Phase 2 Study of MK-6482 in Participants With Advanced Renal Cell Carcinoma
Phase: PHASE2
Conditions: Carcinoma, Renal Cell
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
Protocol/Amendment No.: 013-02 Phase 2
Study of MK-6482 in Participants With
Advanced Renal Cell Carcinoma
NCT04489771
30 June 2022

PRODUCT: MK-6482  
1
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: Phase 2 Study of MK-6482 in Participants With Advanced Renal Cell 
Carcinoma
Protocol Number: 013-02
Compound Number: MK-6482
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
132,120
EudraCT
2020-001907-18
Approval Date: 30 June 2022
08CHFV

PRODUCT: MK-6482  
2
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
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
08CHFV

PRODUCT: MK-6482  
3
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 2
30-JUN-2022
To add an optional tumor tissue sample collection after receiving belzutifan treatment
to enable exploratory biomarker research on the mechanisms of response and/or
resistance to belzutifan treatment.
Amendment 1
22-FEB-2021
To update contraception language to align with program wide requirements.
Original Protocol
09-MAY-2020
Not applicable
08CHFV

PRODUCT: MK-6482  
4
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
To add an optional tumor tissue sample collection after receiving belzutifan treatment to enable exploratory biomarker research on the
mechanisms of response and/or resistance to belzutifan treatment.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities
Added an optional tumor tissue sample 
collection after receiving belzutifan.
To add an optional tumor tissue sample collection after 
receiving belzutifan treatment to enable exploratory 
biomarker research on the mechanisms of response 
and/or resistance to belzutifan treatment.
1.3 Schedule of Activities
Added an optional ICF for biomarker 
tissue collection.
To obtain consent for optional biopsy. 
3  Hypotheses, Objectives, 
and Endpoints
Updated tertiary biomarker endpoint to 
include new optional tissue collection after 
receiving belzutifan treatment.
Clarification.
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity 
name and address change to Merck Sharp & Dohme 
LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and update to the address.
08CHFV

PRODUCT: MK-6482  
5
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Section # and Name
Description of Change 
Brief Rationale 
8.1.9.1  Withdrawal From 
Future Biomedical Research
10.6  Appendix 6: collection 
and Management of 
Specimens for Future 
Biomedical Research
Sponsor email address change from 
“@merck” to “@MSD.com”.
Merck Sharp & Dohme Corp. underwent an entity 
name and address change to Merck Sharp & Dohme 
LLC, Rahway, NJ, USA.
1.3 Schedule of Activities
Added that starting at Week 9 Day 1 and 
thereafter, blood samples for ctDNA 
analyses do not need to be collected 
predose.
Clarification on timing of blood sample collections.
8.4 Adverse Events, Serious 
Adverse Events, and Other 
Reportable Safety Events
Added text that SAEs associated with 
medication errors, misuse, or abuse are to 
be documented.
Per REGULATION (EU) No 536/2014 OF THE 
EUROPEAN PARLIAMENT AND OF THE 
COUNCIL.
10.3.1 Definitions of 
Medication Error, Misuse, 
and Abuse
Added new section with definitions for 
medication errors, misuse, or abuse are to 
be documented. Renumbered subsequent 
sections accordingly.
Per REGULATION (EU) No 536/2014 OF THE 
EUROPEAN PARLIAMENT AND OF THE 
COUNCIL
1.3 Schedule of Activities
8.11.3.3  Survival Follow-up
Changed survival status to vital status.
To align with terminology updates previously 
approved and ensure consistency throughout the 
protocol.
08CHFV

PRODUCT: MK-6482  
6
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
1.2 Schema
1.3 Schedule of Activities
8.11.3.2 Imaging Follow-up
Added “end of the study” to list of reasons 
for discontinuation of imaging, or revised 
study termination to this wording.
To align with Section 8.2.1.2.
4.2.1.5 Planned Exploratory 
Biomarker Research
Changed Tumor and RNA collection to 
Tumor and/or RNA in subsection title and 
in text.
Changed “belzutifan and other therapies” 
to “antitumor therapies”.
To ensure exploratory biomarker section allows 
flexibility.
6.1 Study Intervention(s) 
Administered
Changed IMP/NIMP to IMP or 
NIMP/AxMP
Changed use designation from 
“experimental” to “test product”.
To align with EU Clinical Trials Registration.
6.4  Study Conduct 
Compliance
8.1.1.1  General Informed 
Consent
10.3.5  Recording of AE and 
SAE
Changed “his/her” to “their”.
Gender references are not necessary.
8.1.4 Medical History
Changed the description of what medical 
history will be collected from clinically
significant to clinically important.
For consistency of terminology and to add clarity to 
baseline medical conditions.
08CHFV

PRODUCT: MK-6482  
7
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Section # and Name
Description of Change 
Brief Rationale 
8.1.11  Tissue Collection
Added that a tumor lesion is inclusive of 
fresh tissue collected after receiving study 
intervention.
Clarity.
8.2.1  Tumor Imaging and 
Assessment of Disease
Revised wording to better explain handling 
of unscheduled scans.
Clarity.
8.2.1.2 Tumor Imaging 
During the Study
Deleted ambiguous statement “or 
notification by the Sponsor.”
Changed format of list items for reasons to 
discontinue scans from paragraph to 
bullets and revised “or notification by the 
Sponsor” to “end of the study.”
Clarity.
To align with text in Section 8.2.1.3.
8.2.1.3 RECIST 1.1 
Assessment of Disease
Revised to give more specific instructions 
on when scans are to be collected “(the 
next scheduled scan should be ≥4 weeks 
from the most recent scan acquired)”.
Clarity.
8.2.2 End of Treatment and 
Follow-up Tumor Imaging
Changed format of list items for reasons to 
discontinue scans from paragraph to 
bullets and revised study conclusion/early 
termination to “end of the study.”
To align with text in Section 8.2.1.3.
8.8 Biomarkers
Changed tissue sample description from 
archival or newly obtained to tumor tissue.
Per biomarker group guidance to use broader 
terminology.
10.2  Appendix 2  Clinical 
Laboratory Tests
Added time period for continuation of 
pregnancy testing after study intervention 
termination.
To ensure consistency with Section 5.1 and Section
8.4.1.
08CHFV

PRODUCT: MK-6482  
8
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Section # and Name
Description of Change 
Brief Rationale 
Throughout Document
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document
To ensure clarity and accurate interpretation of the 
intent of the protocol.
08CHFV

PRODUCT: MK-6482  
9
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................17
1.1
Synopsis.................................................................................................................17
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities...........................................................................................22
2
INTRODUCTION..........................................................................................................37
2.1
Study Rationale....................................................................................................37
2.2
Background ..........................................................................................................37
RCC Epidemiology and Current Therapeutic Options................................37
Pharmaceutical and Therapeutic Background .............................................38
Preclinical Studies........................................................................................39
2.2.3.1
Preclinical Pharmacokinetics and Metabolism ..................................39
2.2.3.2
Preclinical Toxicology.......................................................................40
Clinical Studies............................................................................................41
2.3
Benefit/Risk Assessment......................................................................................42
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................43
4
STUDY DESIGN............................................................................................................45
4.1
Overall Design......................................................................................................45
4.2
Scientific Rationale for Study Design.................................................................47
Rationale for Endpoints ...............................................................................47
4.2.1.1
Efficacy Endpoints.............................................................................47
4.2.1.2
Safety Endpoints................................................................................47
4.2.1.3
Pharmacokinetic Endpoints ...............................................................47
4.2.1.4
Pharmacodynamic Endpoints.............................................................48
4.2.1.5
Planned Exploratory Biomarker Research.........................................48
4.2.1.6
Future Biomedical Research..............................................................49
4.3
Justification for Dose...........................................................................................49
Starting Dose for This Study........................................................................49
Maximum Dose/Exposure for This Study ...................................................50
4.4
Beginning and End of Study Definition .............................................................50
Clinical Criteria for Early Study Termination .............................................50
5
STUDY POPULATION ................................................................................................50
5.1
Inclusion Criteria.................................................................................................50
5.2
Exclusion Criteria................................................................................................54
08CHFV

PRODUCT: MK-6482  
10
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
5.3
Lifestyle Considerations......................................................................................56
Meals and Dietary Restrictions....................................................................56
Tobacco Use.................................................................................................56
5.4
Screen Failures.....................................................................................................56
5.5
Participant Replacement Strategy......................................................................56
6
STUDY INTERVENTION............................................................................................57
6.1
Study Intervention(s) Administered...................................................................57
6.2
Preparation/Handling/Storage/Accountability .................................................59
Dose Preparation..........................................................................................59
Handling, Storage, and Accountability........................................................59
6.3
Measures to Minimize Bias: Randomization and Blinding..............................60
Intervention Assignment..............................................................................60
Stratification.................................................................................................60
Blinding........................................................................................................61
6.4
Study Intervention Compliance..........................................................................61
6.5
Concomitant Therapy..........................................................................................61
Prohibited Concomitant Medications ..........................................................62
Rescue Medications and Supportive Care ...................................................63
6.6
Dose Modification ................................................................................................63
Management of Anemia...............................................................................66
Management of Hypoxia..............................................................................66
6.7
Intervention After the End of the Study............................................................67
6.8
Clinical Supplies Disclosure................................................................................67
6.9
Standard Policies..................................................................................................67
Study Site Retention Samples......................................................................67
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................67
7.1
Discontinuation of Study Intervention...............................................................67
7.2
Participant Withdrawal From the Study...........................................................68
7.3
Lost to Follow-up .................................................................................................69
8
STUDY ASSESSMENTS AND PROCEDURES........................................................69
8.1
Administrative and General Procedures ...........................................................70
Informed Consent.........................................................................................70
8.1.1.1
General Informed Consent.................................................................70
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................71
Inclusion/Exclusion Criteria ........................................................................71
Participant Identification Card.....................................................................71
08CHFV

PRODUCT: MK-6482  
11
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Medical History ...........................................................................................71
Prior and Concomitant Medications Review...............................................72
8.1.5.1
Prior Medications...............................................................................72
8.1.5.2
Concomitant Medications..................................................................72
Assignment of Screening Number...............................................................72
Assignment of Treatment/Randomization Number.....................................72
Study Intervention Administration ..............................................................72
8.1.8.1
Timing of Dose Administration.........................................................73
Discontinuation and Withdrawal .................................................................73
8.1.9.1
Withdrawal From Future Biomedical Research ................................73
Participant Blinding/Unblinding..................................................................74
Tissue Collection .........................................................................................74
Calibration of Equipment.............................................................................74
8.2
Efficacy Assessments ...........................................................................................74
Tumor Imaging and Assessment of Disease................................................74
8.2.1.1
Initial Tumor Imaging........................................................................75
8.2.1.2
Tumor Imaging During the Study......................................................75
8.2.1.3
RECIST 1.1 Assessment of Disease..................................................76
End of Treatment and Follow-up Tumor Imaging.......................................77
8.3
Safety Assessments...............................................................................................78
Physical Examinations.................................................................................78
Vital Signs....................................................................................................78
Electrocardiograms ......................................................................................78
Clinical Safety Laboratory Assessments .....................................................79
KPS and ECOG Performance Status ...........................................................79
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................79
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................80
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......81
Follow-up of AE, SAE, and Other Reportable Safety Event Information...82
Regulatory Reporting Requirements for SAE .............................................82
Pregnancy and Exposure During Breastfeeding ..........................................82
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................83
Events of Clinical Interest............................................................................83
8.5
Treatment of Overdose........................................................................................84
8.6
Pharmacokinetics.................................................................................................84
08CHFV

PRODUCT: MK-6482  
12
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Blood Collection for Plasma Belzutifan ......................................................84
8.7
Pharmacodynamics..............................................................................................84
8.8
Biomarkers ...........................................................................................................84
Planned Genetic Analysis Sample Collection..............................................85
8.9
Future Biomedical Research Sample Collection...............................................85
8.10
Medical Resource Utilization and Health Economics.......................................85
8.11
Visit Requirements...............................................................................................85
Screening......................................................................................................85
Treatment Period..........................................................................................86
Poststudy......................................................................................................86
8.11.3.1
Posttreatment Safety Follow-up Visit................................................86
8.11.3.2
Imaging Follow-up.............................................................................86
8.11.3.3
Survival Follow-up ............................................................................87
9
STATISTICAL ANALYSIS PLAN .............................................................................87
9.1
Statistical Analysis Plan Summary.....................................................................87
9.2
Responsibility for Analyses/In-house Blinding .................................................88
9.3
Hypotheses/Estimation ........................................................................................88
9.4
Analysis Endpoints...............................................................................................89
Efficacy Endpoints.......................................................................................89
Safety Endpoints..........................................................................................89
9.5
Analysis Populations............................................................................................89
Efficacy Analysis Population.......................................................................89
Safety Analysis Population..........................................................................89
9.6
Statistical Methods...............................................................................................90
Statistical Methods for Efficacy Analyses...................................................90
9.6.1.1
Objective Response Rate ...................................................................90
9.6.1.2
Progression-free Survival...................................................................90
9.6.1.3
Duration of Response.........................................................................91
9.6.1.4
Clinical Benefit Rate..........................................................................92
9.6.1.5
Overall Survival.................................................................................92
9.6.1.6
Analysis Strategy for Key Efficacy Endpoints..................................92
Statistical Methods for Safety Analyses ......................................................93
Demographics and Baseline Characteristics................................................95
9.7
Interim Analyses ..................................................................................................95
9.8
Multiplicity ...........................................................................................................95
9.9
Sample Size and Power Calculations .................................................................96
9.10
Subgroup Analyses...............................................................................................96
9.11
Compliance (Medication Adherence).................................................................96
08CHFV

PRODUCT: MK-6482  
13
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
9.12
Extent of Exposure...............................................................................................97
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................98
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........98
Code of Conduct for Clinical Trials.............................................................98
Financial Disclosure...................................................................................100
Data Protection...........................................................................................100
10.1.3.1
Confidentiality of Data ....................................................................101
10.1.3.2
Confidentiality of Participant Records.............................................101
10.1.3.3
Confidentiality of IRB/IEC Information..........................................101
Committees Structure.................................................................................102
10.1.4.1
Scientific Advisory Committee (SAC)............................................102
Publication Policy......................................................................................102
Compliance with Study Registration and Results Posting Requirements .102
Compliance with Law, Audit, and Debarment ..........................................102
Data Quality Assurance .............................................................................103
Source Documents .....................................................................................104
Study and Site Closure...............................................................................104
10.2
Appendix 2: Clinical Laboratory Tests............................................................105
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................107
Definitions of Medication Error, Misuse, and Abuse................................107
Definition of AE ........................................................................................107
Definition of SAE ......................................................................................108
Additional Events Reported in the Same Manner as SAE.........................109
Recording AE and SAE .............................................................................110
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................113
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................115
Definition of Device Event........................................................................115
Definition of Adverse Device Event..........................................................115
Definition of Medical Device Incident (Including Malfunction) ..............115
Documenting Device Events, Adverse Device Events, and Medical 
Device Incidents.........................................................................................115
10.5
Appendix 5: Contraceptive Guidance..............................................................116
Definitions..................................................................................................116
Contraception Requirements......................................................................117
08CHFV

PRODUCT: MK-6482  
14
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................118
10.7
Appendix 7: Country-specific Requirements..................................................123
United Kingdom.........................................................................................123
10.8
Appendix 8: Abbreviations ...............................................................................124
11
REFERENCES.............................................................................................................127
08CHFV

PRODUCT: MK-6482  
15
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values .................................................53
Table 2
Study Interventions..........................................................................................58
Table 3
Dose Modification Guidelines for Belzutifan (MK-6482)-related 
Toxicities..........................................................................................................64
Table 4
Belzutifan Dose Levels – 120 mg QD Starting Dose ......................................66
Table 5
Belzutifan Dose Levels –200 mg QD Starting Dose .......................................66
Table 6
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................81
Table 7
Censoring Rules for PFS..................................................................................91
Table 8
Censoring Rules for DOR................................................................................92
Table 9
Analysis Strategy for Key Efficacy Endpoints................................................93
Table 10
Analysis Strategy for Safety Parameters..........................................................95
Table 11
Protocol-required Safety Laboratory Assessments........................................106
08CHFV

PRODUCT: MK-6482  
16
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
LIST OF FIGURES
Figure 1
Study Design..............................................................................................21
08CHFV

PRODUCT: MK-6482  
17
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: Phase 2 Study of MK-6482 in Participants With Advanced Renal Cell 
Carcinoma
Short Title: Phase 2 Study of MK-6482 in Participants With Advanced Renal Cell 
Carcinoma
Acronym: MK-6482-013
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
This study will be conducted in male and female participants with previously treated 
advanced renal cell carcinoma (RCC) with clear cell component.
Objectives
Endpoints
Objectives
Endpoints
Primary
•
Objective: To compare the 120 mg once 
daily (QD) dose and 200 mg QD dose of 
belzutifan with respect to objective 
response rate (ORR) based on Response 
Criteria in Solid Tumors (RECIST) 1.1 as 
assessed by blinded independent central 
review (BICR).
•
Hypothesis (H1): Belzutifan 200 mg QD 
is superior to belzutifan 120 mg QD in 
terms of ORR per RECIST 1.1 by BICR.
Objective response (OR): complete 
response (CR) or partial response (PR).
Secondary
•
Objective: To evaluate the 120 mg QD 
dose and 200 mg QD dose of belzutifan
with respect to progression-free survival 
(PFS) as assessed by BICR according to 
RECIST 1.1.
•
PFS: the time from randomization to 
the first documented disease 
progression or death due to any cause, 
whichever occurs first. 
08CHFV

PRODUCT: MK-6482  
18
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Objectives
Endpoints
•
Objective: To evaluate the 120 mg QD 
dose and 200 mg QD dose of belzutifan
with respect to duration of response 
(DOR) as assessed by BICR according to 
RECIST 1.1.
•
DOR: the time from first documented 
evidence of CR or PR until either 
disease progression or death due to 
any cause, whichever occurs first.
•
Objective: To evaluate the 120 mg QD 
dose and 200 mg QD dose of belzutifan
with respect to clinical benefit rate (CBR) 
as assessed by BICR according to 
RECIST 1.1.
•
Clinical benefit: stable disease ≥6 
months or CR or PR based on 
assessments by BICR per RECIST 
1.1.
•
Objective: To evaluate the 120 mg QD 
dose and 200 mg QD dose of belzutifan
with respect to overall survival (OS).
•
OS: the time from randomization to 
death due to any cause.
•
Objective: To evaluate the safety and 
tolerability of the 120 mg QD dose 
compared with the 200 mg QD dose of 
belzutifan.
•
Adverse events (AEs).
•
Study intervention discontinuation due 
to AEs.
•
Objective: To evaluate the 
pharmacokinetics (PK) of the 120 mg QD
dose and 200 mg QD dose of belzutifan
administered orally as monotherapy.
•
Maximum concentration (Cmax), 
trough concentration (Ctrough).
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Renal cell carcinoma with clear cell component
Population
Participants with locally advanced or metastatic RCC after 
prior therapy
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
None
08CHFV

PRODUCT: MK-6482  
19
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Blinding
Unblinded Open-label
Blinding Roles
Outcomes Assessor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 4 years from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 150 participants will be randomized.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admini-
stration
Regimen/ Treatment 
Period
Belzutifan
120 mg QD
Belzutifan
120 mg
QD
oral
Until progressive 
disease or 
discontinuation
Belzutifan
200 mg QD
Belzutifan
200 mg
QD
oral
Until progressive 
disease or 
discontinuation
QD=once daily.
Other current or former name(s) or alias(es) for study intervention are as 
follows: MK-6482, formerly PT2977 (belzutifan).
Total 
Number of 
Intervention 
Groups/ 
Arms
2 arms
08CHFV

PRODUCT: MK-6482  
20
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Duration of 
Participation
Each participant will participate in the study from the time the participant 
provides documented informed consent through the final contact. After a
Screening Phase of up to 28 days, each participant will receive belzutifan
until: disease progression is radiographically documented per RECIST 1.1,
unacceptable AEs, intercurrent illness that prevents further administration 
of treatment, investigator’s decision to discontinue the participant, or 
administrative reasons requiring cessation of treatment (Section 7.1).
Treatment beyond disease progression may be allowed (Section 4.1).
After the end of treatment, each participant will be followed for the 
occurrence of AEs and other reportable safety events as described under 
Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have posttreatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1, 
initiation of a new anticancer treatment, withdrawal of consent, pregnancy, 
death, loss to follow-up, or end of the study. All participants will be 
followed for OS until death, withdrawal of consent, or the end of the study.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Scientific Advisory Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
08CHFV

PRODUCT: MK-6482  
21
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
IMDC=International Metastatic Renal Cell Carcinoma Database Consortium; QD=once daily; RCC=renal cell 
carcinoma; TKI=tyrosine-kinase inhibitor.
a. Participants who discontinue study treatment for reasons other than disease progression should continue with 
imaging assessments per the protocol-defined schedule until disease progression, initiation of a new anticancer 
treatment, death, pregnancy, withdrawal of consent, or end of the study, whichever occurs first.
b. [Cella, D. 2011] [Heng, D. Y., et al 2013]
Stratification Factors
1.
IMDC prognostic scores b: 0 vs 1-2 vs 3-6
2.
Number of prior TKI therapies for advanced RCC:
0 vs 1 vs 2-3
Screening Phase
≤28 days prior to 
randomization
Stratification
Randomization 
1:1
Belzutifan
120 mg oral QD
N=75
Imaging 
Follow-upa
Survival 
Follow-up
Safety 
Follow-up
Participant Population
•
Advanced RCC with clear cell component
•
Progressed after ≥1 prior therapy for 
advanced RCC
Belzutifan
200 mg oral QD
N=75
08CHFV

PRODUCT: MK-6482  
22
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
1.3
Schedule of Activities
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Administrative Procedures
ICF
X
Consent must be 
obtained before
performing any 
protocol-specific 
procedures.
If the investigator 
plans to treat beyond 
the initial radiologic 
disease progression, 
per RECIST 1.1, 
additional consent is 
required at initial 
radiographic disease 
progression.
Future 
Biomedical 
Research ICF 
(optional)
X
Participants can still 
participate in the 
study if they decline 
to sign the Future 
Biomedical Research 
ICF.
Consent for 
optional tissue
collection
Optional consent
Inclusion/
exclusion 
criteria
X
08CHFV

PRODUCT: MK-6482  
23
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Participant ID 
card
X
X
At Week 1, site 
personnel should add 
the allocation number 
to the Participant ID 
card.
Demographics 
and medical 
history
X
Medical history 
includes alcohol and 
tobacco use, history 
of cardiac and 
respiratory 
disease/abnormal 
conditions, and 
surgical history.
RCC disease 
history
X
Prior/
con-comitant 
medication 
review
X
X
X
X
X
X
X
X
X
X
Include blood 
transfusions and 
supplemental oxygen 
administration during 
review of 
concomitant 
medication. 
Concomitant 
medications 
administered >30 
days after the last 
dose of study 
intervention will be 
recorded for SAEs as 
outlined for AE 
monitoring 
timeframes below.
08CHFV

PRODUCT: MK-6482  
24
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Randomizat-
ion
X
Participants may be 
randomized up to 3 
days before initiation 
of study interventiona
and after 
confirmation of 
eligibility. All 
procedures and 
assessments 
performed on Week 1 
Day 1 are to be 
performed after 
randomization.
Subsequent 
antineoplastic 
therapy status
X
X
X
All anticancer therapy 
will be recorded until 
time of death or 
termination of 
survival follow-up. If 
a clinic visit is not 
feasible, follow-up 
information may be 
obtained by telephone 
or email.
08CHFV

PRODUCT: MK-6482  
25
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Vital status
X
Continued after 
investigator 
determined disease 
progression or 
initiation of new 
anticancer treatment. 
In addition, on
Sponsor request, 
participants may be 
contacted for vital 
status at any time 
during the study.
Administration of Study Intervention
Belzutifan
dispensing
X
X
X
X
Participants will hold 
dosing of belzutifan
on clinic visit days at 
Weeks 1, 3, and 5 
until after completion 
of blood collection. 
The time of ingestion 
of belzutifan will be 
recorded and 
subsequent time-
dependent procedures 
will be performed 
relative to the 
ingestion time.
Review study 
intervention 
compliance
X
X
X
X
08CHFV

PRODUCT: MK-6482  
26
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Efficacy Procedures
Imaging will continue 
to be performed until 
disease progression is 
documented by the 
investigator, the 
initiation of new 
anticancer treatment, 
withdrawal of 
consent, pregnancy, 
death, or end of the 
study, whichever 
occurs first.
Tumor 
imaging (chest, 
abdomen, 
pelvis)
Xd
Xd
Xd
Xd
Screening images are 
to be captured within 
28 days before
randomization. First 
on-study imaging 
should be performed 
at Week 9 Day 1 
(±7 days) then Q8W 
(every 56 days 
±7 days) through 
Week 49 then Q12W 
(±7 days; (±14 days 
after Week 109) 
thereafter 
(Section 8.2.1.2). 
Imaging timing is to 
follow calendar days 
and is not to be 
adjusted for delays in 
study intervention.
08CHFV

PRODUCT: MK-6482  
27
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Bone imaginge
Xe
Xe
Xe
Xe
Screening images are 
to be captured within 
28 days before
randomization.e All 
imaging visits on 
study will have a visit 
window of ±7 days 
(±14 days after Week 
109).
Brain imagingf
Xf
Xf
Xf
Screening images are 
to be captured within 
28 days before
randomization. All 
imaging visits on 
study will have a visit 
window of ±7 days. 
Perform at baseline 
ONLY for 
participants with 
previously 
documented brain 
metastases (to 
confirm stability) or 
who are clinically 
symptomatic. 
08CHFV

PRODUCT: MK-6482  
28
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Safety Procedures
AE/SAE 
review
X
X
X
X
X
X
X
X
X
Any AEs noted 
before ICF are to be 
recorded as medical 
history. AEs that 
occur within 30 days 
of the end of 
treatment are to be 
followed and 
recorded. SAEs are to 
be reported from the 
time of intervention 
allocation 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. Details are 
provided in Section 
8.4.1.
Complete 
physical 
examination 
including 
height 
X
X
Height at screening 
only.
08CHFV

PRODUCT: MK-6482  
29
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Directed 
physical 
examination
X
X
X
X
X
X
X
Directed physical 
examination
performed as 
clinically indicated 
before treatment 
administration and at 
Safety Follow-up.
Vital signs 
(weight, 
systolic and 
diastolic blood 
pressure, 
respiratory 
rate, heart rate, 
and pulse 
oximetry)
X
X
X
X
X
X
X
X
X
Vital signs will be 
obtained before study 
intervention 
administration on 
Week 1 Day 1.
All blood pressure 
measurements are to 
be taken after the 
participant has rested 
in a seated position 
for at least 3 minutes.
12-lead ECG
X
X
X
X
X
X
X
X
Single 12-lead ECG. 
Participants must be 
in the recumbent 
position for a period 
of 5 minutes before
the ECG. All ECGs 
are to be before blood 
draw or at least 60 
minutes after. 
Additional 
assessments are to be 
performed if 
clinically indicated.
08CHFV

PRODUCT: MK-6482  
30
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Karnofsky 
performance 
status
X
KPS performance 
status is collected at 
screening only and is 
to be ≤10 days before
the first dose of study 
intervention.
ECOG 
performance 
status
X
X
X
X
X
X
X
X
X
ECOG performance 
status at screening is 
to be ≤10 days before
the first dose of study 
intervention.
Safety Laboratory Procedures/Assessment: Analysis Performed by LOCAL Laboratory
EPO
X
EPO levels will be 
measured ≤10 days 
before the first dose 
of study intervention 
in all participants and 
will be measured 
before initiating EPO 
replacement therapy.
Hematology
X
X
X
X
X
X
X
X
X
All screening 
laboratory tests are to 
be performed 
≤10 days before the 
first dose of study 
intervention.  
Chemistry
X
X
X
X
X
X
X
X
X
All screening 
laboratory tests are to 
be performed 
≤10 days before the 
first dose of study 
intervention. 
08CHFV

PRODUCT: MK-6482  
31
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Urinalysis
X
X
X
X
X
X
HBV, HCV, 
and HIV 
testing
X
Not required unless 
mandated by local 
health authorities
(Refer to Appendix 7
for country-specific 
requirements).
Urine or serum
hCG -
WOCBP only
X
X
X
X
X
X
X
WOCBP require 
negative test before
randomization. If 
more than 24 hours 
have elapsed before
first dose of study 
intervention, another 
pregnancy test is 
required before
starting study 
intervention.
Thereafter, pregnancy 
tests will be 
conducted monthly.
08CHFV

PRODUCT: MK-6482  
32
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
PT or INR and 
aPTT
X
X
X
X
X
X
Screening samples 
collected before
obtaining allocation 
number and ≤10 days 
before the first dose 
of study intervention. 
Test Q8W (every 56 
days ±7 days) after 
Week 9 through 
Week 49 then Q12W 
(±7 days) thereafter.
Additional testing to 
be conducted as 
clinically indicated 
for participants taking 
anticoagulant therapy. 
08CHFV

PRODUCT: MK-6482  
33
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Pharmacokinetics/ Pharmacodynamics/ Biomarkers: Analyses Performed by CENTRAL Laboratory
Blood for PK 
analysesg
X
X
X
On days of PK blood 
sample collection, 
perform ECG before
blood draw.
Blood for 
genetic 
analyses 
X
Collect predose only 
on Week 1 Day 1.
CCI
08CHFV

PRODUCT: MK-6482  
34
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
CCI
08CHFV

PRODUCT: MK-6482  
35
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Study Period
Screen
-ing
Treatment Period
EOT
Post-treatment
Notes
Visit:
Screen
-inga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety 
Follow-up
Imaging 
Follow-
up Visits
Survival 
Follow-
upc
Scheduling 
Window 
(Days):
–28 to 
–1
+3
±3
±3
±3
±3
Q4W
±5
Q8W
±5
At time 
of DC
30 Days 
After Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Archival or 
newly obtained 
tissue 
collection
X
Submit an archival 
tumor tissue sample 
or newly obtained 
core or excisional 
biopsy of a tumor 
lesion not previously 
irradiated. FFPE 
tissue blocks are 
preferred to slides. 
Newly obtained 
biopsies are preferred 
to archived tissue. 
Details pertaining to 
tumor tissue 
submission can be 
found in the 
laboratory manual.
Optional newly 
obtained tissue 
collection
Separate consent 
required before 
collecting tissue for 
optional biomarker 
research.
Details pertaining to 
tumor tissue 
submission can be 
found in the 
laboratory manual.
08CHFV

PRODUCT: MK-6482  
36
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
AE=adverse event; aPTT=activated partial thromboplastin time; hCG=human chorionic gonadotropin; BICR=blinded independent central review; CBC=complete blood count; 
CR=complete response; CT=computed tomography; ctDNA=circulating tumor deoxyribonucleic acid; DC=discontinuation; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; EOT=end of treatment; EPO=erythropoietin; HBV=hepatitis B virus; HBsAg=Hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; ICF=informed consent form; ID=identification; INR=International normalized ratio; KPS=Karnofsky performance status; MRI=magnetic resonance 
imaging; PK=pharmacokinetics; PT=prothrombin time; PTT= partial thromboplastin time; Q4W=every 4 weeks; Q8W=every 8 weeks; Q12W=every 12 weeks; Q16W=every 
16 weeks; QD=once daily; QOL=quality of life; RCC=renal cell carcinoma; RECIST=Response Evaluation Criteria in Solid Tumors; RNA=ribonucleic acid; SAE=serious 
adverse event; SoA=schedule of activities; Wk=week; WOCBP=women of childbearing potential.
a. Week 1 Day 1 denotes the first dose of study intervention, which should be on the date of randomization, but can be ≤3 days after randomization. Every effort should be 
made to ensure the participants receive the first dose of study intervention on the day of randomization.
b.  Clinic visits after Week 13 are Q4W.
c.  Long-term follow-up may be accomplished via an in-person visit, telephone contact, chart review, etc. Participant status information includes vital status and subsequent 
antineoplastic therapies for RCC.
d.  Tumor assessment including CT or MRI of chest, abdomen, and pelvis should follow the schedule per the SoA until disease progression is documented by the investigator. 
Imaging visit window may be ±14 days after Week 109. Unscheduled imaging can be performed as clinically indicated. Imaging anatomic coverage should be the same as that 
at screening; see Section 8.2.1.1 for details. Participants who discontinue treatment for reasons other than disease progression should continue with imaging assessments per the 
protocol-defined schedule until: 1) disease progression, 2) initiation of a new anticancer treatment, 3) death, 4) pregnancy, 5) withdrawal of consent, or 6) end of the study, 
whichever comes first.
e.  Baseline bone scan is required for all participants at screening. Bone scans are not required to be repeated at screening if performed ≤42 days before randomization. If a 
participant has a positive baseline bone scan, after randomization, bone scans will be performed at Week 17 (±7 days) and should continue to be performed Q16W (±7 days) 
through Week 49, subsequently Q24W (±7 days; ±14 days after Week 109) until disease progression. The timing of imaging assessments should follow calendar days and 
should not be adjusted for delays in study intervention. Bone scans must be performed for confirmation of CR for participants with a positive bone scan at baseline.
f.  A brain scan will be performed during screening for participants with brain metastases to ensure participant is stable. After randomization, brain imaging should be 
performed as clinically indicated in participants with previously documented brain metastases or who are clinically symptomatic, and to confirm a CR in participants with brain 
metastases at baseline.
g.  On Week 1 Day 1, Week 3 Day 1, and Week 5 Day 1, participants will hold dosing of belzutifan tablets, which will be administered in the clinic. The Week 1 Day 1 and 
Week 3 Day 1 dose should be taken fasted (at least 2 hours after a meal); food should be withheld for 1-hour postdose. To ensure appropriate PK sample collection, it is 
recommended that study intervention be taken in the morning for the first month of dosing (ie, until Week 5 Day 1). A blood sample for PK assessments will be obtained on 
Week 1 Day 1 and Week 3 Day 1 at predose, 1, 2 and 4 hours postdose. On Week 5 Day 1 a blood sample will be collected predose. A window of 30 minutes is permitted for 
all time points at which samples are collected. If a participant has a treatment interruption or discontinues treatment before Week 5, every effort should be taken to collect the 
PK sample for the Week 5 time point at the time of treatment interruption or discontinuation.
h.  On Week 1 Day 1, Week 3 Day 1, and Week 5 Day 1, participants will hold dosing of belzutifan tablets, which will be administered in the clinic. The Week 1 Day 1 and 
Week 3 Day 1 dose should be taken fasted (at least 2 hours after a meal); food should be withheld for 1-hour postdose. A blood sample for pharmacodynamic assessments will 
be obtained on Week 1 Day 1 and Week 3 Day 1 at predose, 1, 2 and 4 hours postdose. On Week 5 Day 1 a blood sample will be collected predose. A window of 30 minutes is 
permitted for all time points at which samples are collected. If a participant has a treatment interruption or discontinues treatment before Week 5, every effort should be taken to 
collect the pharmacodynamics sample for the Week 5 time point at the time of treatment interruption or discontinuation.
08CHFV

PRODUCT: MK-6482  
37
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
2
INTRODUCTION
This study will evaluate the efficacy and safety of the 120 mg QD dose compared with the 
200 mg QD dose of the HIF-2α inhibitor, belzutifan (also known as MK-6482, formerly 
PT2977), in participants with advanced RCC with clear cell component after prior therapy.
2.1
Study Rationale
The hypoxia-inducible factor, HIF-2α, is believed to play a critical role in tumorigenesis and 
tumor progression in RCC. Belzutifan is an orally available, small molecule inhibitor of 
HIF-2α, that selectively disrupts the heterodimerization of HIF-2α with HIF-1β. The safety 
profile of belzutifan in 55 heavily pretreated advanced RCC participants (median 3 prior 
regimens) in Study MK-6482-001 (also known as PT2977-101) together with the ORR of 
24% suggest that belzutifan may be a treatment option for participants with advanced RCC 
who have progressed after prior therapy [Jonasch, E., et al 2019]. The rationale for this study 
is to compare efficacy and safety between the 120 mg and 200 mg doses. If 200 mg shows 
significant and relevant efficacy and an acceptable safety profile, it may be considered for 
further development.
2.2
Background
Refer to the IB for detailed background information on belzutifan.
RCC Epidemiology and Current Therapeutic Options
Worldwide, there were 403,262 new cases of kidney cancer and 175,098 deaths due to the 
disease reported in 2018 [Bray, F., et al 2018]. RCC comprises approximately 3.7% of all 
cancers, with a median age at diagnosis of 64 years [National Cancer Institute 2016]. 
Approximately 85% of kidney tumors are RCC, and approximately 70% of these have a clear 
cell histology [Moch, H., et al 2000] [Leibovich, B. C., et al 2010] [Lipworth, L., et al 2016]. 
Other less common cell types include papillary, chromophobe, translocation, and Bellini duct 
(collecting duct) tumors. Smoking, obesity, and hypertension are established risk factors for 
RCC development. Analysis of the SEER database indicates that RCC incidence has been 
rising on average 0.6% each year and death rates have been falling on average 0.7% each 
year from 2006 through 2015 [National Cancer Institute 2016]. The 5-year survival for 
localized RCC has increased from 88.4% (during 1992 to 1995) to 92.6% (during 2007 to 
2013) [Howlader, N., et al 2017]. The most important prognostic determinants of 5-year 
survival are the tumor stage, grade, local extent of the tumor, presence of regional nodal 
metastases, and evidence of metastatic disease at presentation [Ficarra, V., et al 2005] [Frank, 
I., et al 2005] [Zisman, A., et al 2001] [Klatte, T., et al 2007] [Lam, J. S., et al 2007] 
[Minervini, A., et al 2002] [Dall'Oglio, M. F., et al 2007] [Dall'Oglio, M. F., et al 2007] 
[Lam, J. S., et al 2005] [Sengupta, S., et al 2005]. RCC primarily metastasizes to the lung, 
bone, liver, lymph nodes, adrenal gland, and brain [DeVita, et al 2008] [Bianchi, M., et al 
2012].
A substantial proportion of patients with RCC progress to advanced stage disease; about one-
third of patients with RCC present with unresectable disease or metastasis at diagnosis, and 
08CHFV

PRODUCT: MK-6482  
38
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
between 20% to 30% of patients with localized tumors will eventually relapse after 
nephrectomy [National Comprehensive Cancer Network 2019]. The 5-year survival rate for 
patients with advanced RCC is 12%. 
Treatment options for advanced and metastatic RCC have evolved greatly over the last 2 
decades. Early lines of treatment for patients with advanced RCC include VEGF-targeting 
and immunotherapy agents [Escudier, B., et al 2019]. Recently, combination therapy with the 
immune checkpoint inhibitor antibodies nivolumab and ipilimumab was shown to be 
effective in the randomized Phase 3 CheckMate 214 study in participants with treatment-
naïve advanced RCC with intermediate or poor IMDC risk [Motzer, R. J., et al 2018]. Two 
combination regimens of immune checkpoint inhibitors with VEGF-targeted therapies in the 
first-line setting have also recently reported positive Phase 3 data [Motzer, R. J., et al 2019] 
[Rini, B. I., et al 2019]. In the KEYNOTE-426 study, the pembrolizumab and axitinib 
combination prolonged OS (HR 0.53) and PFS (median PFS of 15.1 months for 
pembrolizumab and axitinib vs 11.1 months for sunitinib), and had an increased ORR (59.3% 
for pembrolizumab and axitinib vs 35.7% for sunitinib) [Rini, B. I., et al 2019]. Thus, the 
treatment paradigm for patients with advanced RCC is rapidly evolving, with incorporation 
of immune checkpoint inhibitor combinations as first-line standard of care, and VEGF-
targeting and mTOR inhibitors as subsequent lines of care [McKay, R. R., et al 2018].
There is no evidence-based treatment recommendation for the optimal management of 
patients in the late-line setting after immunotherapy and VEGF-targeting therapy. Among 
available agents, everolimus, an mTOR inhibitor, is frequently used in late-line settings in 
accordance with recently published expert/clinical practice guidelines [Escudier, B., et al
2019] [National Comprehensive Cancer Network 2019]. The NCCN and ESMO strongly 
recommend clinical study participation for patients, particularly with relapsed disease. 
Current therapeutic options are outlined in the current ESMO guidelines, released in 
February 2019 [Escudier, B., et al 2019], and the NCCN guidelines, released in August 2019 
[National Comprehensive Cancer Network 2019].
As patients rapidly progress on therapy in late-line settings, improved therapeutic options 
with superior efficacy are in great need and enrollment into clinical studies investigating 
promising therapies with new mechanisms of action is recommended.
Pharmaceutical and Therapeutic Background
HIF-2α is a transcription factor that has been established as an oncogenic driver in ccRCC. 
PT2385 was the first HIF-2α antagonist to be evaluated in clinical development and has 
showed clinical activity in ccRCC participants who had previously been treated with multiple 
lines of therapy. There is continuing effort to characterize additional HIF-2α antagonists 
possessing attributes that may contribute to enhanced clinical activity. The second HIF-2α
antagonist to be evaluated, belzutifan, is a potent and selective inhibitor both in vitro and in 
vivo and inhibits HIF-2α function by disrupting its hetero-dimerization with the ARNT in 
cells. HIF-2α is believed to have a role in tumorigenesis and tumor progression and 
epigenetic inactivation of VHL expression has been found in many cancers including 
multiple myeloma, retinoblastoma, NSCLC, pancreatic endocrine tumors, squamous cell 
carcinoma, acute myeloid leukemia, myelodysplastic syndrome, and esophageal squamous 
08CHFV

PRODUCT: MK-6482  
39
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
cell carcinoma [Nguyen, M. P., et al 2013]. A strong connection has been established 
between ccRCC, mutations in the VHL tumor suppressor gene and the subsequent activation 
of HIF-2α transcriptional activity [Shen, C. 2013]. More than 90% of ccRCC tumors have 
defective or modulated VHL function through deletion, mutation, or post-translational 
modification [Sato, Y., et al 2013]. In tumor cells where HIF-2α is activated, belzutifan
blocks the transcription of several genes involved in oncogenesis, including CCND1, 
VEGFA, and the glucose transporter SLC2A1. 
 
 
 
 
 
 
 
 
Refer to the belzutifan IB for additional information.
Preclinical Studies
2.2.3.1
Preclinical Pharmacokinetics and Metabolism
PK and TK evaluations characterized the ADME of belzutifan. In vivo PK study assessments 
were conducted in mice, rats, dogs, and monkeys. Belzutifan has low aqueous solubility and 
high permeability (BCS Class 2) and is well absorbed after oral administration in animals at 
clinically relevant doses. The oral bioavailability of belzutifan was shown to be high in mice 
(>100%), moderate in dogs and monkeys (33% and 53%, respectively), and low in rats 
(18%).
The volume of distribution of belzutifan was greater than total body water in all species, 
suggesting extensive tissue distribution.
In vitro and in vivo metabolism studies revealed primarily oxidation and O-glucuronidation 
biotransformation pathways. The oxidation biotransformation pathways were greatest in rats 
and similar between humans and dogs. In the ADME study of 14C-belzutifan in rats, 
belzutifan was primarily metabolized by the liver. The presence of a glycosidic glucuronide 
metabolite (PT3317) in vivo in rats and dogs led to UGT reaction phenotyping with 
recombinant UGTs, which suggested that the formation of PT3317 is mediated by 
UGT2B17, an isoform primarily expressed in the small intestine. PT3317 has no activity 
against HIF-2α.
In vitro studies assessing the inhibition or induction of CYP metabolic enzymes showed that 
belzutifan did not inhibit any CYP enzymes by either competitive (7 CYP isoforms) or time-
dependent (CYP3A4) mechanisms at concentrations of at least 50 µM. In vitro and 
physiologically based PK modeling results indicated that belzutifan is a weak inducer of 
CCI
08CHFV

PRODUCT: MK-6482  
40
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
CYP3A4. Belzutifan is not a substrate of P-gp or BCRP and does not inhibit P-gp or BCRP 
(IC50 >100 µM) at clinically relevant concentrations (~4.67 µM).
Urinary excretion was found to be a minor pathway for elimination of belzutifan (≤4% of 
dose) and PT3317 (≤13% of dose) for dogs and monkeys.
Refer to the belzutifan IB for additional information.
2.2.3.2
Preclinical Toxicology
Belzutifan was not genotoxic in the in vitro bacterial mutagenicity assay (Ames) and the in 
vitro micronucleus assay, indicating a low genotoxic risk from belzutifan exposure.
The in vivo safety pharmacology assessments of the cardiovascular, central nervous, and 
respiratory systems included in general toxicology studies did not yield any adverse findings. 
The cardiovascular system was assessed by hemodynamic and electrocardiographic 
parameters in the GLP 28-day and 13-week repeat-dose toxicity studies in dogs, and no 
change from baseline was observed with belzutifan treatment.
The toxicity of orally administered belzutifan was evaluated in 28-day and 13-week repeat-
dose GLP studies in rats and dogs. Effects on the RBC compartment were observed 
consistently in both species. The magnitude of effect stabilized over time at an approximate 
30% reduction in the RBC count, hemoglobin and hematocrit levels, with repeated 
administration. The effects on the RBC compartment were reversed once belzutifan
administration stopped and are considered an “on-target” pharmacologic activity of HIF-2α 
antagonism on erythropoietin production.
In the rat toxicity studies with belzutifan, off-target organ toxicity was identified in the male 
reproductive system. The belzutifan related effects involved testes (smaller/soft testes and 
decreased weight associated with hypospermatogenesis, germ cell degeneration, and 
multinucleated giant cells), and epididymis (oligospermia), and were not reversible within 
26-week recovery periods. These findings were associated with decreased sperm motility and 
sperm counts, and increased number of abnormal sperms in the sperm analysis. No effects on 
sperm evaluation and histopathology of testes/epididymides were observed in male dogs. No 
effects on the female reproductive organs were observed in either rats or dogs. 
In a pEFD study where pregnant rats were administered belzutifan, a significant level of post 
implantation loss indicative of embryo-fetal lethality and/or reduced fetal body weight, 
reduced ossification, and malformations in surviving fetuses was observed at an exposure 
close to the clinically relevant exposure at 120 mg/day.
Refer to the belzutifan IB for additional information.
08CHFV

PRODUCT: MK-6482  
41
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Clinical Studies
As of 06-SEP-2019, a total of 34 healthy volunteers and 185 participants had been treated 
with MK-6482 in 5 clinical studies: MK-6482-002 (also known as PT2977-103), MK-6482-
001 (PT2977-101), MK-6482-004 (PT2977-202), MK-6482-003 (PT2977-201) and 
MK-6482-006 (PT2977-104):

16 healthy adult volunteers in the Phase 1 MK-6482-002 (PT2977-103) food effect 
study.

104 participants in the Phase 1 Study MK-6482-001 (PT2977-101). This included 
43 participants with various advanced solid tumors in the dose-escalation cohort 
(Part 1A) of the study, 52 participants with advanced RCC (Part 1B) and 
9 participants with GBM in the dose expansion cohort (Part 2) of the study.

61 participants with VHL disease-associated RCC in the Phase 2 Study MK-6482-
004 (PT2977-202).

20 participants with ccRCC in the Phase 2 Study MK-6482-003 (PT2977-201).

18 healthy adult volunteers in the Phase 1 MK-6482-006 (PT2977-104)
bioavailability study.
 
 
 
MK-6482-001 (PT2977-101) is an ongoing Phase 1 study designed to assess the tolerability, 
safety, PK, and pharmacodynamic properties of belzutifan in participants with various 
advanced solid tumors. As of 06-SEP-2019 a total of 104 participants had been enrolled, 
including 43 participants with various advanced solid tumors in the dose-escalation portion 
(Part 1A) ranging from 20 to 240 mg QD and 120 mg BID. The MTD was not reached and 
2 treatment-related DLTs were observed, 1 Grade 4 event of thrombocytopenia in the 240 mg 
QD cohort, and 1 Grade 3 event of hypoxia in the 120 mg BID cohort. The 120 mg QD dose 
was selected for further clinical development based on favorable PK, pharmacodynamic, and 
safety findings. A total of 52 additional participants with advanced RCC were treated in an 
expansion cohort (Part 1B) at the clinical dose of 120 mg QD. In the combined 
dose-escalation and expansion cohorts, the most common AEs (occurring in ≥20% of 
participants) were anemia, fatigue, dyspnea, nausea, hypoxia, and peripheral edema. The 
most common Grade 3 AEs were anemia and hypoxia (in ≥5% of participants). The median 
tmax for belzutifan was 1 to 2.8 hours and exposure increased with dose. The mean steady 
state t1/2 in the 120 mg QD expansion cohort (Part 1B) on Day 15 was 15.3 hours, resulting in 
CCI
08CHFV

PRODUCT: MK-6482  
42
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
a 1.5-fold accumulation from Day 1 to Day 15. The mean steady state Cmax in the 120 mg QD 
expansion cohort (Part 1B) on Day 15 was 1.79 µg/mL (4.67 µM). The estimated CL/F was 
5.22 to 14.4 L/h. The mean steady state AUC0-tau of belzutifan was 20.42 h*μg/mL with 50% 
CV. The estimated CL/F and the Vz/F at the steady state for belzutifan were 7.56 L/h and 
138 L, respectively. In total, 55 participants with previously treated advanced RCC have been 
treated in this study with belzutifan at 120 mg QD (3 participants in the dose-escalation 
portion of the study and 52 participants in the dose expansion portion of the study). Best 
response among these 55 participants included 13 participants (24%) with PR and 
31 participants (56%) with SD as assessed by RECIST 1.1 [Choueiri, T. K., et al 2020].
During the dose-escalation portion of the MK-6482-001 (PT2977-101) study, the dose of 
120 mg BID was well tolerated in the 6-participant cohort with only 1 DLT of Grade 3 
hypoxia observed. The BID dosing regimen had a higher steady state plasma exposure 
compared with other dose levels.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MK-6482-004 (PT2977-202) is a Phase 2, open-label, efficacy, and safety study in 
participants with VHL disease-associated RCC. As of 06-SEP-2019, 61 participants had been
enrolled at a dose of 120 mg QD. Efficacy data are not yet available. Fatigue was the most 
common AE of ≥Grade 3 toxicity (reported by ≥5% of participants).
Refer to the belzutifan IB for additional information.
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.
CCI
08CHFV

PRODUCT: MK-6482  
43
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
The proposed study will enroll participants with advanced RCC who have progressed after 
prior therapy. As described in Section 2.2.3, belzutifan is a potent and selective inhibitor of 
HIF-2α in preclinical studies and clinical data as described in Section 2.2.4 show antitumor 
activity of belzutifan, which warrants further investigation. In MK-6482-001 (PT2977-101),
the ORR for 55 heavily pretreated advanced RCC participants (62% having received ≥3 prior 
lines of therapy) was 24% (95% CI: 13, 37), with median DOR not yet reached, a median 
PFS of 11 months (95% CI: 6, 17) and clinical activity seen across IMDC risk categories 
[Choueiri, T. K., et al 2020]. This compares favorably to the ORR seen with nivolumab in 
Checkmate 25 (25%, 95% CI: 3.68, 9.72) and cabozantinib in METEOR (17%, 95% CI: 13, 
22), both studies in advanced RCC participants with at least 2 prior lines of therapy including 
post TKI treatment [Motzer, R. J., et al 2015] [Choueiri, T. K., et al 2016]. While there are
no data on the efficacy of 200 mg, as described in Section 2.2.4 and 4.3.1, there is potential 
for benefit at least equal if not exceeding that seen for the 120 mg QD dose. The safety 
profile seen in MK-6482-006 (PT2977-104) at the 200-mg dose was similar to that seen 
previously for the 120 mg dosing, with the limitations that it was a single-dose study. Given 
the high risk of progression of disease in patients with advanced RCC, there is an unmet 
medical need for more effective and tolerable treatment, and as belzutifan has been shown to 
be well tolerated across various tumor types, a positive benefit/risk profile is expected.
Recent preclinical findings in rats suggest that belzutifan may cause embryo-fetal lethality in 
humans (Section 2.2.3.2). However, there are no data in humans on the effects of belzutifan
on embryonic or fetal development. Precautions for participants regarding this newly 
identified risk are implemented in Section 5.1, Section 5.2, and Sections 10.5 through 10.5.2 
(Appendix 5).
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
08CHFV

PRODUCT: MK-6482  
44
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
This study will be conducted in male and female participants with previously treated 
advanced renal cell carcinoma (RCC) with clear cell component.
Objectives
Endpoints
Primary
•
Objective: To compare the 120 mg once 
daily (QD) dose and 200 mg QD dose of 
belzutifan with respect to objective 
response rate (ORR) based on Response 
Criteria in Solid Tumors (RECIST) 1.1 as 
assessed by blinded independent central 
review (BICR).
•
Hypothesis (H1): Belzutifan 200 mg QD 
is superior to belzutifan 120 mg QD in 
terms of ORR per RECIST 1.1 by BICR.
•
Objective response (OR): complete 
response (CR) or partial response 
(PR).
Secondary
•
Objective: To evaluate the 120 mg QD 
dose and 200 mg QD dose of belzutifan
with respect to progression-free survival 
(PFS) as assessed by BICR according to 
RECIST 1.1.
•
PFS: the time from randomization to 
the first documented disease 
progression or death due to any cause, 
whichever occurs first. 
•
Objective: To evaluate the 120 mg QD 
dose and 200 mg QD dose of belzutifan
with respect to duration of response 
(DOR) as assessed by BICR according to 
RECIST 1.1.
•
DOR: the time from first documented 
evidence of CR or PR until either 
disease progression or death due to any 
cause, whichever occurs first.
•
Objective: To evaluate the 120 mg QD 
dose and 200 mg QD dose of belzutifan
with respect to clinical benefit rate (CBR)
as assessed by BICR according to 
RECIST 1.1.
•
Clinical benefit: stable disease ≥6 
months or CR or PR based on 
assessments by BICR per RECIST 1.1.
•
Objective: To evaluate the 120 mg QD 
dose and 200 mg QD dose of belzutifan
with respect to overall survival (OS).
•
OS: the time from randomization to 
death due to any cause.
•
Objective: To evaluate the safety and 
tolerability of the 120 mg QD dose 
compared with the 200 mg QD dose of 
belzutifan.
•
Adverse events (AEs).
•
Study intervention discontinuation due 
to AEs.
08CHFV

PRODUCT: MK-6482  
45
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Objectives
Endpoints
•
Objective: To evaluate the 
pharmacokinetics (PK) of the 120 mg QD 
dose and 200 mg QD dose of belzutifan
administered orally as monotherapy.
•
Maximum concentration (Cmax), trough 
concentration (Ctrough).
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2, open-label, multicenter, randomized, study to compare the safety and 
efficacy of the 120 mg QD dose and the 200 mg QD dose of belzutifan in participants with 
advanced RCC that has progressed after a maximum of 3 prior systemic therapies.
Approximately 150 eligible participants who meet all inclusion criteria and none of the 
exclusion criteria will be randomly assigned in a 1:1 ratio to receive either 120 mg QD or 
200 mg QD of belzutifan (~75 participants in each arm).
The study will include a Screening Phase, a Treatment Phase, and a Posttreatment Follow-up 
Phase.
The Screening Phase assessments must be performed ≤28 days before randomization unless 
otherwise specified. Potential participants will be screened to determine if they meet the 
required eligibility criteria.
CCI
08CHFV

PRODUCT: MK-6482  
46
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
At randomization, participants will be stratified by the following factors (Section 6.3.2):

IMDC prognostic scores [Cella, D. 2011] [Heng, D. Y., et al 2013]: 0 vs 1-2 vs 3-6

Number of prior TKI therapies for advanced RCC: 0 vs 1 vs 2-3
During the Treatment Phase, randomized participants will receive their assigned study 
intervention and undergo assessments according to the SoA (Section 1.3). Participants will be 
evaluated radiologically at Week 9 then Q8W thereafter for the first 49 weeks and then 
Q12W thereafter. Treatment may continue after radiographic progression of RCC per 
RECIST 1.1, as long as the investigator believes that the participant is still receiving clinical 
benefit from study intervention and that the potential benefit of continuing study intervention 
outweighs potential risks. Treatment beyond disease progression requires Sponsor 
consultation and approval. If approved by the Sponsor, continued participation requires 
additional consent (Section 8.1.1). Participants who continue treatment beyond disease 
progression will continue with all protocol-required assessments and procedures.
Crossover between treatment arms is not allowed.
AE monitoring will be ongoing throughout the study and graded in severity according to the 
guidelines outlined in the NCI CTCAE v5. AEs will be reported by the investigator or 
delegate from informed consent through 30 days after cessation of study intervention 
(Section 8.4.1). SAEs will be reported by the investigator or delegate from the time of 
intervention allocation 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.
Study intervention will continue until documented disease progression, unacceptable AEs, 
intercurrent illness that prevents further administration of study intervention, investigator’s 
decision to discontinue the participant, participant withdrawal of consent, interruption of 
study intervention for >28 days without Sponsor consultation, required use of prohibited 
medication, pregnancy of the participant, noncompliance, or administrative reasons requiring 
cessation of study intervention (Section 7.1).
The Posttreatment Follow-up Phase includes a Posttreatment Safety Follow-up Visit to occur 
30 days after the date of discontinuation of study intervention. Participants who discontinue 
study treatment for reasons other than disease progression should continue with imaging 
assessments as described in the SoA and Section 8.2.2. All participants will be followed for 
survival (in-person visit, telephone contact, chart review, etc.) until death, withdrawal of 
consent, loss to follow-up, or until the study is concluded or terminated early, whichever 
comes first.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
08CHFV

PRODUCT: MK-6482  
47
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
4.2
Scientific Rationale for Study Design
The open-label study design enables appropriate dose modifications for AEs in both study 
intervention treatment groups. Specific measures have been taken to ensure that PFS and 
ORR are evaluated rigorously in this study. For determination of the study endpoints of PFS 
and ORR, a BICR will review all radiographic images. The BICR will be blinded to 
treatment identity and to clinical data that may lead to inadvertent unblinding. 
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary objective of this study is to evaluate the efficacy of the 120 mg QD dose of 
belzutifan compared with the 200 mg QD dose of belzutifan for the treatment of advanced 
RCC as assessed by ORR as determined by BICR per RECIST 1.1. This study will use PFS,
DOR, and CBR as determined by BICR per RECIST 1.1, and OS, as secondary efficacy 
endpoints.
ORR and PFS are acceptable measures of clinical benefit for a study that demonstrates 
efficacy of a new antineoplastic therapy, especially if the magnitude of the effect is large and 
the therapy has an acceptable risk/benefit profile. The use of BICR and RECIST 1.1 to assess 
ORR and PFS is typically considered acceptable by regulatory authorities. Images will be 
submitted to an iCRO and read by BICR, an independent central review blinded to treatment 
assignment to minimize bias in the response assessments.
DOR and CBR are considered acceptable measures of clinical benefit when considered with 
ORR.
OS is standardly used to show benefit in oncology clinical studies.
4.2.1.2
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 NCI CTCAE v5.
4.2.1.3
Pharmacokinetic Endpoints
The plasma concentration of belzutifan will be analyzed by the Sponsor or designee using a 
validated bioanalytical method. Descriptive statistics will be used to describe the 
concentration-time data including the Cmax and Ctrough. The concentration data from the 
present study and other studies may be pooled together to perform population PK data 
analysis and the results would be reported in a separate report.
08CHFV

PRODUCT: MK-6482  
48
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
4.2.1.4
Pharmacodynamic Endpoints
Blocking HIF-2α leads to downregulation of EPO. Therefore, EPO levels will be assessed by 
dose level using descriptive statistics. Assessment of serum EPO levels and other 
pharmacodynamic markers will be performed by the Sponsor or designee using a validated 
method.
4.2.1.5
Planned Exploratory Biomarker Research
Although the mechanism of action of these therapies is not well understood, not all patients 
respond and much remains to be learned regarding how best to leverage these new drugs in 
treating patients. Thus, to aid future patients, it is important to investigate the determinants of 
response or resistance to cancer treatments administered, as well as determinants of AEs in 
the course of our clinical studies. These efforts may identify novel 
predictive/pharmacodynamic biomarkers and generate information that may better guide 
single-agent and combination therapy with oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include, but are not limited to:
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest in oncology drug 
development include the mutational burden of tumors. Increased mutational burden 
(sometimes called a ‘hyper-mutated’ state) may generate neoantigen presentation in the 
tumor microenvironment. To conduct this type of research, it is important to identify tumor-
specific mutations that occur across all genes in the tumor genome. Thus, genome-wide 
approaches may be used for this effort. Besides mutational burden, DNA analysis could 
assist in determining genomic status of drug metabolizing enzymes and other hypoxia 
pathway components that may influence drug exposure and/or response to belzutifan
treatment. Note that to understand tumor-specific mutations, it is necessary to compare the 
tumor genome with the germline genome. ctDNA and/or RNA may also be evaluated from 
blood samples.
CCI
08CHFV

PRODUCT: MK-6482  
49
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Tumor and/or blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or in blood may be performed to define gene signatures that correlate to clinical response 
to treatment with antitumor therapies. MicroRNA profiling may also be pursued as well as 
exosomal profiling.
Proteomics and IHC using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, IHC). 
Therefore, tumor tissue may be subjected to proteomic analyses using a variety of platforms 
that could include, but are not limited to immunoassays and liquid chromatography/mass 
spectrometry. This approach could identify novel protein biomarkers that could aid in patient 
selection for belzutifan therapy. In addition to expression on the tumor tissue, tumor derived 
proteins can be shed from tumor and released into the blood. Assays such as ELISA measure 
such proteins in serum. Correlation of expression with response to belzutifan therapy may 
identify new approaches for predictive biomarkers in blood, representing a major advance 
from today’s reliance on assessing tumor biomarkers. Samples for pharmacodynamic 
analyses will be collected from all participants. Pharmacodynamic biomarkers to be assessed 
include, but are not limited to, levels of EPO.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.3
Justification for Dose
Starting Dose for This Study
The doses of belzutifan used in this study are 120 mg QD and 200 mg QD, based on previous 
clinical study experience as described in Section 2.2.4. Based on favorable PK, 
pharmacodynamic, safety, and efficacy findings in MK-6482-001 (PT2799-101) Parts 1A 
and 1B in participants with advanced tumor types including RCC, the 120-mg dose was 
chosen for continued evaluation in the population of previously treated participants with 
08CHFV

PRODUCT: MK-6482  
50
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
advanced RCC. 
 
 
 
 
Maximum Dose/Exposure for This Study
There is no maximum duration of treatment for belzutifan.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Male and female participants with advanced RCC with clear cell component who are at least 
18 years of age will be randomized in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Must have a histologically confirmed diagnosis of locally advanced/metastatic RCC with 
clear cell component (with or without sarcomatoid features), ie, Stage IV RCC per AJCC
(8th Edition).
2. Has measurable disease per RECIST 1.1 as assessed by BICR.
CCI
08CHFV

PRODUCT: MK-6482  
51
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
3. Submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a 
tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Newly 
obtained biopsies are preferred to archived tissue. Details pertaining to tumor tissue 
submission can be found in the laboratory manual.
Prior Therapy
4. Has experienced disease progression on or after systemic treatment with an anti-PD-1/L1 
therapy for locally advanced or metastatic RCC. The anti-PD-1/L1 therapy may be 
monotherapy or in combination with other agent(s) such as CTLA4 or VEGF targeted-
TKI. The immediately preceding line of treatment has to have been an anti-PD-1/L1 
therapy.
Treatment progression is defined by meeting ALL of the following criteria:
o
Has received at least 2 doses of an anti-PD-1/L1 mAb.
o
Has demonstrated radiographic disease progression during or after an anti-PD-
1/L1 mAb as assessed by investigator.
5. Has received no more than 3 prior systemic regimens for locally advanced or metastatic
RCC.
6. Has received only 1 prior anti-PD-1/L1 therapy for locally advanced or metastatic RCC.
7. Has recovered from all AEs due to previous therapies to ≤Grade 1 or baseline, with the 
exception of ≤Grade 2 neuropathy or endocrine-related AEs ≤Grade 2 requiring treatment 
or hormone replacement.
Demographics
8. Is male or female, who is at least 18 years of age at the time of signing the informed 
consent.
9. Has a KPS score of at least 70% [Karnofsky, D. A., et al 1948] assessed within 10 days 
prior to the first dose of study intervention.
Male Participants
10. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days after the last dose of study intervention:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
08CHFV

PRODUCT: MK-6482  
52
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
-
Male participants must also agree to use male condom when engaging in any activity 
that allows for passage of ejaculate to another person of any sex.
•
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent 
basis), as described in Appendix 5 during the intervention period and for at least 30 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.
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours 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 
located in Appendix 2.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
08CHFV

PRODUCT: MK-6482  
53
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Informed Consent
12. The participant (or legally acceptable representative if applicable) has provided 
documented informed consent/assent for the study. The participant may also provide 
consent/assent for FBR. However, the participant may participate in the main study 
without participating in FBR.
Additional Categories
13. Has adequate organ function, as detailed in Table 1; all screening laboratory tests should 
be performed within 10 days prior to the first dose of study intervention.
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
ANC
≥1500 cells/µL
Platelets
≥100 000 cells/µL
Hemoglobin
≥10.0 g/dL or ≥6.2 mmol/La
Renal
Creatinine ANDb/OR
Measured or calculatedc creatinine 
clearance (GFR can also be used in place of 
creatinine or CrCl)
≤1.5 × ULN ANDb/OR
≥30 mL/min for participant with creatinine levels >1.5 ×
ULN
Hepatic
Total bilirubin
≤1.5 × ULN OR direct bilirubin ≤ULN for participants with 
total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
INR OR PT and aPTT
≤1.5 × ULN unless participant is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic range of 
intended use of anticoagulants
Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
ANC=absolute neutrophil count; aPTT=activated partial thromboplastin time; AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); CrCl=creatinine clearance; GFR=glomerular 
filtration rate; INR=international normalized ratio; pRBC=packed red blood cells; PT=prothrombin time; 
ULN=upper limit of normal.
a  Criteria must be met without erythropoietin dependency and without pRBC transfusion within last 28 days.
b  Applicable only when local guidelines require both assessments.
c  CrCl should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
08CHFV

PRODUCT: MK-6482  
54
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has any of the following:

Hypoxia as defined by a pulse oximeter reading <92% at rest, or

Requires intermittent supplemental oxygen, or

Requires chronic supplemental oxygen.
2. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
3. Has known CNS metastases and/or carcinomatous meningitis.
Note: Participants with previously treated brain metastases may participate provided 
they are radiologically stable (ie, without evidence of progression) for at least 4 weeks 
(28 days) by repeat imaging (repeat imaging should be performed during study 
screening), clinically stable, and without requirement for steroid treatment for at least 
14 days prior to the first dose of study intervention.
4. Has clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction ≤6 months from Day 1 of study drug administration, or New York Heart 
Association Class III or IV congestive heart failure. Medically controlled arrhythmia 
stable on medication is permitted.
5. Has moderate to severe hepatic impairment (Child-Pugh B or C).
6. Received colony-stimulating factors (eg, G-CSF, GM-CSF or recombinant EPO) 
≤28 days prior to the first dose of study intervention.
7. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the study.
8. Is unable to swallow orally administered medication or has a gastrointestinal disorder 
affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption).
9. Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any 
component of the study intervention (belzutifan) formulations.
08CHFV

PRODUCT: MK-6482  
55
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Prior/Concomitant Therapy
10. Has received prior treatment with belzutifan or another HIF-2α inhibitor.
11. Has received any type of small molecule kinase inhibitor (including investigational 
kinase inhibitor) ≤2 weeks before randomization.
12. Has received any type of systemic anticancer antibody (including investigational 
antibody) ≤4 weeks before randomization.
13. Has received prior radiotherapy ≤2 weeks prior to first dose of study intervention. 
Participants must have recovered from all radiation-related toxicities and not require 
corticosteroids. A 1-week washout is required for palliative radiation (≤2 weeks of 
radiotherapy) to non-CNS disease.
14. Has had major surgery ≤3 weeks prior to first dose of study intervention. Note: Adequate 
wound healing after major surgery must be assessed clinically, independent of time 
elapsed for eligibility.
15. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (eg, 
bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the 
duration of the study.
Note: A current list of strong/moderate inducers of CYP3A4 can be found at the following 
website:
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
Prior/Concurrent Clinical Study Experience
16. Is currently participating in a study of an investigational agent or is currently using an 
investigational device.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
17. Has an active infection requiring systemic therapy.
18. Has active TB.
19. Has a diagnosis of immunodeficiency.
20. Has a known history of HIV infection.
08CHFV

PRODUCT: MK-6482  
56
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Note: Testing for HIV at screening is only required if mandated by local health authority. 
Refer to Appendix 7 for country-specific requirements.
21. Has a known history of HBV (defined as HBsAg reactive) or known active HCV (defined 
as HCV RNA [qualitative] is detected) infection.
Note: Testing for HBV and HCV is only required if mandated by local health authority.
Other Exclusions
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, or is not the best interest of the participant to participate, 
in the opinion of the treating investigator.
5.3
Lifestyle Considerations
Meals and Dietary Restrictions
Participants should avoid grapefruit, grapefruit juice, Seville oranges, Seville orange juice, 
and St. John’s Wort (tablet or tea) while receiving study intervention. Otherwise, participants 
should maintain a normal diet unless modifications are required to manage an AE such as
diarrhea, nausea, or vomiting.
Tobacco Use
Participants should discuss tobacco use with their study physician as it is important to 
understand the pulmonary and cardiac health of study participants. It is not known whether 
prior tobacco use will impact the incidence of hypoxia, an Event of Clinical Interest for 
belzutifan.
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.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention will not be replaced.
08CHFV

PRODUCT: MK-6482  
57
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
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 2.
08CHFV

PRODUCT: MK-6482  
58
PROTOCOL/AMENDMENT NO.: 013-02
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Table 2
Study Interventions
Arm Name
Arm Type
Inter-
vention 
Name
Inter-
vention 
Type
Dose 
Formula-
tion
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen /
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
Belzutifan
120 mg
Experimental
Belzutifan
Drug
Tablet
40 mg 
tablet
120 mg
Oral
QD
Test Product
IMP
Central
Belzutifan 
200 mg
Experimental
Belzutifan
Drug
Tablet
40 mg
tablet
200 mg
Oral
QD
Test Product
IMP
Central
NIMP/AxMP=noninvestigational/auxiliary medicinal product; QD=once daily.
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
08CHFV

PRODUCT:  MK-6482  
59
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
Dose Preparation
Belzutifan tablets are supplied by the Sponsor as an immediate-release tablet in 1 dose 
strength, 40 mg, for oral administration.
The 40-mg strength tablets will be supplied in HDPE bottles with induction-seal liners and a 
child-resistant closure.
The Pharmacy Manual contains additional information.
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).
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.
08CHFV

PRODUCT:  MK-6482  
60
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
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
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 120 mg QD 
belzutifan study intervention and 200 mg QD belzutifan study intervention, respectively.
Stratification
Randomization will be stratified by the following factors:

IMDC prognostic scores [Cella, D. 2011] [Heng, D. Y., et al 2013]: 0 vs 1-2 vs 3-6

Number of prior TKI therapies for advanced RCC: 0 vs 1 vs 2-3
The IMDC prognostic factors are the following:

Clinical Risk Factors
o
Low KPS score (<80%) [Karnofsky, D. A., et al 1948]
o
Time from diagnosis to initiation of first-line treatment <1 year

Laboratory Risk Factors
o
Low hemoglobin (<LLN)
o
High corrected serum calcium (>ULN)
o
High neutrophils (>ULN)
o
High levels of platelets (>ULN)
Prognosis is based on the number of IMDC factors present and determined as follows:

Favorable prognosis: 0 risk factors

Intermediate prognosis: 1-2 risk factors

Poor prognosis: ≥3 risk factors
The most recent evaluations used to establish eligibility should be used to determine the 
IMDC category for stratification.
08CHFV

PRODUCT:  MK-6482  
61
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the study intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment for >28 days require consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
The investigator or their designated and qualified representatives will dispense study 
intervention only to participants enrolled in the study in accordance with the protocol. The 
study intervention must not be used for reasons other than that described in the protocol.
Participants should be given clear instructions on how and when to take their study 
intervention. Participants will self-administer belzutifan, except at on Day 1 of Weeks 1, 3, 
and 5 when belzutifan dosing will occur during the clinic visit.
All participants must return their bottle(s)/packages of belzutifan at the appropriate scheduled 
visit, when a new bottle/package will be dispensed. Participants will be instructed to notify 
study site personnel of missed doses.
Study site staff will make tablet counts at clinic when tablets are returned, the remaining 
tablets will not be returned to the participant, but will be retained by the investigative site 
until reconciliation is completed by the study monitor.
Compliance should be based on participant reporting and confirmed by tablet count where 
possible. Issues with compliance should be discussed with the participant and addressed as 
deemed appropriate by the investigator.
Participants who fail to comply with the dosing requirements of the study may be withdrawn 
from the study.
6.5
Concomitant Therapy
All concomitant medications received within 28 days before the first dose of study 
intervention and up to 30 days after the last dose of study intervention will be recorded. All 
concomitant medications administered during SAEs or ECIs are to be recorded. SAEs and 
ECIs are defined in Section 8.4.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, blood transfusions, supplemental oxygen, 
and IV medications and fluids. If changes occur during the study period, documentation of 
drug dosage, frequency, route, and date will also be included on the eCRF.
08CHFV

PRODUCT:  MK-6482  
62
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
In vitro and physiologically based PK modeling results indicated that belzutifan may be a 
weak inducer of CYP3A4 enzyme. Belzutifan may, therefore, decrease the exposure of 
concomitant medications that are mainly metabolized by CYP3A4; however, the magnitude 
and clinical relevance of these effects is not clear. Thus, participants taking medications 
metabolized by CYP3A4 with narrow therapeutic index should be monitored carefully for 
potential decreases in drug effect. 
Belzutifan exposures may increase with strong CYP3A4 inhibitors in certain subpopulations 
of participants who have poor metabolizer phenotypes for both UGT2B17 and CYP2C19
enzymes; however, the clinical relevance of these effects is not clear.
Prohibited Concomitant Medications
Medications or vaccinations specifically prohibited in the exclusion criteria (Section 5.2) are 
not allowed during screening and during the study intervention phase of the ongoing study, 
unless noted below. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor 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, the Sponsor, and the 
participant.
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):
1. Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol.
2. Investigational agents other than belzutifan.
3. Radiation therapy for disease control.
•
Note: Palliative radiation therapy to a symptomatic nontarget lesion or to the brain 
is allowed after Sponsor consultation.
4. As a precaution, it is recommended that strong inhibitors of CYP3A4 be avoided in 
participants receiving belzutifan If it is not possible to avoid strong inhibitors of 
CYP3A4, careful monitoring should be applied for enhanced drug effect with
belzutifan.
Note: A current list of strong/moderate inhibitors of CYP3A4 can be found at the 
following website:
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
08CHFV

PRODUCT:  MK-6482  
63
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
5. Chronic use of strong or moderate inducers of CYP3A4.
Note: A current list of strong/moderate inducers of CYP3A4 can be found at the 
following website:
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
There are no prohibited therapies during the Posttreatment Phase.
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
6.6
Dose Modification
Guidelines for dose modification for belzutifan are listed in Table 3. Specific dose reduction 
levels are listed in Table 4 for the 120 mg QD starting dose and Table 5 for the 200 mg QD 
starting dose.
The following should be taken into consideration in decisions regarding dose modifications 
(reductions or interruption):

As a general approach, all AEs should be managed with supportive care at the earliest 
signs of toxicity if considered related to belzutifan treatment. Should this be 
ineffective, dose reductions or interruptions are to be considered to prevent worsening 
of toxicity.

Dose reductions and/or interruptions, at any time while on study, should be 
implemented for unacceptable toxicity.

Dose modifications or interruptions may also occur in the setting of lower grade 
toxicity than defined in Table 3, if the investigator feels it is in the interest of a 
participant’s safety and will optimize drug tolerability.

Interruption of belzutifan treatment for AEs may occur at any time per investigator 
discretion. An interruption for >28 days will require Sponsor approval before 
treatment can be resumed.
The AE profile of belzutifan indicates that anemia and hypoxia have been associated with 
belzutifan treatment. Guidelines for the management of anemia and hypoxia are provided in 
Section 6.6.1.1 and Section 6.6.1.2, respectively. ECIs for belzutifan and guidelines for 
reporting these AEs as ECIs are provided in Section 8.4.7. Please refer to the ECI Guidance 
document for additional practice guidelines and management recommendations for AEs 
potentially related to belzutifan treatment.
08CHFV

PRODUCT:  MK-6482  
64
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Table 3
Dose Modification Guidelines for Belzutifan (MK-6482)-related Toxicities
Belzutifan (MK-6482)-Related Toxicity
Action
Anemia

Grade 4 anemia 

1st episode: Hold belzutifan. Once toxicity 
has resolved to ≤Grade 2 or baseline, dose 
reduce belzutifan by 1 level

2nd episode: Permanently discontinue 
belzutifan
Neutropenia/Febrile 
neutropenia

Grade 3 febrile neutropenia 
(ANC <1000/mm3 with a 
single temperature of >38.3 
degrees C [101 degrees F] or 
a sustained temperature of 
≥38 degrees C [100.4 
degrees F] for more than 1
hour), or

Grade 4 neutropenia for >5 
days

1st and 2nd episodes: Hold belzutifan. Once 
toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by 1 level

3rd episode: Permanently discontinue 
belzutifan

Grade 4 febrile neutropenia

Permanently discontinue belzutifan
Thrombocytopenia

Grade 3 thrombocytopenia 
with bleeding

1st and 2nd episodes: Hold belzutifan. Once 
toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by 1 level

3rd episode: Permanently discontinue 
belzutifan

Grade 4 thrombocytopenia 

1st episode: Hold belzutifan. Once toxicity 
has resolved to ≤Grade 2 or baseline, dose 
reduce belzutifan by 1 level

2nd episode: Permanently discontinue 
belzutifan
Hypoxia
or
Dyspnea

Grade 3 dyspnea

Grade 3 hypoxia 
(asymptomatic), belzutifan
may be continued at the 
discretion of the investigator

Grade 3 hypoxia 
(symptomatic)

1st and 2nd episodes: Hold belzutifan. Once 
toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by 1 level

3rd episode: Permanently discontinue 
belzutifan

Grade 4 dyspnea

Grade 4 hypoxia 

Permanently discontinue belzutifan
08CHFV

PRODUCT:  MK-6482  
65
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Belzutifan (MK-6482)-Related Toxicity
Action
Gastrointestinal

Grade 3 or 4 nausea, 
vomiting, or diarrhea if 
persistent for >48 hours 
despite optimal antiemetic or 
antidiarrheal therapy

1st and 2nd episodes: Hold belzutifan. Once 
toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by 1 level

3rd episode: Permanently discontinue 
belzutifan
Hepatic

Grade 3 increase in AST 
and/or ALT levels, if 
confirmed on repeat testing 
within 48 hours

1st episode: Hold belzutifan. Once toxicity 
has resolved to ≤Grade 2 or baseline, dose 
reduce belzutifan by 1 level

2nd episode: Permanently discontinue 
belzutifan

Grade 4 increase in AST 
and/or ALT levels, if 
confirmed on repeat testing 
within 48 hours, or

Grade 3 or 4 increase in AST 
and/or ALT levels if 
accompanied by a Grade 2 
increase in bilirubin level 
and an alkaline phosphatase 
level <2 × ULN

Permanently discontinue belzutifan
Cardiovascular, 
vascular, or 
thrombotic

Grade 3 or 4 cardiovascular, 
vascular or thrombotic 
events

Permanently discontinue belzutifan
Other Non-
Laboratory 
Toxicities

Any other nonlaboratory
Grade 3 toxicity

1st and 2nd episodes: Hold belzutifan. Once 
toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by 1 level

3rd episode: Permanently discontinue 
belzutifan

Any other nonlaboratory
Grade 4 toxicity

Permanently discontinue belzutifan
Other Laboratory 
Toxicities

Grade 3 or 4 laboratory 
toxicity that does not resolve 
within 48 hours and is 
considered clinically 
significant by the 
investigator

Permanently discontinue belzutifan
Abbreviations: ANC=absolute neutrophil count; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; ULN=upper limit of normal.
Re-escalation to the next higher dose level may be permitted after Sponsor consultation for a participant who
has resumed belzutifan at a given dose level for at least 28 days and original toxicity has not reappeared. Re-
escalation of belzutifan will not be permitted for events of Grade 3 symptomatic hypoxia.
If Action is “dose reduce by 1 dose level” and participant is already at dose level -2 when a toxicity occurred, 
belzutifan should be permanently discontinued.
08CHFV

PRODUCT:  MK-6482  
66
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Table 4
Belzutifan Dose Levels – 120 mg QD Starting Dose
Belzutifan Dose Levels
Dose Level 
Dose 
Starting Dose 
120 mg QD
-1  
80 mg QD
-2 
40 mg QD 
QD=once daily.
Table 5
Belzutifan Dose Levels –200 mg QD Starting Dose
Belzutifan Dose Levels
Dose Level 
Dose 
Starting Dose
200 mg QD
-1
120 mg QD
-2
80 mg QD
QD=once daily.
Management of Anemia
Participants enrolled in the study will have a baseline hemoglobin level of ≥10 g/dL (no 
transfusion or growth factor support within 4 weeks of the hematology screening 
assessment). During the study, participants should undergo hematology assessments at each 
clinic visit (Appendix 2) to monitor their hemoglobin and hematocrit to detect onset or 
worsening of anemia. If clinically indicated, anemia will be appropriately managed by the 
investigator. Given that decreased EPO is the etiology of potential anemia with belzutifan
treatment, EPO replacement is an effective management strategy for participants who may 
develop and subsequently require intervention for belzutifan-induced anemia. EPO levels 
will be measured at baseline in all participants and will be measured before initiating EPO 
replacement therapy.
Management of Hypoxia
Per the NCI CTCAE v5, hypoxia is defined as pulse oximetry finding of <88%. Participants 
enrolled in the study will have a baseline pulse oximetry of at least 92% at rest and will not 
be in need of intermittent or chronic supplemental oxygen. During the study, participants 
undergo pulse oximetry monitoring at each clinic visit (Section 1.3). If clinically indicated, 
management of hypoxia should include treating any underlying acute medical conditions and 
providing supplemental oxygen therapy as necessary.
08CHFV

PRODUCT:  MK-6482  
67
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
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
For studies using controlled substances, all Federal, State, Province, Country, etc., 
regulations must be adhered to in regard to their shipping, storage, handling, and dispensing
of controlled substances. Additionally, the investigator should have the appropriate 
controlled drug license(s) as mandated by Federal, State, Province, Country, etc., laws in 
which the study is being conducted.
Study Site Retention Samples
Not applicable.
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 prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and 
Section 8.11.3.
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. Specific details regarding procedures to be 
08CHFV

PRODUCT:  MK-6482  
68
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
performed at study intervention discontinuation are provided in Section 8.1.9 and 
Section 8.11.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Documented radiographic disease progression per RECIST 1.1.
Note: Participants may be permitted to continue treatment beyond disease progression, 
after Sponsor consultation, and the participant is tolerating study intervention (Sections 
4.1 and 8.2.1.2).
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment. Exceptions to second malignancy include basal 
cell carcinoma of the skin, squamous cell carcinoma of the skin, new nonulcerated 
primary melanoma <1 mm in depth with no nodal involvement, or carcinoma in situ (eg, 
breast carcinoma, cervical cancer in situ) that undergo potentially curative therapy. 
Exceptions should be discussed with the Sponsor before continuing therapy.
•
Unacceptable AEs or toxicities (Section 6.6).
•
The participant interrupts study intervention administration for >28 consecutive days
without Sponsor consultation. Participants may continue on study on Sponsor 
consultation.
•
Required use of prohibited medications.
•
Intercurrent illness that prevents further administration of study treatment.
•
Noncompliance with study treatment or procedure requirements.
•
The participant has a confirmed positive serum or urine pregnancy test.
•
Sponsor discontinuation of study.
As described in Sections 4.1 and 8.2.1.2, treatment may continue beyond investigator-
assessed disease progression, but requires Sponsor consultation and approval. If approved by 
the Sponsor, continued participation requires additional consent (Section 8.1.1). Participants 
who continue treatment beyond investigator-assessed disease progression will continue with 
all protocol-specified assessments and procedures.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
08CHFV

PRODUCT:  MK-6482  
69
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, 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.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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.
08CHFV

PRODUCT:  MK-6482  
70
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met 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.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. 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 consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
Treatment beyond disease progression requires Sponsor consultation and approval. If 
approved by the Sponsor, the participant or their legally acceptable representative will be 
08CHFV

PRODUCT:  MK-6482  
71
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
asked to provide documented informed consent at the point of initial radiographic disease 
progression.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to future biomedical research. A copy of the 
informed consent will be given to the participant.
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.
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 identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
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. Medical history should 
include information about alcohol and tobacco use, history of cardiac and respiratory 
disease/abnormal conditions, and surgical history. Details regarding the disease for which the 
participant has enrolled in this study will be recorded separately and not listed as medical 
history.
08CHFV

PRODUCT:  MK-6482  
72
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
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 the first dose of study intervention. 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 and up to 30 days after the last dose of study intervention. Concomitant 
medications administered 30 days after the last dose of study intervention should be recorded 
for SAEs and ECIs as defined in Section 8.4.7. In the posttreatment follow-up period, 
information about new anticancer therapies will be collected.
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 prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Study Intervention Administration
Study intervention should begin on the date of randomization, but can be ≤3 days after
randomization. Every effort should be made to ensure the participants receive the first dose 
of study intervention on the day of randomization.
Study intervention may be administered at home except on clinic visit days on Day 1 of 
Weeks 1, 3, and 5. Study intervention on these days will occur in the clinic after completion 
of blood collection. On the Day 1 of Week 1 and Week 3 visits, study drug should be taken 
fasted (at least 2 hours after a meal; Section 8.6.1) and food should be withheld for 1 hour 
postdose.
08CHFV

PRODUCT:  MK-6482  
73
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
8.1.8.1
Timing of Dose Administration
Participants should be given clear instructions on how and when to take their study 
intervention. Participants in the 120 mg QD belzutifan dose arm will take three 40-mg tablets 
of belzutifan orally QD, and participants in the 200 mg QD belzutifan dose arm will take five 
40-mg tablets of belzutifan orally QD, with doses taken at approximately the same time of 
day. To ensure appropriate PK sample collection, it is recommended that study intervention 
be taken in the morning for the first month of dosing (ie, until Week 5 Day 1). Belzutifan can 
be taken without regard to food, except when it should be taken fasted on Day 1 of Week 1 
and Week 3 as described in Section 8.6.1.
Missed doses may be made up if taken within 6 hours after the scheduled administration 
time. Participants who vomit after study drug administration should not retake that study 
drug dose, but should resume taking study drug with the next scheduled dose.
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to 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 8.11.3.
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 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
08CHFV

PRODUCT:  MK-6482  
74
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
Tissue Collection
A tumor specimen for biomarker assessment will be provided or collected before
randomization in the study.
A core or excision biopsy of a tumor lesion (inclusive of fresh tissue collected after receiving 
study intervention) is preferred. Submission of either FFPE tumor blocks or unstained slides 
is acceptable; FFPE tumor blocks are preferred.
Participants must sign the main study ICF before submitting existing tissue samples and/or 
undergoing a new biopsy.
 
 
 
 
Details for the collection, processing, storage and shipment of tissue samples can be found in 
the study laboratory manual.
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.
8.2
Efficacy Assessments
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.
The process for scan collection and transmission to the iCRO can be found in the SIM. In 
general, scans should include the chest, abdomen, and pelvis. Tumor scan is strongly 
preferred to be acquired by CT. For the abdomen and pelvis, contrast-enhanced MRI may be 
used when CT with iodinated contrast is contraindicated, or when mandated by local 
practice. Contrast-enhanced MRI is the strongly preferred modality for scan of the brain. 
Scan of any anatomy that shows disease either at screening or in subsequent evaluations will 
CCI
08CHFV

PRODUCT:  MK-6482  
75
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
be required and should be submitted to the iCRO. The same scan technique regarding 
modality, ideally the same scanner, and the use of contrast should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the assessment of response or progression based 
on scans.
Note: for the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer located at the site or at an offsite 
facility.
All scheduled scans for all study participants from the sites will be submitted to the iCRO. In 
addition, a scan that is obtained at an unscheduled time point, for any reason (including 
suspicion of progression or other clinical reason), should also be submitted to the iCRO if it 
shows progression, or if it is used to support a response assessment.
8.2.1.1
Initial Tumor Imaging
Initial tumor scans at screening must be performed ≤28 days before randomization. The 
screening scans must be submitted to the iCRO for confirmation of measurable disease per 
RECIST 1.1 for eligibility before randomization.
Tumor scans performed as part of routine clinical management is acceptable for use as 
screening tumor scans if it is of diagnostic quality, performed ≤28 days before randomization
and can be assessed by the iCRO.
Tumor scans at screening includes the following:

CT (preferred) or MRI of the abdomen and pelvis, must include IV contrast

CT of the chest

Bone scan is required for all participants at screening. Bone scans are not required to 
be repeated at screening if performed ≤42 days before randomization. Additionally, 
X-ray or MRI may also be taken for symptomatic sites even if bone scan is negative 
and there is clinical suspicion for metastatic disease.

Brain scan is required at screening for those participants with known brain metastases 
at baseline (ie, to confirm stability) or in those who are clinically symptomatic. MRI 
is preferred; however, CT imaging will be acceptable, if MRI is medically 
contraindicated.
8.2.1.2
Tumor Imaging During the Study
The first on-study scan assessment should be performed at Week 9 Day 1 (±7 days) from the 
date of randomization. Subsequent tumor scans should be performed Q8W (±7 days) through 
Week 49, or more frequently if clinically indicated. After Week 49 (±7 days), participants 
who remain on study intervention will have scans performed Q12W (±7 days). The scan visit 
08CHFV

PRODUCT:  MK-6482  
76
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
window is ±14 days after Week 109. Scan timing should follow calendar days from the date 
of randomization and should not be adjusted for delays in study intervention. Scans should 
continue to be performed until disease progression is determined by the investigator (unless 
the investigator elects to continue treatment after Sponsor approval [Section 7.1]), or until
any of these conditions are met:

The initiation of new anticancer treatment

Withdrawal of consent

Pregnancy

Death

The end of the study
whichever occurs first. All supplemental scans must be submitted to the iCRO.
Objective response should be confirmed by a repeat scan assessment. Tumor scans to 
confirm PR or CR should be performed at least 4 weeks (at least 28 days) after the first 
indication of a response is observed. Participants will then return to regular scheduled scans, 
starting with the next scheduled scan time point. Participants who receive additional scans for 
confirmation do not need to undergo the next scheduled tumor scan if it is less than 4 weeks 
(<28 days) later; tumor scans may resume at the subsequent scheduled scan time point. 
If a participant has a positive baseline bone scan at screening, after randomization, bone 
scans will be performed at Week 17 (±7 days) and should continue to be performed Q16W 
(±7 days) through Week 49, then subsequently Q24W (±7 days; ±14 days after Week 109) 
until disease progression is determined by the investigator (unless the investigator elects to 
continue treatment after Sponsor approval [Section 7.1]). The timing of scans assessments 
should follow calendar days and should not be adjusted for delays in study intervention. 
Bone scans must be performed for confirmation of CR for participants with a positive bone 
scan at baseline.
After randomization, brain scans should be performed as clinically indicated and to confirm a 
CR in participants with brain metastases at baseline.
Participants who have disease progression will discontinue study intervention (unless the 
investigator elects to continue treatment after Sponsor approval [Section 7.1 and Section 
8.2.1.3]). Participants who continue treatment beyond disease progression must sign a 
separate ICF and will continue with all protocol-specified assessments and procedures.
8.2.1.3
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by the investigator as the primary measure for assessment of tumor 
response, date of disease progression, and as a basis for all protocol guidelines related to 
08CHFV

PRODUCT:  MK-6482  
77
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
disease status (eg, discontinuation of study intervention). If disease progression is established 
by the investigator, the process continues as follows:

Investigator judgment will determine action

If the participant is clinically stable and study intervention is to continue, 
communication with the sponsor is required and a reconsent addendum must be 
signed. In addition, the following are to occur:

Continue scans per protocol schedule (the next scheduled scan should be ≥4 
weeks from the most recent scan acquired)

Send scans to iCRO
For the purpose of this decision process, lack of clinical stability is defined as:

Unacceptable toxicity

Clinical signs or symptoms indicating clinically significant disease progression

Decline in performance status

Rapid disease progression or threat to vital organs or critical anatomical sites (eg, 
CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention.
End of Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor scans should be performed at the 
time of treatment discontinuation (±4 week window). If previous scan was obtained ≤4 
weeks (28 days) before the date of discontinuation, then scans at treatment discontinuation is 
not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor scan.
Participants who discontinue study treatment for reasons other than disease progression
should continue with scan assessments per the protocol-defined schedule until one of the 
following conditions are met:

Disease progression

The start of a new anticancer treatment

Pregnancy

Death

Withdrawal of consent
08CHFV

PRODUCT:  MK-6482  
78
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022

The end of the study
whichever occurs first. For participants who discontinue for reasons other than disease 
progression, scans should be performed using the same imaging schedule used while on 
treatment calculated from the randomization date (see Section 8.2.1) until disease 
progression, the initiation of new anticancer treatment, withdrawal of consent, pregnancy, 
death, or notification by the Sponsor, whichever occurs first.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the laboratory 
manual.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard and at the time 
points specified in the SoA (Section 1.3). Height (screening only) 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.
Vital Signs
The investigator or qualified designee will measure vital signs at the time points specified in 
the SoA (Section 1.3) including weight, systolic and diastolic blood pressure, respiratory rate, 
heart rate, and pulse oximetry. Height will be measured at screening only.
Electrocardiograms
A standard 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) as outlined in the SoA (Section 1.3). 
Clinically significant abnormal findings at screening should be recorded as medical history. 
QTc will be calculated locally using Fridericia’s formula. Additional ECGs should be 
performed when clinically necessary.
08CHFV

PRODUCT:  MK-6482  
79
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
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 SoA and local guidelines.
•
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).
•
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.
KPS and ECOG Performance Status
The investigator or qualified designee will assess KPS and ECOG performance status at 
screening (≤10 days before the first dose of study intervention) [Karnofsky, D. A., et al 1948] 
[Oken, M.M., et al 1982]. The investigator or qualified designee will assess ECOG 
performance status as listed in the SoA (Section 1.3). ECOG performance status will be 
assessed before the administration of the study intervention or study-related procedures.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
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 remain responsible for following up AEs, SAEs, and other reportable safety 
08CHFV

PRODUCT:  MK-6482  
80
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
events for outcome according to Section 8.4.3. Investigators need to document if an SAE was 
associated with a medication error, misuse, or abuse.
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.
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 following cessation 
of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention randomization through 90 
days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention  
through the time required to eliminate systemic exposure after cessation of study 
intervention as described in Section 5.1 and Appendix 2, or 30 days following 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 of 
the time period 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 he/she 
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.
08CHFV

PRODUCT:  MK-6482  
81
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Table 6
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing 
to outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any protocol-
specified intervention (eg, 
procedure, washout or 
run-in treatment including 
placebo run-in)
Exception: A positive 
pregnancy test at the time 
of initial screening is not 
a reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 24 
hours of 
learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
ECI (do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
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.
08CHFV

PRODUCT:  MK-6482  
82
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
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.
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 towards 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 SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
08CHFV

PRODUCT:  MK-6482  
83
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that on review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
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: 

An overdose of Sponsor's product, as defined in Section 8.5.

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon 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).
Any ≥Grade 2 anemia/decreased hemoglobin.
Any ≥Grade 2 hypoxia.
Any ≥Grade 2 dyspnea.
Any ≥Grade 3 AE deemed related to belzutifan by the investigator, including 
laboratory abnormalities.
Any ≥Grade 4 AEs (all causality).
08CHFV

PRODUCT:  MK-6482  
84
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
8.5
Treatment of Overdose
An overdose will be defined as any dose greater than 240 mg QD. No specific information is 
available on the treatment of overdose of belzutifan. In the event of overdose, belzutifan
should be interrupted and the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
Blood Collection for Plasma Belzutifan
 
 
 
 
 
 
 
 
 
 
 
8.7
Pharmacodynamics
Blood samples for analysis of pharmacodynamic effects will be collected as listed in the SoA
(Section 1.3). Pharmacodynamic biomarkers to be assessed include, but are not limited to, 
levels of EPO.
Details for the collection, processing, storage, and shipment of samples for the determination 
of pharmacodynamic effects and biomarker assessments can be found in the study laboratory 
manual.
8.8
 
 
CCI
CCI
08CHFV

PRODUCT:  MK-6482  
85
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022

 
 
 
 
 
8.9
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
Leftover specimens as listed in Section 8.8.
8.10
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from the 
time of treatment 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.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
Screening
From -28 days to -1 day before randomization, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.
Documented informed consent must be obtained 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 
CCI
CCI
08CHFV

PRODUCT:  MK-6482  
86
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
specified time frame. Screening procedures are to be completed ≤28 days before the first 
dose of study intervention except for the following:

Laboratory tests are to be performed ≤10 days before the first dose of study 
intervention. An exception is HIV (if required by local health authority) and hepatitis 
testing which may be performed up to 28 days before the first dose of study 
intervention. Refer to Appendix 7 for country-specific requirements.

Evaluation of KPS and ECOG is to be performed ≤10 days before the first dose of 
study intervention.

WOCBP require negative test before randomization. If more than 24 hours have 
elapsed before first dose of study intervention, another pregnancy test is required 
before starting study intervention. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required (performed by the local study site 
laboratory).

Screening images are to be captured within 28 days before randomization.
Participants may be rescreened once 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.
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1. Assessments/procedures will be performed before the 
administration of study intervention.
Poststudy
8.11.3.1
Posttreatment Safety Follow-up Visit
The mandatory Safety Follow-up Visit will be conducted approximately 30 days after the last 
dose of study intervention or before the initiation of a new anticancer treatment, whichever 
comes first.
8.11.3.2
Imaging Follow-up
Participants who discontinue study treatment for reasons other than disease progression will
continue with imaging assessments per the protocol-defined schedule until: 1) disease 
progression, 2) initiation of a new anticancer treatment, 3) death, 4) pregnancy, 5) 
withdrawal of consent, or 6) end of the study, whichever occurs first. Tumor imaging will be 
performed Q8W (±7 days) through Week 49, or more frequently if clinically indicated. After 
08CHFV

PRODUCT:  MK-6482  
87
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Week 49 (±7 days), participants who remain on study intervention will have imaging 
performed Q12W (±7 days). The imaging visit window is ±14 days after Week 109.
8.11.3.3
Survival Follow-up
Participants who experience documented disease progression or start a new anticancer 
therapy, will move into the Survival Follow-up Phase and will be followed for survival (vital 
status) (in-person visit, telephone contact, chart review, etc.) approximately Q12W from the 
treatment discontinuation visit or from Imaging Follow-up discontinuation. Every effort 
should be made to assess for vital status until death, withdrawal of consent, or the end of the 
study, whichever occurs first. Information regarding initiation of a new anticancer treatment
will also be collected.
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 course of the study by the 
Sponsor. For example, updated vital status may be requested before, but not limited to an IA 
and/or FA. Upon Sponsor notification, all participants who do not/will not have a scheduled 
study visit or study contact during the Sponsor-defined time period will be contacted for their 
vital status.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but before final database lock, will be 
documented in a sSAP and referenced in the CSR for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A randomized, open-label, Phase 2 study of 120 mg QD of belzutifan
compared with 200 mg QD of belzutifan in participants with advanced 
RCC after prior therapy
Treatment Assignment
Participants will be randomly assigned in a 1:1 ratio to receive either 
belzutifan at 120 mg QD or belzutifan at 200 mg QD.
Stratification factors are as follows:

IMDC prognostic scores: 0 vs 1-2 vs 3-6

Number of prior TKI therapies for advanced RCC: 0 vs 1 vs 2-3
Analysis Populations
Efficacy: ITT
Safety: APaT
Primary Endpoints

ORR
08CHFV

PRODUCT:  MK-6482  
88
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Secondary Endpoints

PFS

DOR

CBR

OS

AEs and discontinuations due to AEs
Statistical Methods for
Key Efficacy Analyses
The primary hypotheses comparing the 120 mg QD dose of belzutifan to 
the 200 mg QD dose of belzutifan with respect to ORR will be evaluated 
using the stratified Miettinen and Nurminen method with strata weighted 
by sample size. PFS and OS will be summarized within each treatment 
group using the Kaplan-Meier method. For PFS and OS, the HR will be 
estimated using a stratified Cox regression model.
Statistical Methods for
Key Safety Analyses
For analyses in which 95% CIs will be provided for between-treatment 
differences in the percentage of participants with events, these analyses 
will be performed using the Miettinen and Nurminen method [Miettinen, 
O. and Nurminen, M. 1985].
Interim Analyses
No formal interim analysis is planned.
Final analysis will be performed at least 6 months after the last 
participant is randomized.
Multiplicity
No multiplicity adjustment will be applied.
Sample Size and Power
The study will randomize approximately 150 participants in a 1:1 ratio to 
the belzutifan 120 mg QD and belzutifan 200 mg QD arms. With 75 
participants at each dose level, the study has ~83% power to detect a 
20% difference in ORR between the 2 doses at the 5% type I error rate 
(one-sided) assuming that the ORR in the lower dose arm is 24%.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IRT.
Although this is an open-label study, analyses or summaries generated by randomized 
treatment assignment, or actual treatment received will be limited and documented. Further 
documentation will be provided in the sSAP.
An independent radiologist(s) will perform the central imaging review without knowledge of 
treatment assignments.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
08CHFV

PRODUCT:  MK-6482  
89
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
9.4
Analysis Endpoints
Efficacy Endpoints
Primary:
ORR – ORR is defined as the proportion of participants in the analysis population who have 
a best overall response of either confirmed CR or PR per RECIST 1.1 as assessed by BICR.
Secondary:
PFS – PFS is defined as the time from randomization to the first documented disease 
progression based on RECIST 1.1 by BICR or death due to any cause, whichever occurs first.
DOR – For participants who showed CR or PR, DOR is defined as the time from the first 
documented evidence of confirmed CR or PR until the first documented date of disease 
progression or death due to any cause, whichever occurs first. Responses and progression 
will be assessed using RECIST 1.1 by BICR.
CBR – CBR is defined as the percentage of participants who have achieved SD of ≥6 months 
or CR or PR based on assessments by BICR per RECIST 1.1.
OS – OS is defined as the time from randomization to death due to any cause.
Safety Endpoints
A description of safety endpoint assessment is provided in Section 4.2.1.2. Assessments 
include, but not limited to, the incidence of, causality of, and outcome of AEs/SAEs; and 
changes in laboratory values.
9.5
Analysis Populations
Efficacy Analysis Population
The ITT population will serve as the population for primary efficacy analyses. All 
randomized participants will be included in this population. Participants will be included in 
the treatment arm to which they are randomized.
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who received at least 1 dose of study 
treatment. Participants will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the APaT population.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
treatment is required for inclusion in the analysis of each specific parameter. To assess
change from baseline, a baseline measurement is also required.
08CHFV

PRODUCT:  MK-6482  
90
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
9.6
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP. If there 
are a small number of responses/events in 1 or more strata, for the purpose of analysis strata 
will be combined to ensure sufficient number of responses/events in each stratum. Details 
regarding the combining of strata will be specified in the sSAP.
9.6.1.1
Objective Response Rate
The stratified Miettinen and Nurminen’s method will be used for comparison of the ORR 
between the 2 belzutifan doses. The difference in ORR and its 95% CI from the stratified 
Miettinen and Nurminen’s method with strata weighting by sample size will be reported. The 
stratification factors used for randomization (See Section 6.3.2) will be applied to the 
analysis.
Sensitivity analyses will be performed to assess ORR based on investigator’s assessment.
9.6.1.2
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment arm. A stratified Cox proportional hazard model with Efron’s method of tie 
handling will be used to assess the magnitude of the treatment difference (ie, the HR) 
between the treatment arms. The HR and its 95% CI from the stratified Cox model with 
Efron’s method of tie handling and with a single treatment covariate will be reported. The 
stratification factors used for randomization (Section 6.3.2) will be applied to the stratified 
Cox model.
Since disease progression is assessed periodically, disease progression can occur any time in 
the time interval between the last assessment where disease progression was not documented 
and the assessment when disease progression is documented. The true date of disease 
progression will be approximated by the earlier of the date of the first assessment at which 
disease progression is objectively documented per RECIST 1.1 by BICR and the date of 
death. Death is always considered a confirmed disease progression event.
For the primary analysis, any participant who experiences an event (disease progression or 
death) immediately after 2 or more missed disease assessments will be censored at the last 
disease assessment before the missed visits. In addition, any participant who initiates new 
anticancer therapy will be censored at the last disease assessment before the initiation of new 
anticancer therapy. Participants who do not start new anticancer therapy and who do not 
experience an event will be censored at the last disease assessment. If a participant meets 
multiple criteria for censoring, the censoring criterion that occurs earliest will be applied.
Sensitivity analyses will be performed for comparison of PFS based on investigator’s 
assessment.
08CHFV

PRODUCT:  MK-6482  
91
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Additional supportive PFS sensitivity analyses may be performed. Details of sensitivity 
analyses will be provided in the sSAP.
Table 7
Censoring Rules for PFS
Situation
Date of Progression/Death or Censoring
Disease progression or death documented 
after ≤1 missed disease assessment, and 
before new anticancer therapy, if any
Progressed at date of documented disease 
progression or death
Disease progression or death documented 
immediately after ≥2 consecutive missed 
disease assessments or after new anticancer 
therapy, if any
Censored at last disease assessment before
the earlier date of ≥2 consecutive missed disease 
assessments and new anticancer therapy, if any
No disease progression and no death; new 
anticancer treatment is not initiated
Censored at last disease assessment 
No disease progression and no death; new 
anticancer treatment is initiated
Censored at last disease assessment before new 
anticancer treatment
PFS=progression-free survival.
9.6.1.3
Duration of Response
If sample size permits, the nonparametric Kaplan-Meier method will be used to estimate the 
DOR curve in each treatment group; estimates of the percentage of participants still in 
response and 95% CIs at specific duration time points will be provided.
Sensitivity analyses will be performed to assess DOR based on investigator’s assessment.
Censoring rules for DOR are summarized in Table 8.
For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responding participants who are alive, have not progressed, 
have not initiated new anticancer treatment, have not been determined to be lost to follow-up, 
and have had a disease assessment within ~5 months of the data cutoff date are considered 
ongoing responders at the time of analysis. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied.
08CHFV

PRODUCT:  MK-6482  
92
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Table 8
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(Non-event)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment 
before new anticancer therapy 
initiated
Censor
(Non-event)
Death or progression immediately 
after ≥2 consecutive missed disease 
assessments or after new anticancer 
therapy, if any
Earlier date of last adequate disease 
assessment before ≥2 missed adequate 
disease assessments and new 
anticancer therapy, if any
Censor
(Non-event)
Death or progression after ≤1 missed 
disease assessments and before new 
anticancer therapy, if any
Disease progression or death
End of response
(Event)
DOR=duration of response.
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation of 
response.
9.6.1.4
Clinical Benefit Rate
The difference in CBR between the 2 belzutifan doses and its 95% CI from the stratified 
Miettinen and Nurminen’s method with strata weighting by sample size will be reported. The 
stratification factors used for randomization (See Section 6.3.2) will be applied to the 
analysis.
9.6.1.5
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the OS curve in each 
treatment arm. A stratified Cox proportional hazard model with Efron’s method of tie 
handling will be used to assess the magnitude of the treatment difference (ie, the HR) 
between the treatment arms. The HR and its 95% CI from the stratified Cox model with 
Efron’s method of tie handling and with a single treatment covariate will be reported. The 
stratification factors used for randomization (Section 6.3.2) will be applied to the stratified 
Cox model.
Participants without documented death at the time of analysis will be censored at the date the 
participant was last known to be alive.
9.6.1.6
Analysis Strategy for Key Efficacy Endpoints
A summary of the primary analysis strategy for the key efficacy endpoints is provided in
Table 9.
08CHFV

PRODUCT:  MK-6482  
93
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Table 9
Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical Method
Analysis 
Population
Missing data 
approach
Primary Endpoint
ORR

RECIST 1.1, BICR 
Testing and estimation:
stratified Miettinen and 
Nurminen method
ITT
Participants with 
missing data are 
considered 
nonresponders
Secondary Endpoints
DOR

RECIST 1.1, BICR
Summary statistics using 
Kaplan-Meier method
Responders in 
ITT population
Censored at last 
assessment date
PFS

RECIST 1.1, BICR

Estimation: Stratified 
Cox model with 
Efron’s tie handling 
method

Summary statistics 
using Kaplan-Meier 
method
ITT
Censored at last 
assessment date
CBR

RECIST 1.1, BICR 
Estimation:

Stratified Miettinen 
and Nurminen method
ITT
Participants with 
missing data are 
considered to be 
participants 
without CR, PR or 
SD
OS

Estimation: Stratified 
Cox model with 
Efron’s tie handling 
method

Summary statistics 
using Kaplan-Meier 
method
ITT
Censored at last 
date the 
participant was 
known to be alive
BICR=blinded independent central review; CBR=clinical benefit rate; CR=complete response; DOR=duration of 
response; ITT=intent-to-treat; ORR=objective response rate; CBR=clinical benefit rate; OS=overall survival; 
PFS=progression-free survival; PR=partial response; RECIST=Response Evaluation Criteria In Solid Tumors; SD=stable 
disease.   
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, ECG, laboratory tests, and vital signs.
The safety analysis will follow a tiered approach (Table 10). The tiers differ with respect to 
the analyses that will be performed. AEs (specific terms as well as system organ class terms) 
and events that meet predefined limits of change in laboratory and vital signs parameters are 
either prespecified as Tier-1 endpoints, or will be classified as belong to “Tier 2” or “Tier 3”, 
based on the number of events observed.
08CHFV

PRODUCT:  MK-6482  
94
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute Tier 1 safety 
endpoints that will be subject to inferential testing for statistical significance.
There are no known AEs associated with participants with RCC for which determination of a 
p-value is expected to impact the safety assessment. Therefore, there are no Tier 1 events for 
this protocol.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment group show
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 10% of participants was chosen for Tier 2 events because the population enrolled 
in this study is in critical condition and usually experiences various AEs of similar types 
regardless of treatment; events reported less frequently than 10% of participants would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of 
participants in 1 of the treatment groups),SAEs (≥5% of participants in 1 of the treatment 
groups), Grade 2 to 5 anemia/decreased hemoglobin (>0% of participants in 1 of the 
treatment groups), Grade 2 to 5 hypoxia (>0% of participants in 1 of the treatment groups), 
and Grade 2 to 5 dyspnea (>0% of participants in 1 of the treatment groups) will be 
considered Tier 2 endpoints. Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in safety 
review, not as a formal method for assessing the statistical significance of the between-group 
differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
Continuous measures such as changes from baseline in laboratory parameters, summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group in table format.
08CHFV

PRODUCT:  MK-6482  
95
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Table 10
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥10% of participants in one of the treatment 
groups)
X
X
Any serious AE (≥5% of participants in one of the 
treatment groups)
X
X
Any Grade 3 to 5 AE (≥5% of participants in one of 
the treatment groups)
X
X
Grade 2 to 5 anemia/decreased hemoglobin (>0% of 
participants in 1 of the treatment groups) 
X
X
Grade 2 to 5 hypoxia (>0% of participants in 1 of the 
treatment groups)
X
X
Grade 2 to 5 dyspnea (>0% of participants in 1 of the 
treatment groups)
X
X
Tier 3
AEs, Specific AEs, SOCs 
X
Discontinuation due to AE
X
Dose interruption due to AE
X
Change from baseline results (laboratory, ECGs, Vital 
Signs) 
X
AE=adverse event; ECG=electrocardiogram; SOC=system organ class; X=results will be provided.
Demographics and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants
screened and randomized and the primary reasons for screening failure and discontinuation
will be displayed. Demographic variables baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
No formal IA is planned.
Final analysis will be performed at least 6 months after the last participant is randomized.
9.8
Multiplicity
There will be no multiplicity adjustments.
08CHFV

PRODUCT:  MK-6482  
96
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
9.9
Sample Size and Power Calculations
The study will randomize approximately 150 participants in a 1:1 ratio to the belzutifan 120 
mg QD and belzutifan 200 mg QD arms. With 75 participants at each dose level, the study 
has ~83% power to detect a 20% difference in ORR between the 2 doses of belzutifan at the 
5% type I error rate (one-sided) assuming that the ORR in the lower dose arm is 24%. A 
p-value of 5% approximately corresponds to 12% observed difference in ORR.
The sample size and power calculations were performed using EAST 6.4 and gsDesign 3.6.1 
(R package).
9.10
Subgroup Analyses
The treatment effect of the primary endpoint will be estimated and/or plotted within each 
category of the following classification variables:

IMDC risk category [IMDC prognostic score] (favorable [0] vs intermediate [1-2] 
vs poor [3-6]; favorable [0] vs intermediate plus poor [1-6])

Number of prior TKI therapies: 0 vs 1 vs 2-3

Geographic region (North America vs Western Europe vs Rest of the World)

Age category (<65 vs ≥65 years)

Sex (male vs female)

Race (white vs non-white)

Number of prior lines of therapy (1 vs 2 vs 3)
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
For each participant, percent compliance will be calculated using the following formula:
For participants who are followed for the entire study period, the “Number of Days Should 
be on Therapy” is the total number of days from the first scheduled intervention day to the 
last scheduled intervention day. For participants who discontinue from the study 
permanently, the “Number of Days Should Be on Therapy” is the total number of days from 
the first scheduled intervention day to the last dose day.
08CHFV

PRODUCT:  MK-6482  
97
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Summary statistics will be provided on percent compliance by treatment group for the APaT 
population. Details of the calculations will be provided in the sSAP.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as number of days in which the participant 
receives the study intervention. Summary statistics will be provided on extent of exposure for 
the APaT population.
08CHFV

PRODUCT:  MK-6482  
98
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
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.
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 
08CHFV

PRODUCT:  MK-6482  
99
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
08CHFV

PRODUCT:  MK-6482  
100
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly 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.
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
08CHFV

PRODUCT:  MK-6482  
101
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
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 prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
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.
08CHFV

PRODUCT:  MK-6482  
102
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Committees Structure
10.1.4.1
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
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 International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
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, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
08CHFV

PRODUCT:  MK-6482  
103
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
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.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
08CHFV

PRODUCT:  MK-6482  
104
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
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.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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).
08CHFV

PRODUCT:  MK-6482  
105
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 11 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.
•
Pregnancy testing:
- Pregnancy testing requirements for study inclusion are described in Section 5.1.
- Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
- Pregnancy testing (urine or serum as required by local regulations) should be 
conducted for the time required to eliminate systemic exposure after the last dose of 
study intervention as noted in Section 5.1. The length of time required to continue 
pregnancy testing for study intervention is as follows:
o
Belzutifan: at least 30 days after the last dose of study intervention
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
08CHFV

PRODUCT:  MK-6482  
106
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Table 11
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytesa
WBC count with 
Differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN or ureab
Potassium
AST/ SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above the 
ULN)
Albumin
CO2 or bicarbonatec
Chloride
Phosphorous
Creatinine or CrCld
Sodium
ALT/SGPT
Total protein
Glucose
Calciume
Alkaline 
phosphatase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, (bilirubin, urobilinogen, nitrite, leukocyte 
esterase) by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests
•
Follicle stimulating hormone (as needed in women of nonchildbearing potential only)
•
Serum or urine hCG pregnancy test (as needed for WOCBP)
•
Serology (HIV antibody, HBsAg, and HCV antibody) as required by local health 
authority or institutional regulations. Refer to Appendix 7 for country-specific 
requirements.
•
Coagulation factors (PT or INR, and aPTT). Additional testing to be conducted as 
clinically indicated for participants taking anticoagulation therapy.
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; CO2=carbon dioxide; CrCl=creatinine clearance; GFR=glomerular filtration rate; 
HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; INR=international normalized ratio; MCH=mean corpuscular hemoglobin; MCV=mean 
corpuscular volume; PT=prothrombin time; RBC=red blood cell; SoA=Schedule of Activities; SGOT=serum glutamic-
oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of normal; WBC=white blood 
cell; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential
NOTES:
a
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
b
BUN is preferred; if not available, urea may be tested.
c
Performed only if considered the local standard of care.
d
GFR (measured or calculated) or CrCl can be used in place of creatinine.
e
Corrected calcium is needed at screening (this is used to determine IMDC criteria).
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
08CHFV

PRODUCT:  MK-6482  
107
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
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 non-therapeutic 
effect.
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 (also referred to as Sponsor’s 
product) 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.
08CHFV

PRODUCT:  MK-6482  
108
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
    Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
    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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
    Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
    Refer to Section 8.4.6 for protocol-specific exceptions.
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.
08CHFV

PRODUCT:  MK-6482  
109
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
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 pre-existing condition that has not 
worsened is not an SAE.) A pre-existing 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.
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.
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
08CHFV

PRODUCT:  MK-6482  
110
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
•
Is associated with an overdose
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.
    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. 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.
08CHFV

PRODUCT:  MK-6482  
111
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
08CHFV

PRODUCT:  MK-6482  
112
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
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.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
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.
08CHFV

PRODUCT:  MK-6482  
113
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
•
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.
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
    The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
    The site will enter the SAE data into the electronic system as soon as it becomes 
available.
    After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
    If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
08CHFV

PRODUCT:  MK-6482  
114
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
    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 e-mail 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).
08CHFV

PRODUCT:  MK-6482  
115
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable for this study.
Definition of Device Event
Not applicable for this study.
Definition of Adverse Device Event
Not applicable for this study.
Definition of Medical Device Incident (Including Malfunction)
Not applicable for this study.
Documenting Device Events, Adverse Device Events, and Medical Device 
Incidents
Not applicable for this study.
08CHFV

PRODUCT:  MK-6482  
116
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
10.5
Appendix 5: Contraceptive Guidance
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
08CHFV

PRODUCT:  MK-6482  
117
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Contraception Requirements
Highly Effective Contraception Methods
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb, c
•
IUSc, d
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.
a    Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c   Male condoms must be used in addition to female participant hormonal contraception.
d   IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
08CHFV

PRODUCT:  MK-6482  
118
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b   Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.  Summary of Procedures for Future Biomedical Research
a.   Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
08CHFV

PRODUCT:  MK-6482  
119
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.  Confidential Participant Information for Future Biomedical Research
To optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number, which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
08CHFV

PRODUCT:  MK-6482  
120
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
5.  Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6.  Withdrawal from Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant’s specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed before the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the main study are no longer available (eg, if the investigator is 
no longer required by regulatory authorities to retain the main study records) or the 
specimens have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7.  Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which
08CHFV

PRODUCT:  MK-6482  
121
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.  Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.  Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website to rapidly 
report this information to doctors and participants. Participants will not be identified by 
name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
08CHFV

PRODUCT:  MK-6482  
122
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
13. References
1.  National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.   International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html
3.   Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4.  Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
08CHFV

PRODUCT:  MK-6482  
123
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
10.7
Appendix 7: Country-specific Requirements
United Kingdom
Study 
Period
Screening
Treatment Period
EOT
Notes
Week
Screeninga
(Visit 1)
Wk 1
Day 1
Wk 3
Day 1
Wk 5
Day 1
Wk 7
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Visit 
Number
1
2
3
4
5
6
7+
Scheduling 
Window 
(Days):
–42 
to -1
–28 
to –1
±3
±3
±3
±3
±3
±3
At 
time of 
DC
Safety 
Procedures
HIV testing
X
Testing is 
required.
a.
All screening procedures should be performed within 42 days before treatment allocation, unless otherwise noted.
b.
After Week 13, visits are to occur approximately every 4 weeks (~28 days) until documented disease progression, 
death, withdrawal of consent, or the end of the study, whichever occurs first.
Section 5.2 Exclusion Criteria
20. Participant has a known history of HIV infection. Testing for HIV is required at 
screening.
Section 8.11.1 Screening

Laboratory tests are to be performed within 10 days before the first dose of study 
intervention. An exception is HIV and hepatitis testing which may be performed up to 
42 days before the first dose of study intervention.
Appendix 2 Clinical Laboratory Tests
Other Screening Tests: Serology (HIV antibody).
08CHFV

PRODUCT:  MK-6482  
124
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living  
ADME
adsorption, distribution, metabolism, excretion
AE
adverse event 
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APaT
All-Participants-as-Treated
aPTT
activated partial thromboplastin time
ARNT
aryl hydrocarbon receptor nuclear translocator
AST
aspartate aminotransferase
AUC
area under the curve
BCRP
breast cancer resistance protein
BICR
blinded independent central review
BID
twice daily
BUN
blood urea nitrogen
CBR
clinical benefit rate
ccRCC
clear cell renal cell carcinoma
Cmax
maximum concentration
CI
confidence interval
CL/F
clearance
CNS
central nervous system
CO2
carbon dioxide
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE v5
Common Terminology Criteria for Adverse Events, Version 5.0
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
trough plasma concentration
CYP
cytochrome P450
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOT
end of treatment
EPO
erythropoietin
ESMO
European Society for Medical Oncology
FA
final analysis
FBR
future biomedical research
08CHFV

PRODUCT:  MK-6482  
125
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Abbreviation
Expanded Term
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded
FSH
follicle stimulating hormone 
GBM
glioblastoma
GCP
Good Clinical Practice 
G-CSF
granulocyte colony-stimulating factor
GFR
glomerular filtration rate
GLP
Good Laboratory Practice
GM-CSF
granulocyte macrophage colony-stimulating factor
GMR
geometric mean ratio
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
human chorionic gonadotropin
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIF
hypoxia-inducible factor
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ICMJE
International Committee of Medical Journal Editors
iCRO
imaging CRO
ID
identification
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IMDC
International Metastatic Renal Cell Carcinoma Database Consortium
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
INR
international normalized ratio
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
KPS
Karnofsky performance status
LAM
lactational amenorrhea method
LLN
lower limit of normal
mAb
monoclonal antibody
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MRI
magnetic resonance imaging
mRNA
messenger RNA
MTD
maximum tolerated dose 
mTOR
mammalian target of rapamycin
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIMP
Non-investigational Medicinal Product
08CHFV

PRODUCT:  MK-6482  
126
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
Abbreviation
Expanded Term
NSAE
nonserious adverse event
NSCLC
non–small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PD-1
programmed cell-death 1
pEFD
preliminary embryo-fetal development
PFS
progression-free survival
P-gp
P glycoprotein
PK
pharmacokinetic
PR
partial response
pRBC
packed red blood cells
PT
prothrombin time
PTT
partial thromboplastin time
Q4W
every 4 weeks
Q8W
every 8 weeks
Q12W
every 12 weeks
Q24W
every 24 weeks
QD
once daily
RCC
renal cell carcinoma
RECIST
Response Criteria in Solid Tumors
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SD
stable disease
SEER
Surveillance, Epidemiology, and End Results Program
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SIM
Site Imaging Manual
SNP
single-nucleotide polymorphism
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TK
toxicokinetic
TKI
tyrosine-kinase inhibitor
tmax
time to maximum concentration
UGT
uridine 5’-diphospho-glucuronosyltransferase-glucuronosyltransferase
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
VHL
Von Hippel-Lindau disease
Vz/F
apparent volume of distribution
WBC
white blood cell
Wk
week
WOCBP
woman/women of childbearing potential 
08CHFV

PRODUCT:  MK-6482  
127
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
11
REFERENCES
[Bianchi, M., et al 
2012]
Bianchi M, Sun M, Jeldres C, Shariat SF, Trinh 
QD, Briganti A, et al. Distribution of metastatic 
sites in renal cell carcinoma: a population-based 
analysis. Ann Oncol. 2012 Apr;23(4):973-80.
[0587XF]
[Bray, F., et al 2018]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, 
Torre LA, Jemal A. Global cancer statistics 
2018: GLOBOCAN estimates of incidence and 
mortality worldwide for 36 cancers in 185 
countries. CA Cancer J Clin. 2018;68:394-424.
[059RKM]
[Cella, D. 2011]
Cella D. Beyond traditional outcomes: 
improving quality of life in patients with renal 
cell carcinoma. Oncologist. 2011;16(suppl 2):23-
31.
[059L94]
[Choueiri, T. K., et 
al 2016]
Choueiri TK, Escudier B, Powles T, Tannir NM, 
Mainwaring PN, Rini BI, et al. Cabozantinib 
versus everolimus in advanced renal cell 
carcinoma (METEOR): final results from a 
randomised, open-label, phase 3 trial. Lancet 
Oncol. 2016 Jul;17:917-27.
[059HGM]
[Choueiri, T. K., et 
al 2020]
Choueiri TK, Plimack ER, Bauer TM, Merchan 
JR, Papadopoulos KP, McDermott DF, et al. 
Phase 1/2 study of the oral HIF-2alpha inhibitor 
MK-6482 in patients with advanced clear cell 
renal cell carcinoma. Slides presented at: 2020 
American Society of Clinical Oncology (ASCO) 
Genitourinary Cancers Symposium; 2020 Feb 
13-15; San Francisco, CA.
[05GHCM]
[Dall'Oglio, M. F., et 
al 2007]
Dall'Oglio MF, Antunes AA, Sarkis AS, Crippa 
A, Leite KR, Lucon AM, et al. Microvascular 
tumour invasion in renal cell carcinoma: the 
most important prognostic factor. BJU Int. 
2007;100:552-5.
[0587YY]
[Dall'Oglio, M. F., et 
al 2007]
Dall'Oglio MF, Ribeiro-Filho LA, Antunes AA, 
Crippa A, Nesrallah L, Goncalves PD, et al. 
Microvascular tumor invasion, tumor size and 
Fuhrman grade: a pathological triad for 
prognostic evaluation of renal cell carcinoma. J 
Urol. 2007 Aug;178:425-8.
[0587YD]
08CHFV

PRODUCT:  MK-6482  
128
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
[DeVita, et al 2008]
DeVita, Hellman, Rosenberg. Cancer: principles 
and practice of Oncology. 8th ed. Philadelphia: 
Lippincott Willliams & Wilkins; 2008. Chapter 
36.2, Cancer of the Head and Neck; p. 818.
[042HNK]
[Escudier, B., et al 
2019]
Escudier B, Porta C, Schmidinger M, Rioux-
Leclercq N, Bex A, Khoo V, et al. Renal cell 
carcinoma: ESMO Clinical Practice Guidelines 
for diagnosis, treatment and follow-up. Ann 
Oncol. 2019;30(5):706-20.
[058TJC]
[Ficarra, V., et al 
2005]
Ficarra V, Schips L, Guille F, Li G, De La Taille 
A, Prayer Galetti T, et al. Multiinstitutional 
European validation of the 2002 TNM staging 
system in conventional and papillary localized 
renal cell carcinoma. Cancer. 2005 Sep 
1;104(5):968-74.
[05877Z]
[Frank, I., et al 
2005]
Frank I, Blute ML, Leibovich BC, Cheville JC, 
Lohse CM, Zincke H. Independent validation of 
the 2002 American Joint Committee on cancer 
primary tumor classification for renal cell 
carcinoma using a large, single institution 
cohort. J Urol. 2005 Jun;173(6):1889-92.
[04J9KZ]
[Heng, D. Y., et al 
2013]
Heng DY, Xie W, Regan MM, Harshman LC, 
Bjarnason GA, Vaishampayan UN, et al. 
External validation and comparison with other 
models of the international metastatic renal-cell 
carcinoma database consortium prognostic 
model: a population-based study. Lancet Oncol. 
2013 Feb;14(2):141-8.
[04TVHY]
[Howlader, N., et al 
2017]
Howlader N, Noone AM, Krapcho M, Miller D, 
Bishop K, Kosary CL, et al. SEER Cancer 
Statistics Review, 1975-2014, National Cancer 
Institute. Bethesda, MD, 
https://seer.cancer.gov/csr/1975_2014/, based on 
November 2016 SEER data submission, posted 
to the SEER web site, April 2017.
[04TWYZ]
08CHFV

PRODUCT:  MK-6482  
129
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
[Jonasch, E., et al 
2019]
Jonasch E, Plimack ER, Bauer T, Merchan JR, 
Papadopoulos KP, McDermott DF, et al. A first-
in-human phase I/II trial of the oral HIF-2a 
inhibitor PT2977 in patients with advanced RCC 
[abstract]. Presented at: European Society for 
Medical Oncology (ESMO) Congress; 2019 Sep 
27-Oct 1; Barcelona (Spain). Ann Oncol. 2019 
Oct;30(suppl 5):v361-2. Abstract no. 911PD.
[05H6ZZ]
[Karnofsky, D. A., et 
al 1948]
Karnofsky DA, Abelmann WH, Craver LF, 
Burchenal JH. The use of the nitrogen mustards 
in the palliative treatment of carcinoma: with 
particular reference to bronchogenic carcinoma. 
Cancer. 1948 Nov:634-56.
[05FCMZ]
[Klatte, T., et al 
2007]
Klatte T, Patard JJ, Goel RH, Kleid MD, Guille 
F, Lobel B, et al. Prognostic impact of tumor 
size on pT2 renal cell carcinoma: an 
international multicenter experience. J Urol. 
2007 Jul;178:35-40.
[0587CK]
[Lam, J. S., et al 
2005]
Lam JS, Shvarts O, Said JW, Pantuck AJ, 
Seligson DB, Aldridge ME, et al. 
Clinicopathologic and molecular correlations of 
necrosis in the primary tumor of patients with 
renal cell carcinoma. Cancer. 2005 Jun 
15;103(12):2517-25.
[058CBQ]
[Lam, J. S., et al 
2007]
Lam JS, Klatte T, Patard JJ, Goel RH, Guille F, 
Lobel B, et al. Prognostic relevance of tumour 
size in T3a renal cell carcinoma: a multicentre 
experience. Eur Urol. 2007;52:155-62.
[0587CL]
[Leibovich, B. C., et 
al 2010]
Leibovich BC, Lohse CM, Crispen PL, Boorjian 
SA, Thompson RH, Blute ML, et al. Histological 
subtype is an independent predictor of outcome 
for patients with renal cell carcinoma. J Urol. 
2010 Apr;183(4):1309-15.
[04CN7F]
[Lipworth, L., et al 
2016]
Lipworth L, Morgans AK, Edwards TL, Barocas 
DA, Chang SS, Herrell SD, et al. Renal cell 
cancer histological subtype distribution differs 
by race and sex. BJU Int. 2016;117:260-5.
[0587CM]
08CHFV

PRODUCT:  MK-6482  
130
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
[McKay, R. R., et al 
2018]
McKay RR, Bosse D, Choueiri TK. Evolving 
systemic treatment landscape for patients with 
advanced renal cell carcinoma. J Clin Oncol. 
2018 Dec 20;36(36):3615-23.
[059L96]
[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O, Nurminen M. Comparative analysis 
of two rates. Stat Med 1985;4:213-26.
[00VMQY]
[Minervini, A., et al 
2002]
Minervini A, Lilas L, Minervini R, Selli C. 
Prognostic value of nuclear grading in patients 
with intracapsular (pT1-pT2) renal cell 
carcinoma: long-term analysis in 213 patients. 
Cancer. 2002 May 15;94(10):2590-5.
[0586VM]
[Moch, H., et al 
2000]
Moch H, Gasser T, Amin MB, Torhorst J, Sauter 
G, Mihatsch MJ. Prognostic utility of the 
recently recommended histologic classification 
and revised TNM staging system of renal cell 
carcinoma: a Swiss experience with 588 tumors. 
Cancer. 2000 Aug 1;89(3):604-14.
[04CN7W]
[Motzer, R. J., et al 
2015]
Motzer RJ, Escudier B, McDermott DF, George 
S, Hammers HJ, Srinivas S, et al. Nivolumab 
versus Everolimus in advanced renal-cell 
carcinoma. N Engl J Med. 2015 Nov 
5;373(19):1803-13.
[04PTPH]
[Motzer, R. J., et al 
2018]
Motzer RJ, Tannir NM, McDermott DF, Aren 
Frontera O, Melichar B, Choueiri TK, et al. 
Nivolumab plus ipilimumab versus sunitinib in 
advanced renal-cell carcinoma. N Engl J Med. 
2018 Apr 5;378(14):1277-1290. doi: 
10.1056/NEJMoa1712126. Epub 2018 Mar 21.
[04WHNV]
[Motzer, R. J., et al 
2019]
Motzer RJ, Penkov K, Haanen J, Rini B, Albiges 
L, Campbell MT, et al. Avelumab plus axitinib 
versus sunitinib for advanced renal-cell 
carcinoma. N Engl J Med. 2019 Mar 
21;380(12):1103-15.
[0587BY]
[National Cancer 
Institute 2016]
National Cancer Institute. SEER stat fact sheets: 
kidney and renal pelvis cancer [Internet]. 
Bethesda (MD): National Cancer Institute; 2016. 
Available from: 
http://seer.cancer.gov/statfacts/html/kidrp.html.
[04CMDG]
08CHFV

PRODUCT:  MK-6482  
131
PROTOCOL/AMENDMENT NO.:  013-02  
MK-6482-013-02 FINAL PROTOCOL
30-JUN-2022
[National 
Comprehensive 
Cancer Network 
2019]
National Comprehensive Cancer Network. 
NCCN clinical practice guidelines in oncology: 
kidney cancer; version 2.2020. Plymouth 
Meeting (PA): National Comprehensive Cancer 
Network (NCCN); 2019. 64 p.
[059P4B]
[Nguyen, M. P., et al 
2013]
Nguyen MP, Lee S, Lee YM. Epigenetic 
regulation of hypoxia inducible factor in diseases 
and therapeutics. Arch Pharm Res. 2013;36:252-
63.
[05BVLF]
[Oken, M.M., et al 
1982]
Oken MM, Creech RH, Tormey DC, Horton J, 
Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-
55.
[03VZ9S]
[Rini, B. I., et al 
2019]
Rini BI, Plimack ER, Stus V, Gafanov R, 
Hawkins R, Nosov D, et al. Pembrolizumab plus 
axitinib versus sunitinib for advanced renal-cell 
carcinoma. N Engl J Med. 2019 Mar 
21;380(12):1116-27.
[05706K]
[Sato, Y., et al 2013]
Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, 
Okuno Y, Kamura T, et al. Integrated molecular 
analysis of clear-cell renal cell carcinoma. Nat 
Genet. 2013 Aug;45(8):860-7.
[05BTLJ]
[Sengupta, S., et al 
2005]
Sengupta S, Lohse CM, Leibovich BC, Frank I, 
Thompson RH, Webster WS, et al. Histologic 
coagulative tumor necrosis as a prognostic 
indicator of renal cell carcinoma aggressiveness. 
Cancer. 2005 Aug 1;104(3):511-20.
[0587ZW]
[Shen, C. 2013]
Shen C, Kaelin WG Jr. The VHL/HIF axis in 
clear cell renal carcinoma. Semin Cancer Biol. 
2013;23:18-25.
[05BV4N]
[Zisman, A., et al 
2001]
Zisman A, Pantuck AJ, Chao D, Dorey F, Said 
JW, Gitlitz BJ, et al. Reevaluation of the 1997 
TNM classification for renal cell carcinoma: T1 
and T2 cutoff point at 4.5 rather than 7 cm. 
Better correlates with clinical outcome. J Urol. 
2001 Jul;166:54-8.
[0587CP]
08CHFV