.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
ALK=anaplastic lymphoma kinase; C=cycle; D=day; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal 
growth factor receptor; IV=intravenous; NSCLC=non–small cell lung cancer; PD-L1=programmed cell death ligand 1; 
PPQ=Patient Preference Questionnaire; PS=Performance Status; Q3W=every 3 weeks; RCC=renal cell carcinoma; 
ROS1=c-ros oncogene 1; SC=subcutaneous; TASQ=Therapy Administration Satisfaction Questionnaire; TPS=tumor 
proportion score.
*For NSCLC, the absence of EGFR, ALK, and ROS1 sensitizing genetic aberrations is required for eligibility purposes. 
‡Enrollment cap will be implemented to ensure approximately 33% participants with melanoma, 33% participants with 
RCC, and 33% participants with metastatic NSCLC.
†Total duration of treatment: 17 cycles for adjuvant treatment of melanoma and RCC and 35 cycles for first line treatment of 
metastatic NSCLC.
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1.3
Schedule of Activities
Details of each procedure outlined in the SoA are provided in Section 8. Unless otherwise indicated, procedures should be performed 
before study intervention administration. Refer to Appendix 7 for country-specific requirements.
Table 1
Study Schedule of Activities
Study Period:
Screening 
Phase
Intervention Phase 
(21-Day Cycles)
EOT/Discon-
tinuation
Follow-up
Notes
Cycle
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 35*
At treatment 
discontinuation
30 days 
post last 
dose
90 days post 
last dose
contact
*Cycles 18-35 for NSCLC participants 
only.
Cycle Day
-28 to -1
1
1
1
1
1
1
1
Schedule Window
+3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
Participant Identification 
Card
X
X
The Participant Identification Card should 
be updated with the randomization number 
at the time of randomization.
Demographics and Medical 
History 
X
Tobacco Use Assessment 
(NSCLC participants only)
X
See Section 8.1.4.1 for definitions of 
cigarette use.
Prior/Concomitant 
Medication Review
Prior medications: Record medications 
taken within 28 days before first dose and 
medications regularly administered at 
intervals greater than 28 days before first 
dose. Concomitant medications: Record 
new medications started during the study 
through the postintervention follow-up, as 
well as any changes to dose, frequency, and 
route that occur.
Intervention Randomization
X
Randomization can occur up to 3 days 
before C1D1 (start of study intervention).
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Study Period:
Screening 
Phase
Intervention Phase 
(21-Day Cycles)
EOT/Discon-
tinuation
Follow-up
Notes
Cycle
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 35*
At treatment 
discontinuation
30 days 
post last 
dose
90 days post 
last dose
contact
*Cycles 18-35 for NSCLC participants 
only.
Cycle Day
-28 to -1
1
1
1
1
1
1
1
Schedule Window
+3
±3
±3
±3
±3
±3
±3
Vital Status
Participants may be contacted for vital 
status at any time during the study.
Collect Vital Status at 90 days post last dose 
in case of SAE.
Study Intervention 
Administration
MK-3475A SC OR
Pembrolizumab IV 
Administrationa
X
X
X
X
X
X
X*
*17 cycles for adjuvant RCC and 
melanoma; 35 cycles for metastatic 
NSCLC.
Imaging Assessments
Tumor Scan
X
Perform per SoC for each tumor type.
Brain Scan
X
Bone Scan
X
Safety Assessments
Full Physical Examination 
Including Weight and Height
X
X
Collect height at Screening only.
Directed Physical 
Examination
X
X
X
X
X
X
X
X
For melanoma participants: The investigator 
or qualified designee should conduct a 
visual inspection of local recurrence and 
palpation of regional lymph nodes to assess 
regional recurrence.
Vital Signs 
X
X
X
X
X
X
X
X
X
X
Temperature, HR, RR, BP, and weight.
Pregnancy Testing
X
X
X
X
X
X
X
X
X
X
POCBP require a negative pregnancy test 
before the start of study intervention (within 
24 hours for urine or within 72 hours for 
serum).
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Study Period:
Screening 
Phase
Intervention Phase 
(21-Day Cycles)
EOT/Discon-
tinuation
Follow-up
Notes
Cycle
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 35*
At treatment 
discontinuation
30 days 
post last 
dose
90 days post 
last dose
contact
*Cycles 18-35 for NSCLC participants 
only.
Cycle Day
-28 to -1
1
1
1
1
1
1
1
Schedule Window
+3
±3
±3
±3
±3
±3
±3
12-lead ECG
X
Perform at Screening and as clinically 
indicated thereafter.
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Evaluate within 3 days before the planned 
start of study intervention.
Hematology and Chemistry
X
X
X
X
X
X
X
X
X
X
Collect screening samples within 10 days 
before the start of study intervention.
Collect on-treatment samples and review 
results within 72 hours before Day 1 of each 
cycle.
Urinalysis
X
Collect screening samples within 10 days 
before the start of study intervention.
HBV, HCV, HIV Testing
X
Only perform if required by the local health 
authority or if known history of infection.
Thyroid Function Tests 
(TSH, T3, T4)
X
X
X
X
X
X
Screening samples to be collected within 10 
days before the first dose of study 
intervention. Perform at Day 1 of every 
other cycle starting from C2 until C35 
(collect sample within 72 hours prior). 
Participants may be dosed in subsequent 
cycles after C1 while thyroid function tests 
are pending. Free T3 and T4 are acceptable.
PT or INR and aPTT/PTT
(baseline only)
X
Collect screening samples within 10 days 
before the start of study intervention.
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Study Period:
Screening 
Phase
Intervention Phase 
(21-Day Cycles)
EOT/Discon-
tinuation
Follow-up
Notes
Cycle
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 35*
At treatment 
discontinuation
30 days 
post last 
dose
90 days post 
last dose
contact
*Cycles 18-35 for NSCLC participants 
only.
Cycle Day
-28 to -1
1
1
1
1
1
1
1
Schedule Window
+3
±3
±3
±3
±3
±3
±3
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
Report AEs occurring within 30 days after 
last dose of study intervention. Report 
SAEs within 90 days after the last dose of 
study intervention, or 30 days after last dose 
of study intervention if the participant 
initiates new anticancer therapy, whichever 
occurs first. Refer to Section 8.5.3 for 
follow-up of AE/SAE.
Questionnaires
Perform at each visit specified below, in the 
following order: PPQ then TASQ then 
HCP. Ensure the PPQ and TASQ are 
completed BEFORE the participant leaves 
the Cycle 6 clinic visit. 
Patient Preference 
Questionnaire (PPQ)a
X
Administer at C6D1 after study intervention
administration.
Therapy Administration 
Satisfaction Questionnaire-
SC (TASQ SC)
X
X
Administer for Arm A at C3D1 and for 
Arm B at C6D1 after the SC treatment
administration.
Therapy Administration 
Satisfaction Questionnaire-
IV (TASQ IV)  
X
X
Administer for Arm B at C3D1 and for 
Arm A at C6D1 after the IV treatment
administration.
Participant Choice 
Questionnaire for 
Continuation Period
X
Administer after study intervention 
administration and after completion of both 
questionnaires (PPQ & TASQ).
Healthcare Professional 
Questionnaire
X
HCP to complete at C6D1 after the 
participant has completed study intervention
and the PPQ and TASQ.
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Study Period:
Screening 
Phase
Intervention Phase 
(21-Day Cycles)
EOT/Discon-
tinuation
Follow-up
Notes
Cycle
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 35*
At treatment 
discontinuation
30 days 
post last 
dose
90 days post 
last dose
contact
*Cycles 18-35 for NSCLC participants 
only.
Cycle Day
-28 to -1
1
1
1
1
1
1
1
Schedule Window
+3
±3
±3
±3
±3
±3
±3
Tumor Tissue for 
Biomarker Status
PD-L1 Status (NSCLC 
participants only)
X
PD-L1 status from local laboratory before 
randomization. PD-L1 must be determined 
by using the Dako PD-L1 IHC 22C3 
pharmDx diagnostic kit with TPS ≥50 
positive status defined.
EGFR, ALK, ROS1 
(NSCLC participants only)
X
EGFR, ALK, and ROS1 testing from local 
laboratory before randomization (not 
required for predominantly squamous 
histology).
AE=adverse event; ALK=anaplastic lymphoma kinase; aPTT=activated partial thromboplastin time; BP=blood pressure; C=cycle; D=day; ECG=electrocardiogram; EGFR=epidermal growth factor 
receptor; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; HBV=hepatitis B virus; HCP=healthcare professional; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
HR=heart rate; IHC= immunohistochemistry; INR=international normalized ratio; IV=intravenous; NSCLC=non–small cell lung cancer; PD-L1=programmed cell death ligand 1; 
POCBP=participant/participants of childbearing potential; PPQ=Patient Preference Questionnaire; PT=prothrombin time; PTT=partial thromboplastin time; RCC=renal cell carcinoma; ROS1=c-ros 
oncogene 1; RR=respiratory rate; SAE=serious adverse event; SC=subcutaneous; SoC=standard of care; T3=triiodothyronine; T4= thyroxine; TASQ=Therapy Administration Satisfaction 
Questionnaire; TPS=tumor proportion score; TSH= thyroid-stimulating hormone.
a
Participant must complete the Treatment Crossover Period including all 3 MK-3475A SC and 3 pembrolizumab IV cycles to complete the C6D1 PPQ. 
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2
INTRODUCTION
This is a Phase 2 study evaluating patient preference of MK-3475A SC over pembrolizumab 
IV in participants with resected Stage IIB, IIC, III melanoma, intermediate-high or high risk 
resected RCC, or newly diagnosed, untreated Stage IV NSCLC with a PD-L1 TPS ≥50%.
2.1
Study Rationale
KEYTRUDA® (MK-3475, pembrolizumab) is approved globally for the treatment of patients 
across multiple indications. The recommended dose of pembrolizumab in adults is either 
200 mg Q3W or 400 mg Q6W administered by IV infusion. SC formulations of 
pembrolizumab are being developed to provide an alternative route of administration with the 
potential for increased accessibility. Benefits of SC administration include time savings for 
patients and providers, convenience, reduced administration costs, ease of administration, 
and reduced health care resource burden. SC administration will also reduce patient chair 
time, making it feasible for infusion centers to treat more patients. Specific patient preference 
data in support of MK-3475A may help demonstrate value to different stakeholders and 
contribute to the totality of evidence supporting use of MK-3475A SC.
Hyaluronan (also known as hyaluronic acid) is key to creating the skin resistance that limits 
SC dispersion and absorption of drugs [Frost, G. I. 2007]. Hyaluronidases increase tissue 
permeability by degrading glycosaminoglycan hyaluronan [Wohlrab, J., et al 2014]. When 
administered SC, hyaluronidase results in a temporary breakdown of local connective tissue, 
increasing the dispersion and absorption of drugs and fluids. After injection, hyaluronic acid 
is regenerated and the barrier is restored within 48 hours.
There are ovine, bovine, and human recombinant hyaluronidase drug products that have 
received regulatory approval as adjuvants or permeation enhancers to increase the dispersion 
and absorption of drugs injected SC. 
MK-5180 is a variant of rHuPH20. Studies to date have shown that MK-5180 has improved 
thermal and pH stability compared with rHuPH20. MK-5180 is a glycoprotein and is 
expressed in CHO cells (CHO-DG44-DHFR) and has the same function of enzyme-mediated 
hyaluronan degradation, aiding drug product dispersion and dermal layer reconstitution, as 
commercially available hyaluronidases on the market.
MK-3475A is a coformulation of pembrolizumab with MK-5180. This study will evaluate 
the patient preference between MK-3475A SC and pembrolizumab IV, both administered 
Q3W in participants with resected Stage IIB, IIC, III melanoma, intermediate-high or high
risk resected RCC, or newly diagnosed, untreated Stage IV NSCLC with a PD-L1 TPS 
≥50%.
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. 
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Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is 
indicated for the treatment of patients across several indications. For more details on specific 
indications refer to the IB.
2.2.1
Subcutaneous Formulation
A strong patient preference has been shown for oncology therapeutics to be administered by 
SC injection over IV infusion. In an open-label, randomized study of the preference for SC or 
IV administration of trastuzumab, 91.5% of participants preferred SC administration (95% 
CI: 87.2 to 94.7; p<0.0001) [Pivot, X., et al 2013]. The 2 most common reasons for this 
preference were because SC administration saved time and resulted in less pain or 
discomfort. Healthcare professionals also preferred SC administration of trastuzumab; of 
103 healthcare professionals, 73.8% preferred SC, 1.9% preferred IV, and 24.3% had no 
preference [Pivot, X., et al 2013]. Similar results were reported from a study evaluating the 
preference for SC or IV administration of rituximab [Rummel, M., et al 2017].
In a Phase 2, randomized, open-label study of preference for the fixed-dose combination of 
pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early 
breast cancer, 85% of participants (95% CI: 78.5-90.2%) preferred SC; 13.8% preferred IV 
and 1.3% had no preference. The main reasons for SC preference were reduced clinic time 
and comfort during administration. HCP perceptions of median patient treatment room time 
ranged from 33.0-50.0 min with SC and 130.0-300.0 min with IV [O'Shaughnessy, J., et al 
2021].
A SC formulation of pembrolizumab has been developed to provide an alternative route of 
administration with the potential for increased accessibility. Clinical data from Cohort A of 
Study KEYNOTE-555, a Phase 1 evaluation of pembrolizumab SC Q3W, show that the 
estimated bioavailability of pembrolizumab SC was 66% (95% CI: 58% to 74%), which is 
consistent with the bioavailability reported for other SC administered mAbs (range: 50% to 
85%). Clearance was the same for SC and IV formulations and no positive ADA were 
observed. Preliminary safety data from the first 3 cycles of treatment revealed no new safety 
signals. Injection-site data gathered from participant questionnaires as well as reported drug-
related skin and SC tissue disorder AEs indicate a low frequency of primarily mild pruritus, 
rash, or redness. 
Phase 3 study KEYNOTE-A86 is evaluating noninferiority of PK exposure between 
pembrolizumab SC and IV administration. Participants with treatment-naïve metastatic 
NSCLC are randomly assigned in a 2:1 ratio to study intervention Arm A (pembrolizumab 
SC Q3W with chemotherapy) or Arm B (pembrolizumab IV Q3W with chemotherapy). The 
dual primary endpoints of Cycle 1 AUC0-3wks and Cycle 6 Ctrough enable characterization of 
pembrolizumab exposure.
Both KEYNOTE-555 and KEYNOTE-A86 are evaluating SC pembrolizumab as a single 
entity for Q3W dosing. One constraint of SC administration without a hyaluronidase is the 
skin’s resistance to bulk fluid flow that limits drug delivery and dispersion and makes Q6W 
dosing infeasible for SC pembrolizumab as a single entity. MK-3475A, a coformulation of 
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pembrolizumab with a novel hyaluronidase (MK-5180), is being developed to increase the 
volume of SC pembrolizumab delivery and enhance its dispersion. Hyaluronidase products 
have been used clinically for more than 70 years to facilitate the distribution of 
coadministered drugs by temporarily breaking down local connective tissue [Wohlrab, J., et 
al 2014]. MK-3475A SC is being evaluated in the Phase 1 study MK-3475A-C18 and the 
Phase 3 study, MK-3475A-D77.
MK-3475A-C18 is a FIH, Phase 1 study to evaluate the PK, safety, and tolerability of 
MK-3475A administered by SC injection to participants with unresectable, advanced 
melanoma, metastatic NSCLC, or advanced or metastatic RCC. The study is to evaluate the 
safety, tolerability and PK profile (specifically absorption phase) of pembrolizumab when 
administered subcutaneously at a concentration of 165 mg/mL or 130 mg/mL, formulated 
with MK-5180, a recombinant human hyaluronidase dispersant. The primary purpose of this 
study is to establish the bioavailability of pembrolizumab when administered subcutaneously 
as MK-3475A for further clinical development. Due to differences in the viscosity of the 2 
concentrations (165 mg/mL or 130 mg/mL) of pembrolizumab in the MK-3475A SC 
formulation, the bioavailability of pembrolizumab will be assessed at each concentration. 
The results of this study will contribute to an understanding of the PK characteristics of 
pembrolizumab administered SC with MK-5180 in Q3W and Q6W dosing regimens.
Pembrolizumab serum concentration data available from 81 participants collected during 
Cycle 1 (ie, Weeks 1 to 6; MK-3475A SC administration) and Cycle 2 (ie, Weeks 7 to 12; 
pembrolizumab IV administration) across both study arms of MK-3475A-C18, along with 
extensive historical pembrolizumab IV PK data, were used to characterize the PK of SC 
pembrolizumab given as MK-3475A using population PK modeling. The analysis showed 
that pembrolizumab combined with hyaluronidase when administered SC as MK-3475A had 
an estimated bioavailability of 57% (range: 38% to 75%). Median time to achieve maximum
pembrolizumab serum concentration was estimated to be 4 days (range: 2 to 35 days). The 2 
SC solution strengths of pembrolizumab (165 mg/mL and 130 mg/mL) had similar 
absorption PK when administered as MK-3475A. As of 22-JUN-2022, ADA were observed 
in 1 of 83 participants (<2%). A preliminary review of systemic safety data from 
MK-3475A-C18 revealed no new safety signals. All injection-site AEs were nonserious and 
the majority of participants (8 of 9) experienced AEs that were Grade 1. There were 2 
reported Grade 2 injection-site AEs (injection-site pruritus and injection-site erythema) and 
they both occurred in the same participant.
MK-3475A-D77 is a Phase 3 study evaluating the noninferiority of PK exposure between 
MK-3475A SC and pembrolizumab IV Q6W, both administered in combination with 
platinum doublet chemotherapy, in participants with treatment-naïve metastatic NSCLC.
2.2.2
Preclinical and Clinical Studies
The nonclinical development program for MK-3475A relies on previously conducted studies 
in support of pembrolizumab, supplemented with studies related to MK-5180 or the SC drug 
product, MK-3475A. 
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Dye dispersion studies performed using sequential or concomitant administration showed 
that diffusion of Trypan Blue was highest with increasing doses of MK-5180 or when the dye 
was sequentially administered with minimum delay after the MK-5180 injection. Nonclinical 
PK studies of MK-5180 indicate negligible systemic exposure. MK-5180 was well tolerated 
after SC administration in 1-month repeat dose toxicity studies in rats and cynomolgus 
monkeys. 
In light of existing nonclinical and clinical data for pembrolizumab and the lack of toxicity of 
MK-5180 due to its negligible systemic exposure, nonclinical evaluation MK-3475A was 
limited to a 1-month SC tolerability study in monkeys. MK-3475A was well tolerated with 
acceptable local tolerability at the SC injection sites and draining lymph nodes. The 
MK-3475A formulation contained 165 mg/mL pembrolizumab and 13.8 µg/mL (2000 U/mL) 
MK-5180, which is equivalent to the maximum concentration for pembrolizumab and is at 
least 1000-fold higher than the MK-5180 dose in the proposed clinical formulation. In 
addition, systemic exposure to pembrolizumab in monkeys administered MK-3475A is 
consistent with the expected systemic exposure in monkeys administered as pembrolizumab 
alone. The safety of MK-3475A in nonclinical studies is therefore considered comparable to 
the safety of pembrolizumab alone.
Refer to the respective IBs for preclinical data and a summary of ongoing clinical studies.
2.2.3
Ongoing Clinical Studies
Refer to the respective IBs for a summary of ongoing clinical studies for MK-3475A and 
pembrolizumab.
2.2.4
Information on Other Study-related Therapy
Not applicable.
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.
MK-3475A may provide an alternative SC dosage form of pembrolizumab that could offer 
patients an alternate form of administration maintaining the efficacy and safety of IV 
pembrolizumab with shorter administration time, improved patient convenience, satisfaction, 
and quality of life. 
Pembrolizumab delivered by SC administration is expected to maintain a favorable benefit-
risk profile comparable to that of IV administration. 
Due to large volume of drug given under the skin, injection reactions are expected with 
MK-3475A.
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IV pembrolizumab is approved for the indications being evaluated in this study. The benefit 
of MK-3475A is expected to be similar to that of IV pembrolizumab.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IBs and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In participants at least 18 years of age with early-stage or advanced/ metastatic solid tumors.
Primary Objective
Primary Endpoint
To evaluate participant preference for 
MK-3475A SC
Participant preference assessed by response 
of MK-3475A SC on PPQ question 1
Secondary Objectives
Secondary Endpoints
To evaluate the reasons for preference for 
MK-3475A SC
Participant responses to PPQ question 3
To evaluate participant satisfaction with 
route of administration of MK-3475A SC 
and pembrolizumab IV
Participant responses to the TASQ SC and 
TASQ IV
To evaluate participants choice of 
administration for the study Treatment 
Continuation Period
Participant choice of MK-3475A SC for the 
study Treatment Continuation Period
To evaluate the safety and tolerability of 
MK-3475A SC and pembrolizumab IV
AE
Discontinuation of study intervention due to 
AEs
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To evaluate healthcare provider preference 
for route of treatment administration
Healthcare provider preference assessed by 
HCP questionnaire (HCPQ)
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, 2-arm, crossover, multisite, open-label study of MK-3475A SC and 
pembrolizumab IV in participants with resected Stage IIB, IIC, III melanoma, intermediate-
high or high risk resected RCC, or newly diagnosed, untreated Stage IV NSCLC with a PD-
L1 TPS ≥50%.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 (Table 1) of the SoA. Details of each 
procedure are provided in Section 8.
After a screening period of up to 28 days, participants will be randomly assigned in a 1:1 
ratio to Arm A or Arm B. One cycle is 3 weeks.
•
Arm A: MK-3475A SC Q3W for 3 cycles followed by pembrolizumab IV Q3W for 
3 cycles 
•
Arm B: pembrolizumab IV Q3W for 3 cycles followed by MK-3475A SC Q3W for 
3 cycles
This period of 3+3 cycles (6 total cycles) in both treatment arms constitutes the study 
Treatment Crossover Period. The PPQ will be administered at C6D1 after study intervention 
administration. 
After completion of the Treatment Crossover Period as described above, participants will 
enter the Treatment Continuation Period. Participants may continue their preferred 
intervention for up to a total of 17 cycles (for adjuvant melanoma and RCC participants) or 
35 cycles (for metastatic NSCLC participants) of treatment.
Randomization will be stratified by ECOG performance status and tumor type (melanoma vs 
RCC vs NSCLC). Each participant will receive study intervention until one of the conditions 
for discontinuation of study intervention is met (Section 7.1). 
The primary study endpoint is participant preference assessed by response of MK-3475A SC 
on PPQ question 1. Refer to Section 9 for statistical analysis plan details.
After the end of treatment, each participant will be followed for the occurrence of AEs and 
spontaneously reported pregnancy as described in the SoA and Section 8.5. Participants who 
present with SAEs will be contacted by telephone at 90 days post last dose for SAE follow-
up.
Refer to Appendix 7 for country-specific requirements.
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4.2
Scientific Rationale for Study Design
KEYTRUDA® (MK-3475, pembrolizumab) is approved globally for the treatment of patients 
across multiple indications. The recommended dose of pembrolizumab in adults is either 
200 mg Q3W or 400 mg Q6W administered by IV infusion. MK-3475A SC is a 
coformulation of pembrolizumab with MK-5180 that is being developed to provide an 
alternative route of administration with potential benefits for patients. This study will 
evaluate preference of MK-3475A SC or pembrolizumab IV with a crossover design using 
Q3W dosing in participants with selected tumor types.
This is an open-label crossover study with pembrolizumab monotherapy. The intent is to 
evaluate the proportion of participants that prefer SC pembrolizumab over IV 
pembrolizumab.
A crossover study design allows participants to experience both forms of administration and 
minimizes variability as each participant serves as their own control. This removes the 
interparticipant variability from the comparison between groups and the effect of participant-
level covariates.
Randomization will be stratified by the following 2 factors, which all have the potential to 
influence patient preference.
1. ECOG performance status (0 vs 1): ECOG performance status would balance participants 
in both arms as there may be a higher dropout rate in the less stable participants. 
2. Tumor type (melanoma vs RCC vs NSCLC): The oncology clinical studies to date which 
have outcome measures based on patient preferences have been conducted in a single 
tumor type [Rummel, M., et al 2017]. In addition, some of these studies included only 
patients with early-stage disease [Pivot, X., et al 2013] [O'Shaughnessy, J., et al 2021]. 
Pembrolizumab has multiple indications across tumor types and disease stages, hence it is 
important to evaluate patient preference on the mode of administration in multiple tumor 
types and in both the early-stage (adjuvant setting) and metastatic stage. Therefore, the 
study will plan to enroll approximately 33% each of participants to be treated in: 
◦
First line metastatic NSCLC harboring PD-L1≥50% 
◦
Adjuvant indication for intermediate-high or high risk RCC
◦
Adjuvant indication of resected Stage IIB, IIC, III melanoma 
The distribution of approximately 33% for each tumor type was chosen to allow for 
equivalence across the tumors. Further, the 33% metastatic NSCLC tumor type would 
include data in the same population as MK-3475A-D77 Phase 3 noninferiority study
(metastatic NSCLC).
Pembrolizumab monotherapy is approved globally for early-stage RCC and melanoma in the 
adjuvant setting as well for advanced NSCLC with a TPS score of ≥50%. Evaluating patient 
preference in patients receiving pembrolizumab or MK-3475A as monotherapy regimen will 
allow patients to fully appreciate the value of both SC and IV modes of administration with 
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minimal effect of confounders, such as the addition of other IV chemotherapy drugs or orally 
administered agents. 
The study is designed to allow SC and IV mode of administrations to be administered for 3 
cycles each, every 3 weeks (total of 6 cycles) in each arm during the Treatment Crossover 
Period. The timing of switching the mode of administration within the arm (after 3 cycles) 
allows participants to experience both modes of administration, in addition to minimizing the 
overall duration of the study. The 3-week cycle duration allows frequent administrations of 
both SC and IV mode of administration, and minimizes recall bias compared with the 6-week 
cycle duration. Additionally, it allows most participants to complete the first 6 cycles in 18 
weeks for Q3W versus 36 weeks for Q6W in the Treatment Crossover Period with minimal 
discontinuation rates when most participants are in stable condition. 
Prior oncology studies evaluating preference for SC and IV support this decision as these 
have included a switch after 3 to 4 cycles. In all these studies, benefits of SC administration 
were reported with patients experiencing 3 to 4 cycles of each mode of administration, none 
less than 3 cycles have been conducted. Hence, the timing of switching the mode of 
administration (crossover after 3 cycles) for the IV and SC routes of administration within 
the proposed study would provide the necessary insights regarding patient preference and 
lower rates of discontinuations [Center for Drug Evaluation and Research 2019] [Center for 
Drug Evaluation and Research 2020] [Center for Drug Evaluation and Research 2017].
4.2.1
Description of Endpoints
4.2.1.1
Patient Preference Measures
4.2.1.1.1
PPQ
The PPQ (developed and owned by Roche Products Limited [Copyright © 2013]) is an 
instrument that has been developed from patient interviews and includes questions to 
evaluate directly from participants their preference regarding mode of administration, as well 
as the strength of the preference, and the reason for the preference. The PPQ has been 
established as a questionnaire to collect data to derive the primary endpoint to assess patient 
preference of mode of administration, SC or IV, in several randomized crossover clinical 
studies [O'Shaughnessy, J., et al 2021] [Rummel, M., et al 2017]. The questions are worded 
as described below:
Question 1 is “All things considered which method of administration do you prefer” with 
response options of IV, SC or no preference. This is data to support the primary endpoint of 
this study, proportions of patients who prefer IV, SC or have no preference. 
Question 2 is “If you have a preference for one of the administration routes, how strong is 
the preference?” with response options of very strong, fairly strong, not very strong.  
Question 3 asks patients “If you have a preference for one of the administration routes, what 
are the TWO main reasons for your preference?” with response options of feels less 
emotional distressing, requires less time in the clinic, lower level of injection-site pain, feels 
more comfortable during administration, and option for “other, please specify _______” 
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allowing the respondent to specify the reason. The participant responses to this question 
supports the secondary endpoint of proportions of the reasons for patient preference.
As this questionnaire is the primary and secondary endpoint of this study, completion of the 
questionnaire must be checked BEFORE the participant leaves the site at Cycle 6. 
4.2.1.1.2
TASQ
The TASQ is a 12-item questionnaire that asks questions regarding different aspects of 
satisfaction. The TASQ instruments include questions asking the participants about 
satisfaction with the relevant mode of administration, experiences related to the 
administration (eg, pain, swelling, redness, feeling of restriction), convenience and time 
related questions (time for administration, time associated with the ‘setting’, time with the 
HCP), preference and if they would recommend the mode of administration to another 
patient. There are 2 versions of this questionnaire, a subcutaneous version (TASQ SC) and an 
intravenous version (IV). The questions are similar but ask about the relevant mode of 
administration experienced [Theodore-Oklota, C., et al 2016]. In this study, the participant 
will complete the appropriate version of the questionnaire based on the assignment of SC or 
IV at Cycle 3, after completing therapy at this visit, and complete the other version of the 
questionnaire when completing the other mode of administration at Cycle 6.
4.2.1.1.3
Participant Choice Questionnaire
The participant’s choice of MK-3475A SC or pembrolizumab IV for the Treatment 
Continuation Period will be documented on the Participant Choice Questionnaire, 
administered at C6D1 after study intervention administration and completion of the PPQ and 
TASQ.
4.2.1.2
Health Care Professional Questionnaire
This is a questionnaire that asks health care professionals their preference of IV, SC, or “no 
preference”. This will be completed one time by each HCP for each participant. The HCP is 
the study nurse who has administered both IV and SC study intervention to the participant.
4.2.1.3
Safety Endpoints
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.
4.3
Justification for Dose
4.3.1
MK-3475A Subcutaneous Dose
The planned dose of pembrolizumab in MK-3475A for this study is 395 mg Q3W. Available 
PK data from the FIH, Phase 1 study of MK-3475A, Study MK-3475A-C18, was used to 
develop a population PK model and estimate the bioavailability of pembrolizumab when 
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administered SC as MK-3475A (see Section 2.2.1 for details) to enable Phase 3 dose 
selection and further clinical development. Study MK-3475A-C18 was amended to include 
an arm to evaluate the PK profile of pembrolizumab when administered Q3W as MK-3475A 
SC in participants with unresectable, advanced melanoma.
PK model-based simulations indicate that a pembrolizumab SC dose of either 395 mg Q3W 
or 790 mg Q6W leads to comparable exposures as the approved pembrolizumab IV doses. In 
principle, similar PK exposures lead to similar efficacy and safety of pembrolizumab, given 
that the exposure-response relationships for both efficacy and safety are well established for 
pembrolizumab. Refer to the MK-3475A IB for further PK data.
MK-3475A also includes MK-5180 at a 2000 U/mL concentration to maintain consistency 
with marketed mAbs formulated with hyaluronidase. Rituximab and hyaluronidase 
(Genentech), trastuzumab and hyaluronidase (Genentech), and daratumumab and 
hyaluronidase (Janssen) all contain 2000 U/mL of hyaluronidase. The enzyme activity of 
MK-5180 in the dose concentration is comparable to the marketed rHuPH20 from Halozyme 
Therapeutics present in these other products. Limited existing clinical data also indicate no 
specific benefit on bioavailability by increasing the concentration of hyaluronidase. Study 
MK-3475A-C18 will provide data on the safety of MK-5180 being used as part of 
MK-3475A.
4.3.2
Pembrolizumab Intravenous 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 a globally 
approved dose of pembrolizumab for adults across all indications.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant 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 EEA, the local start of the study in the EEA is defined 
as First Site Ready (FSR) in any Member State.
The maximum follow-up period will be when study intervention has been completed (1 year 
for adjuvant RCC and melanoma and 2 years for metastatic NSCLC) for all evaluable 
participants. The last study-related contact will be the LPLV date for the final prespecified 
analysis.
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 is such that the risk/benefit ratio to the study population as a whole is 
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unacceptable. In addition, further recruitment in the study or at (a) particular study site(s) 
may be stopped as described in Appendix 1.10.
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5
STUDY POPULATION
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
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. The participant must have a histologically- or cytologically-confirmed early stage or 
advanced/ metastatic solid tumor by pathology report who meet all the listed conditions 
of eligibility for 1 of the following indications:
•
Melanoma:
-
Has surgically resected and histologically/pathologically confirmed diagnosis of 
Stage IIB and IIC (pathological or clinical), or III cutaneous melanoma per AJCC 
eighth edition guidelines (Appendix 8). Participants with BRAF-mutated melanoma 
are eligible to enroll.
◦
A therapeutic lymph node dissection defined as an anatomically complete 
lymphadenectomy of the involved nodal basin for macroscopic disease (clinically, 
radiographically, or sonographically [if performed] detectable lymph nodes) is 
required (Appendix 9). SLN biopsy and CLND for microscopic disease, however, 
are not required. 
-
Has not received any prior systemic therapy for their melanoma beyond surgical 
resection.
Note: In case of an indication for post lymph node dissection radiotherapy, this must 
have been completed within 11 weeks after surgery and 2 weeks before treatment 
initiation. Radiotherapy may alter the process of wound healing. If the wound healing 
is not adequate, the participant is not eligible.
-
No more than 13 weeks have elapsed between final surgical resection and 
randomization. Treatment should start only after adequate wound healing from the 
surgical procedure as assessed by the investigator. If there is a delay of ≤2 weeks 
exceeding 13 weeks due to unforeseen circumstances, the eligibility should be 
discussed with the Sponsor and the decision documented. A delay of up to 1 week for 
screening imaging requirements will be allowed if Sponsor has allowed up to 1 week 
extension between surgical resection and randomization.
Note: Final surgical resection is defined in this protocol as the final surgical 
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procedure required to achieve complete resection of melanoma and render the 
participant disease free.
-
Has no evidence of metastatic disease on imaging after resection as determined by 
investigator assessment. All suspicious lesions amenable to biopsy should be 
confirmed negative for malignancy.
•
NSCLC: Has histologically or cytologically confirmed diagnosis of squamous or 
nonsquamous Stage IV NSCLC with a PD-L1 TPS ≥50% determined using the Dako PD-
L1 IHC 22C3 pharmDx diagnostic kit (Stage IV: M1a, M1b, M1c, AJCC Staging 
Manual, version 8).
Note: Mixed tumors will be characterized by the predominant cell type (squamous or 
nonsquamous); however, small cell elements are not permitted.
-
Confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as 
primary therapy (documentation of absence of tumor-activating EGFR mutations [eg, 
DEL19 or L858R] AND absence of ALK and ROS1 gene rearrangements).
Note: If participant’s tumor has a predominantly squamous histology, molecular 
testing for EGFR mutation and ALK and ROS1 translocations is not required.
Note: The presence of a KRAS mutation in a participant’s tumor is permitted.
Note: Due to insufficient sensitivity, negative ctDNA results for EGFR, ALK, and 
ROS1 cannot be used to satisfy this inclusion criterion.
-
Has measurable disease as assessed by the local site investigator. Lesions situated in a 
previously irradiated area are considered measurable if progression has been shown in 
such lesions.
•
RCC: Has histologically confirmed diagnosis of RCC with clear cell component with or 
without sarcomatoid features. Diagnosis of RCC with clear cell component is to be made 
by the investigator:
-
Has intermediate-high or high risk of RCC recurrence as defined by the following 
pathological tumor-node-metastasis and Fuhrman grading status [Leibovich, B. C., et 
al 2003] [Rini, B. I., et al 2009] [Fuhrman, S. A., et al 1982]:
a.
Intermediate-high risk RCC

pT2, Gr 4 or sarcomatoid, N0, M0

pT3, Any Gr, N0, M0
b. High risk RCC

pT4, Any Gr N0, M0

pT Any stage, Any Gr, N+, M0
-
Have undergone a partial nephroprotective or radical complete nephrectomy with 
negative surgical margins. 
-
Must have undergone a nephrectomy ≥28 days before signing informed consent and 
≤12 weeks before randomization.
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-
Must be tumor free as assessed by the investigator ≤28 days from randomization. 
2. Have a life expectancy of at least 3 months.
Demographics
3. Is an individual of any sex/gender, from 18 years of age inclusive, at the time of 
providing the informed consent.
Assigned Male Sex at Birth
No measures.
Assigned Female Sex at Birth
4. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
•
Is not a POCBP
OR
•
Is a POCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), or is abstinent from penile-vaginal 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 120 days after the last dose of study 
intervention. The investigator should evaluate the potential for contraceptive method 
failure (ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by POCBPs 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 are more stringent than the requirements above, the local label 
requirements are to be followed.
-
Has a negative highly sensitive pregnancy test (urine or serum) as required by local 
regulations within 24 hours (for a urine test) or 72 hours (for a serum test) 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 8.4.5.
-
Abstains from breastfeeding during the study intervention period and for at least 120
days after study intervention.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
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Informed Consent
5. The participant has provided documented informed consent for the study.
Additional Categories
6. The participant can complete the questionnaires without assistance, in the opinion of the 
primary investigator.
7. Participants who have AEs due to previous anticancer therapies must have recovered to 
≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated 
with hormone replacement or participants who have <Grade 2 neuropathy are eligible.
8. HIV-infected participants must have well controlled HIV on ART, defined as:
a.
Having a CD4+ T-cell count ≥350 cells/mm3 at the time of screening.
b. Having achieved and maintained virologic suppression defined as confirmed HIV 
RNA level below 50 or the LLOQ (below the limit of detection) using the locally 
available assay at the time of screening and for at least 12 weeks before screening.
c.
Have not had any AIDS-defining opportunistic infections within the past 12 months.
d. Have been on a stable ART regimen, without changes in drugs or dose modification, 
for at least 4 weeks before randomization and agree to continue ART throughout the 
study.
e.
The combination ART regimen must not contain any antiretroviral medications that 
interact with CYP3A4 inhibitors/inducers/substrates 
(https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers)
9. Participants who are HBsAg positive are eligible if they have received HBV antiviral 
therapy for at least 4 weeks, and have undetectable HBV viral load before randomization.
Hepatitis B screening tests are not required unless:
a.
Known history of HBV infection
b. As mandated by local health authority
10. Participants with history of HCV infection are eligible if HCV viral load is undetectable 
at screening.
Note: Participants must have completed curative antiviral therapy at least 4 weeks before 
randomization.
Hepatitis C screening tests are not required unless:
a.
Known history of HCV infection 
b. As mandated by local health authority
11. Adequate organ function as defined in the following table Table 2. Specimens must be 
collected within 10 days before the start of study intervention.
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Measured or calculatedb creatinine clearance
OR GFR
Measured or calculated creatinine clearance ≥30 
mL/min OR GFR criterion ≥30 mL/min
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
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; PTT=partial 
thromboplastin time; ULN=upper limit of normal.
a    Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
b    Estimated creatinine clearance using Cockcroft-Gault:
(140-age [years] × weight (kg)     (×F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for participants assigned female sex at birth and F = 1 for participants assigned male sex 
at birth
12. An ECOG performance status of 0 to 1 assessed within 3 days before the start of study 
intervention.
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Diagnostic exclusions related to the tumor types evaluated:
a.
NSCLC 
-
Diagnosis of small cell lung cancer or, for mixed tumors, presence of small cell 
elements. 
b. Melanoma
-
Has ocular, mucosal, or conjunctival melanoma.
Note: resected acral cutaneous melanoma is allowed.
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c.
RCC
-
Has had major surgery, other than nephrectomy, within 12 weeks before 
randomization. 
Note: If participants received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention before starting study 
treatment. 
-
Has received prior radiotherapy for RCC. 
-
Has residual thrombus post nephrectomy in the vena renalis or vena cava.
Prior/Concomitant Therapy
2. Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an 
agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-
40, CD137).
3. Received prior systemic anticancer therapy including investigational agents within 
4 weeks before randomization.
4. Received a live or live-attenuated vaccine within 30 days before the first dose of study 
intervention. Administration of killed vaccines is allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
NSCLC Participants
5. Received prior radiotherapy within 2 weeks of start of study intervention, or has 
radiation-related toxicities, requiring corticosteroids.
Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. 
The last palliative radiotherapy treatment must have been performed at least 7 days 
before the first dose of study intervention.
6. Received prior systemic anticancer therapy for their metastatic NSCLC.
Note: Prior treatment with neoadjuvant or adjuvant therapy for nonmetastatic NSCLC is 
allowed as long as therapy was completed at least 12 months before diagnosis of 
metastatic NSCLC.
7. Received radiation therapy to the lung that is >30 Gray within 6 months of start of study 
intervention.
Prior/Concurrent Clinical Study Experience
8. Has received an investigational agent or has used an investigational device within 
4 weeks prior to study intervention administration.
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Diagnostic Assessments
9. 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 7 days prior the first dose of study medication.Note: 
The use of inhaled or topical steroids and systemic steroids at physiologic doses (up to 
5 mg/m2/day prednisone equivalent with maximum dose of 10 mg daily) is allowed on 
study.
10. 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, melanoma in situ, or carcinoma in situ, excluding carcinoma in situ of the bladder, 
that have undergone potentially curative therapy are not excluded. Participants with low-
risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either 
treated with definitive intent or untreated in active surveillance with stable disease are not 
excluded.
Note: Participants with a history of mucosal or uveal melanoma are excluded from this 
study even if diagnosis and treatment were completed >3 years ago.
11. Known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat 
imaging performed during study screening, are clinically stable and have not required 
steroid treatment for at least 14 days before the first dose of study intervention.
12. Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
13. Active autoimmune disease that has required systemic treatment in the past 2 years.
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed.
14. History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or 
has current pneumonitis/interstitial lung disease.
15. Active infection requiring systemic therapy.
16. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric 
Castleman’s Disease.
17. History or current evidence of any condition, therapy, laboratory abnormality, or other 
circumstance that might confound the results of the study or interfere with the 
participant’s participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
18. Known psychiatric or substance abuse disorder that would interfere with the participant’s 
ability to cooperate with the requirements of the study.
Other Exclusions
19. History of allogeneic tissue/solid organ transplant.
20. Participants who have not adequately recovered from major surgery or have ongoing 
surgical complications.
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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
There are no restrictions on activity.
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.
Participants who fail screening may be rescreened once for eligibility.  
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention 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 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 3.
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Table 3
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-3475A
Biological/Vaccine Injection, 
Solution
165 mg/mL
395 mg
SC
Day 1 of 
each cycle 
(Q3W) for 
C1-C3. On 
completion 
of C3, 
participant 
will be 
switched to 
IV infusion.
Test Product IMP
Central
Arm A
Active 
Comparator
Pembrolizumab Biological/Vaccine Solution
25 mg/mL
200 mg
IV Infusion
Day 1 of 
each cycle 
(Q3W) for 
C4-C6. On 
completion 
of C6, 
participant 
will receive 
preferred 
IMP for up 
to 17 cycles 
(melanoma 
and RCC) or 
35 cycles 
(NSCLC).
Comparator
IMP
Central
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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 B
Active 
Comparator
Pembrolizumab Biological/Vaccine Solution
25 mg/mL
200 mg
IV Infusion
Day 1 of 
each cycle 
(Q3W) for 
C1-C3. On 
completion 
of C3, 
participant 
will be 
switched to 
SC.
Comparator
IMP
Central
Arm B
Experimental MK-3475A
Biological/Vaccine Injection, 
Solution
165 mg/mL
395 mg
SC
Day 1 of 
each cycle 
(Q3W) for 
C4-C6. On 
completion 
of C6, 
participant 
will receive 
preferred 
IMP for up 
to 17 cycles 
(melanoma 
and RCC) or 
35 cycles 
(NSCLC).
Test Product IMP
Central
C=cycle; EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP/AxMP=noninvestigational/auxiliary medicinal product; 
NSCLC=non–small cell lung cancer; Q3W=every 3 weeks; RCC=renal cell carcinoma; SC=subcutaneous.
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 3 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.
6.1.1
Treatment
Treatment consists of a Treatment Crossover Period (3+3 Cycles of either MK-3475A 
followed by pembrolizumab IV [Arm A] or pembrolizumab IV followed by MK-3475A 
[Arm B]) followed by preferred intervention for up to a total of 17 cycles (melanoma and 
RCC) or 35 cycles (NSCLC) of treatment. 
Note: The number of treatments is calculated starting with the first dose. 
Participants are not permitted to switch prematurely to the other study intervention during the 
first 6 cycles of treatment.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of MK-3475A or pembrolizumab are provided in 
the Pharmacy Manual.
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.
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).
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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 Arm A 
(MK-3475A SC Q3W for 3 cycles followed by pembrolizumab IV Q3W for 3 cycles) and 
Arm B (pembrolizumab IV Q3W for 3 cycles followed by MK-3475A SC Q3W for 
3 cycles), respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. ECOG performance status (0 vs 1)
2. Tumor type (melanoma vs RCC vs NSCLC)
A rationale for the selected stratification factors is provided in Section 4.2.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for Dose Modification and Toxicity Management Guidelines for irAEs 
associated with pembrolizumab monotherapy, coformulations, or IO combinations and for 
other allowed dose interruptions.
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6.5
Concomitant Therapy
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.
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, and for 30 days after the last dose of study 
intervention.
•
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
-
Intraarticular joint use
-
For inhalation in the management of asthma or COPD
If the investigator determines that a participant requires any of the following prohibited 
medications and vaccinations for any reason during the study, study intervention must be 
discontinued:
•
Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not 
specified in this protocol
•
Investigational agents other than those specified in this 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.
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.
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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 medications will be recorded on the eCRF including all 
prescriptions, 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. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.5.
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.
6.6
Dose Modification (Escalation/Titration/Other)
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 
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.
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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 4.
Table 4
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, or
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
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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
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -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
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
Continue
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care
Monitor for signs and 
symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinued
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
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/Injection Reactions Related to 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may cause severe or life-
threatening infusion/injection reactions including severe hypersensitivity or anaphylaxis. 
Signs and symptoms usually develop during or shortly after drug infusion/injection and 
generally resolve completely within 24 hours of completion of infusion/injection. Dose 
modification and toxicity management guidelines on pembrolizumab monotherapy, 
coformulations, or IO combinations associated infusion/injection reactions are provided in
Table 5.
Table 5
Pembrolizumab Monotherapy, Coformulations, or IO Combinations 
Infusion/Injection Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction, 
IV infusion/ 
SC administration 
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 
IV infusion/ 
SC administration 
interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 h
Stop IV infusion/SC injection (if not 
already fully administered)
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). Similarly, if symptoms resolve 
within 1 hour of stopping the SC 
injection, the injection may be continued. 
Otherwise dosing will be held until 
symptoms resolve and the participant 
should be premedicated for the next 
scheduled dose.
Participant may be 
premedicated 1.5 h (±30 
min) prior to 
infusion/injection 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
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study intervention.
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of IV infusion or 
SC administration); 
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 IV infusion/SC injection (if not 
already fully administered).
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 intervention.
No subsequent dosing
CTCAE=Common Terminology Criteria for Adverse Events; h=hour; IV=intravenous; NCI=National Cancer 
Institute; NSAIDs=nonsteroidal anti-inflammatory drugs; PO=oral; SC=subcutaneous.
Note: 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 CTCAE v5.0 at http://ctep.cancer.gov.
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations 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 or 21 days of the originally scheduled dose and within 42 days 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.
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6.7
Intervention After the End of the Study
Not applicable.
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 8.12.3 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.
Participants must complete the Treatment Crossover Period (see Section 4.1) including all 3 
MK-3475A SC and 3 pembrolizumab IV cycles in order to complete the C6D1 PPQ. Any 
participant who does not complete the Treatment Crossover Period will be discontinued from 
study intervention. 
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant requests to discontinue study intervention.
•
Any prohibited concomitant therapy outlined in Section 6.5.
•
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 before 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.
•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
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•
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.
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 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, are outlined in Section 8.1.9. 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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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 decisions must be made by an investigator who is a qualified 
physician.
•
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 providing documented informed consent 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 will not exceed the volume mentioned in the laboratory manual.
•
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 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 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 and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant
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 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 dated signature.
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.
8.1.2
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 
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.
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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
Tobacco Use Assessment
Definitions for cigarette use are as follows [Land, S. R., et al 2016]:
•
Current smokers: persons who report smoking ≥100 cigarettes during their lifetime and 
who, at the time of screening, reported smoking every day or some days within the last 
year.
•
Former smokers: persons who report smoking ≥100 cigarettes during their lifetime and 
who, at the time of screening, had stopped smoking 1 year prior.
•
Never smokers: persons who report smoking <100 cigarettes during their lifetime.
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.
8.1.5.2
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. In case of SAE, record medication 
through the 90-day Follow-up Period. 
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.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
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8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or an appropriately 
qualified designee according to the specifications within the pharmacy manual.
8.1.8.1
Timing of Dose Administration
Study interventions should be administered after all procedures and assessments have been 
completed.
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 final study 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 8.5.
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
The local laboratory will use the tissue sample to ascertain PD-L1 status using the Dako PD-
L1 IHC 22C3 pharmDx diagnostic kit. The Dako PD-L1 IHC 22C3 pharmDx assay kit is 
currently approved to assess PD-L1 status in participants with NSCLC for treatment with 
pembrolizumab. EGFR, ALK, and ROS1 at the local laboratory must use tumor tissue for 
testing to confirm absence of sensitizing alterations.
8.2
Questionnaires
Planned time points for all questionnaires are provided in the SoA.
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The PPQ and TASQ in this study will be completed by the participant on an eCOA tablet.
The implementation of the electronic version will follow all necessary global confidentiality 
regulations, including the EMA Guideline on computerized systems and electronic data in 
clinical trials. Refer to the Site Manual for eCOA site level operations.
As the PPQ is the primary and secondary endpoint of this study, completion of the 
questionnaire must be checked BEFORE the participant leaves the site at the Cycle 6 Visit.
The participant’s choice of MK-3475A SC or pembrolizumab IV for the Treatment 
Continuation Period will be documented on the Participant Choice Questionnaire, 
administered at the Cycle 6 Visit after study intervention administration and completion of 
the PPQ and TASQ.
8.3
Imaging Assessments
8.3.1
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.
Imaging should be performed per SoC for each tumor type. Treatment beyond disease 
progression is not allowed.
8.4
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 
Manual.
Planned time points for all safety assessments are provided in the SoA.
8.4.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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8.4.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams 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.
8.4.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
For melanoma participants: The investigator or qualified designee should conduct a visual 
inspection of local recurrence and palpation of regional lymph nodes to assess regional 
recurrence.
8.4.1.3
Injection Site Reactions
Any injection-site AE should be reported using standard AE/SAE reporting methods. 
Injection-site reaction and pain may include, but are not limited to, the following:
•
Injection-site redness/erythema
•
Injection-site swelling/edema 
•
Injection-site tenderness/pain/discomfort/irritation 
•
Injection-site bruising
•
Injection-site infection
•
Injection-site hard lump (mass, nodule)/induration 
•
Injection-site inflammation 
•
Injection-site rash 
•
Injection-site hematoma/hemorrhage 
•
Injection-site extravasation 
•
Injection-site dermatitis 
•
Injection-site discoloration/pallor 
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•
Injection-site vesicles/ulcers
Any injection-site AEs should be recorded in the AE eCRF.
8.4.2
Vital Signs
The investigator or qualified designee will measure vital signs and weight at Screening, 
before administration of each dose of study intervention, end-of-treatment, and during the 30-
day Safety Follow-up as specified in the SoA.
•
VS include temperature, HR, RR, and BP.
•
BP and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
•
BP and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions.
•
VS will be measured in a semisupine position after 5 minutes rest.
8.4.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECG is specified in Section 1.3. Clinically significant abnormal findings should be recorded 
as medical history. Additional ECGs may be performed as clinically necessary. 
8.4.4
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 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 30 days 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.
8.4.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.4.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine and/or serum) should be conducted as per SoA at every
protocol treatment cycle during intervention.
-
Pregnancy testing (urine and/or serum) should be conducted at the end of relevant 
systemic exposure. The length of time required to continue pregnancy testing for each 
study intervention is:
◦
MK-3475A: 120 days
◦
Pembrolizumab: 120 days
-
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 participant’s participation in the study.
8.4.6
Performance Assessments
8.4.6.1
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status 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 will assess ECOG status (see Appendix 10) at 
screening, before the administration of each dose of study intervention and during the 
follow-up period as specified in the SoA (Section 1.3).
8.5
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.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver or surrogate).
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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 8.5.3. 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.
8.5.1
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 8.5.5, 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 6.
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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 6
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
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
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 (requiring
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
ECI (does 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
New Cancer (that is 
not the cancer under 
study)
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
SAE)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
SAE)
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.5.2
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.
The PPQ designed for participant respondents that are included in the study requires the free 
text field to be reviewed for SAE identification and reporting by the investigator or a 
qualified designee. The assessment of these SAEs should follow the requirements outlined in 
Section 8.5.
8.5.3
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.
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8.5.4
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.
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.
8.5.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant 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.
Refer to Appendix 7 for country-specific requirements.
8.5.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Progression of the cancer under study is not considered a reportable event unless it results in 
hospitalization or death.
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8.5.7
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. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× 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).
8.6
Treatment of Overdose
An overdose of MK-3475A will be defined as ≥5 times the recommended dose.
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.
8.7
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.8
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.9
Biomarkers
Biomarker samples will not be collected in this study.
8.10
Future Biomedical Research Sample Collection
FBR samples will not be collected in this study.
8.11
Medical Resource Utilization and Health Economics
Not applicable.
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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.
Screening procedures are to be completed within 28 days before the first dose of study 
intervention.
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.
Participants may be rescreened one time after initially failing to meet the inclusion/exclusion 
criteria. 
8.12.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.
8.12.3
Posttreatment 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.
8.12.4
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
KEY STATISTICAL CONSIDERATIONS
This section outlines the principal statistical analysis strategy and procedures for the study. 
Changes to analyses made after the protocol has been finalized, but prior to final database 
lock, will be documented in an amendment of the SAP and referenced in the CSR for the 
study. Post hoc exploratory analyses will be clearly identified in the CSR.
9.1
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.
This study is being conducted as a randomized, open-label study, i.e., participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
The Clinical Biostatistics department of the Sponsor will generate the randomized allocation 
schedule(s) for study treatment assignment. The algorithm for the randomized allocation of 
participants will be implemented in an IVRS by a study vendor.
9.2
Hypotheses/Estimation
Objectives of the study are stated in Section 3.
There are no hypotheses associated with any of the objectives.
9.3
Analysis Endpoints
Participant preference and satisfaction measure endpoints and safety endpoints that will be 
evaluated for within- and/or between-treatment differences are listed below.
9.3.1
Participant Preference and Satisfaction Measure Endpoints
Primary
•
Participant preference assessed by response of MK-3475A SC on PPQ question 1
Secondary
•
Participant responses to question 3 of the patient preference questionnaire
•
Participant responses to question 1 of the TASQ SC and TASQ IV
•
Participants’ choice of MK-3475A SC for the study treatment Continuation Period
Exploratory
•
Healthcare provider preference assessed by HCP question (HCPQ)
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9.3.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory test results, and vital signs. Safety measurements are provided in Section 
4.2.1.2 and Section 8 of the protocol.
9.4
Analysis Populations
9.4.1
Participant Preference and Satisfaction Measure Analysis Populations
The Full Analysis Set (FAS) population will be used for the analysis of participant preference 
and satisfaction measure primary endpoint in this study.
The FAS population will include all randomized participants who received all three doses of 
MK-3475A subcutaneous and all three doses of Pembrolizumab intravenous during the 
treatment crossover period and subsequently answered at least question 1 of the PPQ at Cycle 
6 Day 1 (C6D1).
9.4.2
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 intervention. Participants will be 
included in the treatment group corresponding to the study intervention they actually 
received for the analysis of safety data using the APaT population. 
Analyses of laboratory test results and vital signs will include only participants with at least 
one measurement obtained after at least one dose of study intervention. If the analysis will 
assess change from baseline, a baseline measurement is also required.
9.5
Statistical Methods
9.5.1
Statistical Methods for Participant Preference and Satisfaction Measure
Analyses
The primary objective of this study is to evaluate participant preference for MK-3475A SC 
based on the participant preference rate (PPR). PPR is defined as the proportion of 
participants indicating an overall preference for MK-3475A SC in question 1 of the PPQ. 
The point estimate of PPR will be provided, together with 95% CI using exact binomial 
method proposed by Clopper and Pearson [Clopper, C. J. and Pearson, E. S. 1934].
Additionally, PPR will be descriptively summarized by treatment arm as a supportive 
analysis.
The secondary participant preference and satisfaction measure variables will be summarized 
descriptively.
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Table 7
Analysis Strategy for Key participant preference and satisfaction measure 
Variables
Endpoint/Variable
(Description, Time Point)
Primary vs 
Supportive 
Approacha
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint Analysis
Proportion of participants who 
prefer MK-3475A SC with 
treatment preference assessed 
by PPQ question 1
P
Estimation: point 
estimate, 95% CI 
using exact binomial 
method proposed by 
Clopper and Pearson
FAS
Not Applicable
Key Secondary Endpoints Analysis
Participant responses to 
question 3 of the patient 
preference questionnaire
P
Descriptive summary
FAS
Participants 
with missing 
data are 
considered to 
have no 
response
Participant responses to 
question 1 of the TASQ SC and 
TASQ IV
P
Descriptive summary
FAS
Participants 
with missing 
data are 
considered to 
have no 
response
Proportion of participants who 
choose MK-3475A SC for the 
study treatment Continuation 
Period
P
Descriptive summary
Participants 
who choose 
to receive a 
treatment in 
continuation 
period
Not Applicable
FAS=Full Analysis Set.
a
P=Primary approach
9.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of AEs and other relevant 
parameters, including laboratory test results and vital signs. Adverse events will be 
summarized by MedDRA term, appropriate MedDRA levels (system organ class [SOC] and 
preferred term [PT]), and when specified by NCI CTCAE grade. For each participant, if 
multiple incidences of the same adverse events occur, the maximum severity reported will be 
used in the summaries.
The overall safety endpoints include the number of participants with at least one AE, drug-
related AE, serious AE, serious, drug-related AE, Grade 3-5 AE, AEOSI, who discontinue 
from study intervention due to an AE, or with an AE resulting in death. The number and 
percentage for injection-site reactions will be provided for participants who receive
MK-3475A SC treatment.
The safety evaluation will include a summary of the number and percentage of participants 
with each type of AE by treatment intervention for cycles 1-3 and cycles 4-6 in the Crossover 
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Period, and by treatment arm in the overall study. For overall safety endpoints, specific AEs 
and safety topics of special interest that meet predefined threshold rules, point estimates and 
95% CIs for the differences between treatment groups (i.e., treatment interventions for cycles 
1-3 in the Crossover Period, treatment interventions for cycles 4-6 in the Crossover Period
and treatment arms in the overall study) in the percentages of participants with events will be 
provided using the M&N method [Miettinen, O. and Nurminen, M. 1985]. 
The number and percentage of participants with laboratory toxicity grade increased from 
baseline will be summarized by the post-baseline maximum toxicity grade per CTCAE V5.0
for each gradable laboratory test.
For continuous safety measures, such as change from baseline in laboratory, vital signs, 
summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment arm.
9.6
Interim Analyses
There are no formal interim analyses planned in this study. An interim analysis may be 
conducted to support a future regulatory submission. The results of this interim analysis will 
be evaluated by a Sponsor’s Executive Oversight Committee. 
The final analysis (FA) is to be performed approximately 14.5 months after the first
participant is enrolled. Participants will continue to be followed after the final analysis until 
the overall study ends.
9.7
Multiplicity
No multiplicity adjustment is planned as there are no hypotheses in this study.
9.8
Sample Size and Power Calculations
In this study, approximately 144 participants will be randomized to treatment arms A or B.
9.9
Subgroup Analyses
To determine whether the participant preference rate (PPR) is consistent across various 
subgroups, the estimate of PPR (with a nominal 95% CI) will be estimated and plotted within 
each category of the following subgroup variables: 
•
ECOG PS (0, 1)
•
Tumor type (Melanoma, RCC, NSCLC)
For subgroups determined by the levels of a stratification factor, the derived strata based on 
eCRF collected information (as compared to the IRT/IVRS strata) will be used as the default. 
If the number of participants in a category of a subgroup variable is less than 10% of the FAS 
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.
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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 Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, 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 MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), Regulation 
(EU) 536/2014, the International Council for Harmonisation Good Clinical Practice 
(ICH GCP) E6 and ICH General Considerations for Clinical Studies E8, and 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 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
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healthcare providers to ensure operational feasibility. Trial design also includes 
proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. 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. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in 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.
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MSD’s policy on authorship is consistent with the recommendations published by the
International Committee of Medical Journal Editors (ICMJE). In summary, 
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 and ICH Guidelines. 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. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
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.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record 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.
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 
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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 
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.
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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 
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
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will decide on 
any recommendations 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.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, 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, https://euclinicaltrials.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 
Regulation 536/2014 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.
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, 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.
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 
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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.
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 
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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 8 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.
Table 8
Protocol-required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCVa
MCHa
%Reticulocytesa
WBC count with 
Differentialb:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN or ureac
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is above 
the ULN)
Albumin
Carbon dioxide 
(CO2 or 
bicarbonate)a
Chloride
Phosphorousa
Creatinined
Sodium
ALT/SGPT
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline phosphatase
Lactate 
dehydrogenase
Routine Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterasea by dipstick
•
Microscopic examinationa (if blood or protein is abnormal)
Pregnancy Testing
•
Highly sensitive serum or urine hCG pregnancy test (as needed for POCBP)
Other Screening 
Tests
•
FSH (as needed in PONCBP only)
•
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) as required by 
local health authority or institutional regulations
•
Coagulation factors (PT or INR, and aPTT/PTT). Additional testing to be 
conducted as clinically indicated for participants taking anticoagulation therapy.
•
Thyroid function tests (T3, FT4, TSH) 
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Laboratory 
Assessments
Parameters
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; FSH=follicle-stimulating hormone; FT4=free thyroxine; hCG=human chorionic 
gonadotropin; HBsAg=hepatitis B surface antigen; HIV=human immunodeficiency virus; INR=international normalized 
ratio; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; POCBP=participant of childbearing 
potential; PONCBP=participant of nonchildbearing potential; RBC=red blood cell; PT=prothrombin time; PTT=partial 
thromboplastin time; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; 
T3=triiodothyronine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal; WBC= white blood cell.
Notes:
a
Performed only if considered the local standard of care.
b
Absolute or % acceptable per institutional standard.
c
BUN is preferred; if not available, urea may be tested.
d
Measured or calculated creatinine clearance. Creatinine clearance should be calculated per the Cockcroft-Gault 
formula.
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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 8.5.6 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.
•
Is a new cancer (that is not the cancer under study) as noted in Section 8.5.1.
•
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.
•
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.
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•
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 study intervention cause the AE?
•
The determination of the likelihood that the study intervention 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 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention 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 study intervention? 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 study intervention 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 study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention 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; (2) the study is a single-dose drug study; or (3) study 
intervention (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 STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION 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 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 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 8.5.1 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
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant 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.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal 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, Müllerian 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
-
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 participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth who are 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 include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantb
IUSc
Nonhormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraceptionb
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraceptionb
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner capable of producing sperm, 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
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation.  
c
IUS is a progestin-releasing IUD.
Note:
Tubal occlusion includes tubal ligation
Refer to Appendix 7 for country-specific requirements.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Argentina
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
Section 1.3 Schedule of Activities – Screening and Treatment Phase
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study intervention.
10.7.2
Chile
8.5.5 Pregnancy and Exposure During Breastfeeding
Follow-up of all reported pregnancies and childbirth is mandatory. Additionally, follow-up of 
the newborns for up to 6 months of age is mandatory.
10.5.2 Contraception Requirements
Use of emergency hormonal contraception is permitted for POCBPs who have engaged in 
unprotected sexual activity.
10.7.3
France
Section 1.3 Schedule of Activities
Pregnancy testing must be performed prior to study intervention administration at each cycle
during the treatment period, as well as before the last dose of study intervention, and 30 days 
after the last dose at the end of study intervention. HBV, HCV, and HIV testing at screening 
is mandatory.
Section 4.1 Overall Design
No efficacy analysis is planned for this open-label study. Additionally, the safety profile of 
pembrolizumab is well established, therefore this study will not include an external or 
internal DMC, however medical monitoring will be performed on a continual basis.
10.7.4
South Africa
Section 1.3 Schedule of Activities
HIV testing at screening is mandatory.
Testing for active tuberculosis is required at screening and every 6 months during treatment 
as mandated by local regulation.
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10.7.5
Poland
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
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10.8
Appendix 8: Melanoma Staging
The AJCC has designated staging by TNM classification to define melanoma.
Staging tables are adapted from the AJCC, Eighth Edition. Refer to the AJCC guidelines for 
more information [Gershenwald, J. E., et al 2017].
Staging tables are provided as follows:
[Table 9]
Melanoma T Category Definition
[Table 10]
Melanoma N Category Definition
[Table 11]
Melanoma M Category Definition
[Table 12]
AJCC Pathological (pTNM) Staging Groups
[Table 13]
AJCC Clinical Prognostic (cTNM) Staging Groups
Table 9
Melanoma T Category Definition
T-Stage
T-Stage Definition (Thickness and Ulceration)
TX
Primary tumor thickness cannot be assessed (ulceration status not 
applicable)
T0
No evidence of primary tumor (ulceration status not applicable)
Tis
Melanoma in situ (ulceration status not applicable)
T1
≤1.0 mm (ulceration status unknown or unspecified)
T1a
<0.8 mm without ulceration
T1b
<0.8 mm with ulceration or
0.8-1.0 mm with or without ulceration
T2
>1.0-2.0 mm (ulceration status unknown or unspecified)
T2a
>1.0-2.0 mm without ulceration
T2b
>1.0-2.0 mm with ulceration
T3
>2.0-4.0 mm (ulceration status unknown or unspecified)
T3a
>2.0-4.0 mm without ulceration
T3b
>2.0-4.0 mm with ulceration
T4
>4.0 mm (ulceration status unknown or unspecified)
T4a
>4.0 mm without ulceration
T4b
>4.0 mm with ulceration
T=primary tumor.
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Table 10
Melanoma N Category Definition
N Category
Number of Tumor-Involved Regional Lymph Nodes
Presence of 
In-transit, 
Satellite, 
and/or 
Microsatellite 
Metastases
NX
Regional Nodes not assessed (exception: pathological N 
category not required for T1 melanomas, use clinical N 
information)
No
N0
No regional metastases detected
No
N1
One tumor-involved node or any number of in-transit, 
satellite, and/or microsatellite metastases with no tumor-
involved nodes
N1a
One clinically occult (detected by SLN biopsy)
No
N1b
One clinically detected
No
N1c
No regional lymph node disease
Yes
N2
Two or 3 tumor-involved nodes or any number of in-
transit, satellite, and/or microsatellite metastases with one 
tumor-involved node
N2a
Two or 3 clinically occult (detected by SLN biopsy)
No
N2b
Two or 3, at least one of which was clinically detected
No
N2c
One clinically occult or clinically detected
Yes
N3
Four or more tumor-involved nodes or any number of in-
transit, satellite, and/or microsatellite metastases with 2 or 
more tumor-involved nodes, or any number of matted 
nodes without or with in-transit, satellite, and/or 
microsatellite metastases
N3a
Four or more clinically occult (detected by SLN biopsy)
No
N3b
Four or more, at least one of which was clinically 
detected, or the presence of any number of matted nodes
No
N3c
Two or more clinically occult or clinically detected and/or 
presence of any number of matted nodes
Yes
N=regional lymph node
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Table 11
Melanoma M Category Definition
M Category
Anatomic Site
Lactate Dehydrogenase 
Level
M0
No evidence of distant metastasis
Not applicable
M1
Evidence of distant metastasis
See below
M1a
Distant metastasis to skin, soft tissue 
including muscle, and/or nonregional 
lymph node
Not recorded or 
unspecified
M1a(0)
Not elevated
M1a(1)
Elevated
M1b
Distant metastasis to lung with or 
without M1a sites of disease
Not recorded or 
unspecified
M1b(0)
Not elevated
M1b(1)
Elevated
M1c
Distant metastasis to non-CNS
visceral sites with or without M1a or 
M1b sites of disease
Not recorded or 
unspecified
M1c(0)
Not elevated
M1c(1)
Elevated
M1d
Distant metastasis to CNS with or 
without M1a, M1b, or M1c sites of 
disease
Not recorded or 
unspecified
M1d(0)
Not elevated
M1d(1)
Elevated
CNS=central nervous system; M=distant metastasis
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Table 12
AJCC Pathological (pTNM) Staging Groups
Staging (AJCC Eighth Edition)
0
Tis
N0
M0
IA
T1a
N0
M0
IA
T1b
N0
M0
IB
T2a
N0
M0
IIA
T2b
N0
M0
IIA
T3a
N0
M0
IIB
T3b
N0
M0
IIB
T4a
N0
M0
IIC
T4b
N0
M0
IIIB
T0
N1b, N1c
M0
IIIC
T0
N2b, N2c, N3b, N3c
M0
IIIA
T1a/b-T2a
N1a or N2a
M0
IIIB
T1a/b-t2a
N1b/c or N2b
M0
IIIB
T2b/T3a
N1a-N2b
M0
IIIC
T1a-T3a
N2c or N3a/b/c
M0
IIIC
T3b/T4a
Any N≥N1
M0
IIIC
T4b
N1a-N2c
M0
IIID
T4b
N3a/b/c
M0
IV
Any T, Tis
Any N
M1
AJCC=American Joint Committee on Cancer; M0 = No evidence of distant metastases; N0 = No regional metastasis 
detected including no tumor-involved nodes and no in-transit, satellite, and/or microsatellite metastasis; 
pTNM=AJCC Pathological; T=primary tumor.
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Table 13
AJCC Clinical Prognostic (cTNM) Staging Groups
Staging (AJCC Eighth Edition)
0
Tis
N0
M0
IA
T1a
N0
M0
IB
T1b
N0
M0
IB
T2a
N0
M0
IIA
T2b
N0
M0
IIA
T3a
N0
M0
IIB
T3b
N0
M0
IIB
T4a
N0
M0
IIC
T4b
N0
M0
III
Any T, Tis
≥N1
M0
IV
Any T
Any N
M1
AJCC = American Joint Committee on Cancer; M0 = No evidence of distant metastases; N0 = No regional metastasis 
detected including no tumor-involved nodes and no in-transit, satellite, and/or microsatellite metastasis.
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10.9
Appendix 9: Surgical Considerations (Melanoma)
Recommendation for Surgical Management:
a.
Wide excision with a 1-2 cm clinical margin surrounding the primary lesion or biopsy 
scar is recommended for entry on to this protocol. If the primary melanoma is completely 
resected within the wide excision margin, the resection is acceptable. 
b. For lesions with Breslow’s thickness >2 mm, a 2 cm minimum clinical margin is 
recommended when anatomically feasible. On other body sites with limited tissue 
availability a narrower margin is acceptable to avoid excessive morbidity. 
c.
For subungual melanoma, interphalangeal metacarpal/metatarsal-phalangeal amputation 
with histologically negative margins constitutes an adequate wide excision. 
d. The specimen shall be excised to include skin and all subcutaneous tissue down to the 
muscular or deep fascia. Fascia may be included at the discretion of the operating 
surgeon. 
e.
The pathology report should report surgical margins and whether surgical resection 
margins are involved with the tumor, including close margin (eg, <1 mm between tumor 
and resection margin) and tumor abutting margin.
Closure of the defect (eg, primary advancement flap closure, split thickness skin graft, 
complex reconstruction) is at the discretion of the surgeon.
Therapeutic lymph node dissection for macroscopic disease
For this study a therapeutic axillary lymph node dissection is required for macroscopic 
disease (ie, clinically, radiographically, sonographically [if performed] detectable nodes).
Axillary Lymphadenectomy: 
Axillary node dissection must include all involved nodes or at least 10 nodes are required for 
adequacy if this exceeds the number of involved nodes taken from Levels I and II and the 
Level III nodes. The boundaries of the dissection should include the axillary vein superiorly 
beginning at the thoracic outlet and coursing to the latissimus dorsi tendon. The lateral border 
of the dissection is the anterior edge of the latissimus dorsi muscle. The posterior boundary is 
the subscapular muscle. The anterior border of the resection is the pectoralis major group. 
The inferior boundary of the dissection should be the juncture of the latissimus dorsi and the 
serratus anterior muscles. 
The contents within these boundaries should be completely removed with the exception of 
the long thoracic nerve and the thoracodorsal nerve, which should be identified during the 
dissection and preserved throughout. As stated, the pectoralis minor muscle may be divided 
or sacrificed with the specimen at the discretion of the surgeon. Care should be exercised that 
in the superior part of the dissection, the anterior pectoral nerve is not injured. The preferable 
approach to the axilla is through a horizontal incision in the line of the skin crease, 3 or 4 cm 
below the apex of the skin fold of the axilla.
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Inguinal Lymphadenectomy: 
A superficial femoral node dissection should be performed by excising all of the nodes 
inferior to the inguinal ligament and bounded by the medical border of the sartorius muscle 
in the lateral border of the adductor magnus muscle. The fatty and lymphatic tissues should 
be dissected carefully off the femoral vessels and nerves all the way up to the inguinal canal 
and for 3 cm superior to the inguinal ligament. The saphenous vein is resected to ensure 
complete excision of the lymph nodes. Transposition of the sartorius muscle should be 
considered (but is not mandatory) to cover the femoral vessels after complete lymphatic 
excision. Ideally, this area should be entered through a curvilinear incision staring laterally 
over the inguinal ligament and curving medially and inferiorly ending over the midpoint of 
the adductor magnus muscle. A minimum of 5 nodes must be resected for adequacy if this 
exceeds the detected number of involved nodes. 
Deep Inguinal and External Iliac Node Dissection: 
Deep inguinal and external iliac node dissection can be most easily approached by incising 
the abdominal wall musculature 3 or 4 cm superior to the inguinal ligament. This incision is 
taken down through the external oblique, internal oblique and transversus muscles, and the 
surgeon at that point stays extraperitoneally as in the approach to the iliac vessels for renal 
transplantation. With this approach, the external, internal and common iliac arteries are 
exposed and the lymphatics coursing among the iliac vessels are excised. A full ilioinguinal 
(deep) inguinal node dissection is advised in case of overt inguinal node- metastasis and 
when Cloquet’s node is positive. 
(Modified) Radical Neck Dissection: 
Classic or modified radical neck dissection must be performed for patients with melanoma of 
the head and neck and involved nodes. A minimum of 15 nodes must be resected for 
adequacy if this exceeds the detected number of involved nodes. Patients with melanoma 
located on the ear and anterior scalp and face require superficial parotidectomy along with a 
radical neck procedure. The boundaries of the radical neck dissection are inferiorly the 
clavicle; the mandible, the mastoid and the tail of the parotid gland superiorly; the anterior 
border of the trapezius muscle posteriorly and the strap muscle of the larynx anteriorly. The 
sternocleidomastoid muscle may be sacrificed or preserved at the surgeon's discretion. For 
posterior nodes, the radical neck incision must be extended posteriorly or a second incision 
must be made so that the suboccipital nodal group can be resected. For posterior neck 
dissection, surgical and pathological resection of at least 5 nodes are required for adequacy if 
this exceeds the detected number of involved nodes.
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10.10 Appendix 10: 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.
Source: adapted from[ECOG ACRIN Cancer Research Group 2016]
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADL
activities of daily living
AE
adverse event
AIDS
acquired immunodeficiency syndrome
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC0-3wks
area under the curve from 0 to 3 weeks
BP
blood pressure
BRAF
proto-oncogene B-raf
C
cycle
CD
cluster of differentiation
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
CI
confidence interval
CLND
complete lymph node dissection
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
COVID-19
Coronavirus disease caused by severe acute respiratory syndrome 
coronavirus 2
CRF
Case Report Form
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
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Abbreviation
Expanded Term
CTFG
Clinical Trial Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
cTNM
AJCC Clinical Prognostic
Ctrough
trough concentration
CYP
cytochrome P450
D
day
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
eCOA
electronic clinical outcome assessment
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection
eDMC
external Data Monitoring Committee
EEA
European Economic Area
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EU CT
European Union Clinical Trials
FA
final analysis
FAS
Full Analysis Set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FIH
first in human
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
Gr
grade
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Abbreviation
Expanded Term
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCP
health care professional
HCPQ
HCP questionnaire
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IgG4
immunoglobulin G4
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug
IO
Immune oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVRS
interactive voice response system
jRCT
Japan Registry of Clinical Trials
KRAS
Kirsten rat sarcoma viral oncogene homolog
LLOQ
lower limit of quantitation
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Abbreviation
Expanded Term
LPLV
Last Patient, Last Visit
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
NCI
National Cancer Institute
NSCLC
non–small cell lung cancer
OTC
over the counter
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PK
pharmacokinetic
POCBP
participant/participants of childbearing potential
PPQ
Patient Preference Questionnaire
PPR
participant preference rate
PSA
prostate-specific antigen
pTNM
AJCC Pathological
Q3W
every 3 weeks
Q6W
every 6 weeks
RCC
renal cell carcinoma
rHuPH20
recombinant human hyaluronidase
RNA
ribonucleic acid
ROS1
c-ros oncogene 1
RR
respiratory rate
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous(ly)
SLAB
supplemental laboratory test(s)
SLN
sentinel lymph node
SoA
schedule of activities
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Abbreviation
Expanded Term
SoC
standard of care
SUSAR
suspected unexpected serious adverse reaction
TASQ
Therapy Administration Satisfaction Questionnaire
TNM
tumor, node, metastasis
TPS
tumor proportion score
ULN
upper limit of normal
US
United States
UTN
Universal Trial Number
VS
vital signs
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11
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