An Open-label, Randomized Phase 3 Study of MK-6482 Versus Everolimus in Participants With Advanced Renal Cell Carcinoma That Has Progressed After Prior PD-1/L1 and VEGF-Targeted Therapies
Phase: PHASE3
Conditions: Carcinoma, Renal Cell
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
An Open-label, Randomized Phase 3 Study of MK-6482 Versus 
Everolimus in Participants with Advanced Renal Cell Carcinoma That 
Has Progressed After Prior PD-1/L1 and VEGF-Targeted Therapies
NCT04195750
14-NOV-2024

PRODUCT: MK-6482
1
PROTOCOL/AMENDMENT NO.: 005-09
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14-NOV-2024
TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: An Open-label, Randomized Phase 3 Study of MK-6482 Versus Everolimus 
in Participants with Advanced Renal Cell Carcinoma That Has Progressed After Prior PD-
1/L1 and VEGF-Targeted Therapies
Protocol Number: 005-09
Compound Number: MK-6482
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT04195750
EU CT
2023-506635-15
EudraCT
2019-003444-72
WHO
Not applicable
UTN
Not applicable
IND
132,120
jRCT
jRCT2080225166
Approval Date: 14 November 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
6482-005-09
14-NOV-2024
To incorporate revised ECI guidelines within the 
protocol as Appendix 8. This replaces the 
previous standalone ECI Guidance document.
6482-005-08
19-MAR-2024
To add text to describe that PRO administration 
is no longer required as of 15-APR-2024.
6482-005-07
13-Jul-2022
Japan-specific amendment: To update the timing 
of statistical analyses, given longer than planned 
accrual and reduce the total number of interim 
analyses in the study.
6482-005-06
13-Jul-2022
To update the timing of statistical analyses, 
given longer than planned accrual and reduce the 
total number of interim analyses in the study.
6482-005-05
16-Feb-2021
Japan-specific amendment: To update 
contraception appendix to align with program 
wide requirements.
6482-005-04
16-Feb-2021
To update contraception appendix to align with 
program wide requirements.
6482-005-03
02-Jun-2020
Japan-specific amendment: To revise the Japan-
specific safety run-in to gain a better 
understanding of PK exposure and safety in a 
larger sample size.
6482-005-02
14-May-2020
To provide an update of the preclinical 
toxicology section to reflect recent preclinical 
toxicology findings, provide inclusion/exclusion 
criteria clarifications and/or refinement, provide 
clarifications on the Schedule of Assessment 
procedures, and enact minor language changes 
throughout the protocol to provide clarifications 
and ensure consistency in language.
6482-005-01
18-Dec-2019
Japan-specific amendment: To add a safety run-
in component for Japan to ensure the correct 
dose of belzutifan is used in that participant 
population.
Original Protocol
30-SEP-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 09
Overall Rationale for the Amendment:
To incorporate revised ECI guidelines within the protocol as Appendix 8. This replaces the 
previous standalone ECI Guidance document.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 10.8, 
Appendix 8: 
Belzutifan ECI 
Guidance
Added new appendix regarding belzutifan ECI 
guidance.
Strategy change:  To incorporate revised
belzutifan ECI guidelines within the protocol as 
Appendix 8. This replaces the previous 
standalone ECI Guidance document.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Throughout
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.
Section 4.4, 
Beginning and End-
of-Study Definition
Added that the last participant enrolling in an 
extension study also is considered end of 
study.
To include if an extension study becomes 
available to transfer participants onto.
Added end of study for reporting purposes 
information. 
See rationale above.
Added beginning of study definition per EEA 
requirements.
See rationale above.
Section 6.5, 
Concomitant 
Therapy
Added text that inhibitors of UGT2B17 or 
CYP2C19 may increase plasma exposure of 
belzutifan and may impact hormonal 
contraceptives.
Inhibitors of these pathways could potentially 
increase plasma exposure of belzutifan.
Added text that inhibitors of UGT2B17 or 
CYP2C19 may increase plasma exposure of 
belzutifan.
See rationale above.
Section 6.6.1, 
Belzutifan Dosing 
Modifications
Updated reference from ECI guidance 
document to Appendix 8.
See rationale for primary reason for 
amendment.
Table 3 (Other nonlaboratory toxicity) – added 
that weight increased is not included as a 
Grade 3 toxicity requiring dose modification.
To align with prescribing information in which 
weight gain is a belzutifan ADR and does not 
require dose modification for Grade 3.
Section 6.6.1.1, 
Management of 
Anemia
Specified that transfusion can also be used to 
manage anemia in participants receiving 
belzutifan.
Anemia is an ADR of belzutifan; text added to 
provide greater clarification on potential 
options to manage anemia.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 6.6.1.2, 
Management of 
Hypoxia
Deleted NCI CTCAE v5.0 definition of 
hypoxia.
To remove unneeded text.
Added text regarding diagnosis and 
management of hypoxia which should follow 
CTCAE v5 and the guidance in Table 3 and 
ECI guidance in Appendix 8.
To provide further details on resources for 
hypoxia diagnosis and management.
Section 8.4.3, 
Follow-up of AE, 
SAE, and Other 
Reportable Safety 
Event Information
Removed text indicating that all AEs require 
follow-up until resolution.
Revised for clarity as only AEs meeting certain 
criteria must be followed until resolution.
Section 8.4.4, 
Regulatory 
Reporting 
Requirements for 
SAE
Added text regarding reporting of SUSARS by 
the Sponsor in compliance with CTR 
536/2014.
Per HA requirements.
Section 8.4.7, 
Events of Clinical 
Interest
Clarified that the events listed in ECI #b are 
DILI events.
To ensure that the laboratory abnormality 
events in ECI #b are captured correctly as DILI 
events.
ECI Criterion #c: Grade level revised to 
Grade ≥3. 
To align with ECI guidelines in new 
Appendix 8.
ECI Criterion #d: Grade level revised to 
Grade ≥3
See rationale above for ECI Criterion #c.
ECI Criterion #e (dyspnea): removed.
See rationale above for ECI Criterion #c.
Former ECI criterion #f renumbered to current 
criterion #e.
To align numbering after removal of ECI 
Criterion #e.
ECI Criterion #g (former numbering; ≥Grade 4 
AEs all causality): removed.
See rationale above for ECI Criterion #c.
Section 8.5, 
Treatment of 
Overdose
Revised wording to remove that belzutifan 
interruption is required.
Belzutifan interruption is not always required 
in the event of overdose.
Section 10.1.3, Data 
Protection
Changed his/her to their.
To use gender neutral language
Added that Sponsor also adheres to EU 
privacy rules.
See rationale for Section 8.4.4.
Section 10.1.6 
Compliance with 
Study Regulation 
and Results Posting 
Requirements
Updated text pertaining to EU compliance 
regulation.
See rationale for Section 8.4.4.
Section 10.1.8, Data 
Quality Assurance
Added example of EU CTR retention period.
See rationale for Section 8.4.4.
Section 10.9, 
Appendix 9: 
Abbreviations
Former Appendix 8 renumbered to current 
Appendix 9.
Due to addition of new Appendix 8.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities...........................................................................................20
2
INTRODUCTION..........................................................................................................35
2.1
Study Rationale....................................................................................................35
2.1.1
Rationale for the Study of Belzutifan in Renal Cell Carcinoma..................35
2.2
Background ..........................................................................................................35
2.2.1
Renal Cell Carcinoma..................................................................................35
2.2.2
Hypoxia-inducible Factor and Renal Cell Carcinoma.................................35
2.2.3
Current Treatment Options ..........................................................................36
2.2.4
Pharmaceutical and Therapeutic Background .............................................36
2.2.4.1
Pharmacology ....................................................................................36
2.2.5
Preclinical Studies........................................................................................37
..................................37
2.2.5.2
Preclinical Toxicology.......................................................................38
2.2.6
Clinical Studies............................................................................................39
2.3
Benefit/Risk Assessment......................................................................................40
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................42
4
STUDY DESIGN............................................................................................................44
4.1
Overall Design......................................................................................................44
4.2
Scientific Rationale for Study Design.................................................................45
4.2.1
Rationale for Endpoints ...............................................................................45
4.2.1.1
Efficacy Endpoints.............................................................................45
4.2.1.2
RECIST 1.1........................................................................................46
4.2.1.3
Safety Endpoints................................................................................46
4.2.1.4
Patient-reported Outcomes.................................................................46
4.2.1.5
Pharmacokinetic Endpoints ...............................................................47
4.2.1.6
Pharmacodynamic Endpoints.............................................................48
4.2.1.7
Planned Exploratory Biomarker Research.........................................48
4.2.1.8
Future Biomedical Research..............................................................49
4.2.2
Rationale for the Use of Comparator...........................................................49
4.3
Justification for Dose...........................................................................................50
4.3.1
Starting Dose for This Study........................................................................50
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4.3.2
Maximum Dose Exposure for This Study ...................................................50
4.4
Beginning and End-of-Study Definition ............................................................50
4.4.1
Clinical Criteria for Early Study Termination .............................................50
5
STUDY POPULATION ................................................................................................51
5.1
Inclusion Criteria.................................................................................................51
5.2
Exclusion Criteria................................................................................................54
5.3
Lifestyle Considerations......................................................................................56
5.3.1
Meals and Dietary Restrictions....................................................................56
5.4
Screen Failures.....................................................................................................57
5.5
Participant Replacement Strategy......................................................................57
6
STUDY INTERVENTION............................................................................................58
6.1
Study Intervention(s) Administered...................................................................58
6.2
Preparation/Handling/Storage/Accountability .................................................60
6.2.1
Dose Preparation..........................................................................................60
6.2.1.1
Belzutifan...........................................................................................60
6.2.1.2
Everolimus.........................................................................................60
6.2.2
Handling, Storage, and Accountability........................................................60
6.3
Measures to Minimize Bias: Randomization and Blinding..............................61
6.3.1
Intervention Assignment..............................................................................61
6.3.2
Stratification.................................................................................................61
6.3.3
Blinding........................................................................................................62
6.4
Study Intervention Compliance..........................................................................62
6.5
Concomitant Therapy..........................................................................................63
6.5.1
Prohibited Concomitant Medications ..........................................................63
6.5.2
Rescue Medications and Supportive Care ...................................................64
6.6
Dose Modification ................................................................................................65
6.6.1
Belzutifan Dosing Modifications.................................................................65
6.6.1.1
Management of Anemia.....................................................................68
6.6.1.2
Management of Hypoxia....................................................................68
6.6.2
Everolimus Dosing Modifications...............................................................68
6.7
Intervention After the End of the Study............................................................68
6.8
Clinical Supplies Disclosure................................................................................68
6.9
Standard Policies..................................................................................................68
6.9.1
Study Site Retention Samples......................................................................68
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................69
7.1
Discontinuation of Study Intervention...............................................................69
7.2
Participant Withdrawal From the Study...........................................................70
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7.3
Lost to Follow-up .................................................................................................70
8
STUDY ASSESSMENTS AND PROCEDURES........................................................71
8.1
Administrative and General Procedures ...........................................................71
8.1.1
Informed Consent.........................................................................................71
8.1.1.1
General Informed Consent.................................................................71
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................72
8.1.2
Inclusion/Exclusion Criteria ........................................................................72
8.1.3
Participant Identification Card.....................................................................72
8.1.4
Medical History ...........................................................................................73
8.1.5
Prior and Concomitant Medications Review...............................................73
8.1.5.1
Prior Medications...............................................................................73
8.1.5.2
Concomitant Medications..................................................................73
8.1.6
Assignment of Screening Number...............................................................73
8.1.7
Assignment of Treatment/Randomization Number.....................................73
8.1.8
Study Intervention Administration ..............................................................74
8.1.8.1
Belzutifan...........................................................................................74
8.1.8.2
Everolimus.........................................................................................74
8.1.8.3
Timing of Dose Administration.........................................................74
8.1.9
Discontinuation and Withdrawal .................................................................74
8.1.9.1
Withdrawal From Future Biomedical Research ................................74
8.1.10
Participant Blinding/Unblinding..................................................................75
8.1.11
Tissue Collection .........................................................................................75
8.1.12
Calibration of Equipment.............................................................................75
8.2
Efficacy Assessments ...........................................................................................76
8.2.1
Tumor Imaging and Assessment of Disease................................................76
8.2.1.1
Initial Tumor Imaging........................................................................76
8.2.1.2
Tumor Imaging During the Study......................................................77
8.2.1.3
End-of-treatment and Follow-up Tumor Imaging .............................79
8.2.2
Quality of Life Assessments........................................................................80
8.3
Safety Assessments...............................................................................................80
8.3.1
Physical Examinations.................................................................................80
8.3.2
Vital Signs....................................................................................................81
8.3.3
Electrocardiograms ......................................................................................81
8.3.4
Clinical Safety Laboratory Assessments .....................................................81
8.3.5
KPS and ECOG Performance Status ...........................................................82
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................82
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................82
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......84
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...85
8.4.4
Regulatory Reporting Requirements for SAE .............................................85
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................85
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................86
8.4.7
Events of Clinical Interest............................................................................86
8.5
Treatment of Overdose........................................................................................86
8.6
Pharmacokinetics.................................................................................................87
......................................................87
8.7
Pharmacodynamics..............................................................................................87
...........................................................................................................87
..............................................88
8.9
Future Biomedical Research Sample Collection...............................................88
8.10
Medical Resource Utilization and Health Economics.......................................88
8.11
Visit Requirements...............................................................................................88
8.11.1
Screening......................................................................................................88
8.11.2
Treatment Period..........................................................................................89
8.11.3
Posttreatment................................................................................................89
8.11.3.1
Posttreatment Safety Follow-up Visit................................................89
8.11.3.2
Imaging Follow-up.............................................................................89
8.11.3.3
Survival Follow-up ............................................................................90
9
STATISTICAL ANALYSIS PLAN .............................................................................91
9.1
Statistical Analysis Plan Summary.....................................................................91
9.2
Responsibility for Analyses/In-house Blinding .................................................92
9.3
Hypotheses/Estimation ........................................................................................92
9.4
Analysis Endpoints...............................................................................................93
9.4.1
Efficacy Endpoints.......................................................................................93
9.4.2
Safety Endpoints..........................................................................................93
9.4.3
Patient-reported Outcome Endpoints...........................................................93
9.5
Analysis Populations............................................................................................93
9.5.1
Efficacy Analysis Population.......................................................................93
9.5.2
Safety Analysis Population..........................................................................94
9.5.3
Patient-reported Outcome Analysis Population...........................................94
9.6
Statistical Methods...............................................................................................94
...................................................94
9.6.1.1
Progression-free Survival...................................................................94
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9.6.1.2
Overall Survival.................................................................................96
9.6.1.3
Objective Response Rate ...................................................................97
9.6.1.4
Duration of Response.........................................................................97
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints..................................97
9.6.2
Statistical Methods for Safety Analyses ......................................................98
9.6.3
Statistical Methods for Patient-reported Outcome Analyses.......................99
9.6.4
Demographics and Baseline Characteristics................................................99
................................................................................................100
9.7.1
Efficacy Interim Analyses..........................................................................100
9.7.2
Safety Interim Analyses.............................................................................101
9.8
Multiplicity .........................................................................................................101
...........................................................................102
...........................................................................102
.........................................................................................104
9.8.4
Safety Analyses..........................................................................................105
9.9
Sample Size and Power Calculations ...............................................................105
............................................................................................106
)...............................................................106
.............................................................................................106
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................107
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......107
10.1.1
Code of Conduct for Clinical Trials...........................................................107
10.1.2
Financial Disclosure...................................................................................110
10.1.3
Data Protection...........................................................................................111
10.1.3.1
Confidentiality of Data ....................................................................111
10.1.3.2
Confidentiality of Participant Records.............................................111
10.1.3.3
Confidentiality of IRB/IEC Information..........................................112
10.1.4
Committees Structure.................................................................................112
10.1.4.1
Scientific Advisory Committee........................................................112
10.1.4.2
Executive Oversight Committee......................................................112
10.1.4.3
External Data Monitoring Committee .............................................112
10.1.5
Publication Policy......................................................................................112
10.1.6
Compliance with Study Registration and Results Posting Requirements .113
10.1.7
Compliance with Law, Audit, and Debarment ..........................................113
10.1.8
Data Quality Assurance .............................................................................114
10.1.9
Source Documents .....................................................................................115
10.1.10
Study and Site Closure...............................................................................115
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10.2
Appendix 2: Clinical Laboratory Tests............................................................116
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................118
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................118
10.3.2
Definition of AE ........................................................................................118
10.3.3
Definition of SAE ......................................................................................119
10.3.4
Additional Events Reported in the Same Manner as SAE.........................120
10.3.5
Recording AE and SAE .............................................................................121
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................124
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................126
10.4.1
Definition of Device Event........................................................................126
10.5
Appendix 5: Contraceptive Guidance..............................................................127
10.5.1
Definitions..................................................................................................127
10.5.2
Contraceptive Requirements......................................................................128
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................129
10.7
Appendix 7: Country-specific Requirements..................................................133
10.7.1
Germany.....................................................................................................133
10.7.2
United Kingdom.........................................................................................134
10.7.3
Ireland ........................................................................................................135
10.7.4
Norway.......................................................................................................137
10.7.5
Czech Republic..........................................................................................139
..........................................................................................................142
.........................................................................142
.......................................147
......................................................147
.............................................................................148
........................148
10.7.6.3
Use of Erythropoiesis-stimulating Agents.......................................148
10.7.7
South Korea ...............................................................................................154
10.8
Appendix 8: Belzutifan ECI Guidance ............................................................155
10.8.1
Belzutifan ECI Criteria ..............................................................................155
10.8.2
Anemia/Decreased Hemoglobin ECI Reporting........................................155
10.8.3
Anemia Management.................................................................................155
10.8.4
Hypoxia ECI Reporting .............................................................................156
10.8.5
Hypoxia Management................................................................................157
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10.9
Appendix 9: Abbreviations ...............................................................................158
11
REFERENCES.............................................................................................................162
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values .............................................53
Table 2
Study Interventions......................................................................................59
Table 3
Dose Modification Guidelines for Belzutifan-related Toxicities.................66
Table 4
Belzutifan Dose Levels................................................................................67
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events ..................................................................84
...................96
.................................................97
Table 8
Analysis Strategy for Key Efficacy Endpoints............................................98
Table 9
Analysis Strategy for Safety Parameters......................................................99
.....................................101
 
..........102
 
....................................................................................................103
Table 13
Efficacy Boundaries and Properties for Overall Survival Analyses..........104
Table 14
Protocol-required Safety Laboratory Assessments....................................117
Table 15
Highly Effective Contraception Methods..................................................128
Table 16
Protocol-required Safety Laboratory Assessments....................................141
Table 17
Decision Guidance Table...........................................................................144
Table 18
Study Interventions....................................................................................150
Table 19
Adequate Organ Function Laboratory Values ...........................................154
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LIST OF FIGURES
Figure 1
Study Design................................................................................................19
Figure 2
Decision-Making Process When Progression Observed by Investigator ....79
Figure 3
Multiplicity Diagram for Type I Error Control (One-Sided).....................102
Figure 4
Schema of Safety Run-in Phase.................................................................142
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-label, Randomized Phase 3 Study of MK-6482 Versus Everolimus 
in Participants with Advanced Renal Cell Carcinoma That Has Progressed After Prior PD-
1/L1 and VEGF-Targeted Therapies
Short Title: An Open-label, Randomized Phase 3 Study of Belzutifan Versus Everolimus in 
Participants With Advanced Renal Cell Carcinoma After Prior Therapy
Acronym: MK-6482-005
Hypotheses, Objectives, and Endpoints:
This study will be conducted in male and female participants with advanced clear cell RCC.
Primary Objectives
Primary Endpoints
To compare belzutifan to everolimus with 
respect to PFS per RECIST 1.1 as assessed 
by BICR.
Hypothesis (H1): Belzutifan is superior to 
everolimus with respect to PFS per 
RECIST 1.1 by BICR.
PFS: the time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first
Objective: To compare belzutifan to 
everolimus with respect to OS.
Hypothesis (H2): Belzutifan is superior to 
everolimus with respect to OS.
OS: the time from randomization to death 
due to any cause
Secondary Objectives
Secondary Endpoints
Objective: To compare belzutifan to 
everolimus with respect to ORR based on 
RECIST 1.1 as assessed by BICR.
Hypothesis (H3): Belzutifan increases ORR 
according to RECIST 1.1 by BICR 
compared to everolimus.
OR: CR or PR
Objective: To evaluate the 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 safety and 
tolerability of belzutifan compared to 
everolimus.
•
AEs
•
Study intervention discontinuation due 
to AEs
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Objective: To evaluate TTD and change 
from baseline in HRQoL using the EORTC 
QLQ-C30 and the FKSI-DRS.
PRO scores for the following domains:
•
EORTC QLQ-C30 global health 
status/HRQoL (Items 29 and 30)
•
EORTC QLQ-C30 physical functioning 
(Items 1-5)
•
FKSI-DRS Subscale (Items 1-9)
Objective: To characterize health utility as 
measured using the EuroQoL EQ-5D-5L.
Health utility scores from the EQ-5D-5L
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Renal cell carcinoma
Population
Participants with unresectable, locally 
advanced, or metastatic RCC after prior 
therapy
Study Type
Interventional
Intervention Model
Parallel
This is a multisite study.
Type of Control
Active Control Without Placebo
Study Blinding
Unblinded open-label
Blinding Roles
Outcomes Assessor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 5.5 years from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 736 participants will be randomized.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period
Use
Belzutifan
Belzutifan
40 mg 
tablet
120 mg
Oral
QD
Test Product
Everolimus Everolimus 10 mg 
tablet
10 mg
Oral
QD
Comparator
Abbreviations: QD=once daily.
Belzutifan: 120 mg dose should be made up of 3 × 40 mg tablets.
Everolimus: 2.5 mg and 5 mg tablets are provided for dose reductions as outlined in Section 6.6.2.
Other current names for study interventions are as follows: belzutifan/PT2977/MK-6482/ and 
everolimus/Afinitor®.
Total Number of Intervention Groups/Arms
2
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 or everolimus 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). 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, lost to follow-up, or the 
end of the study. All participants will be 
followed for OS until death, withdrawal of 
consent, or the end of the study.
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Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
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 9.
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1.2
Schema
The study design is depicted in Figure 1. Refer to Appendix 7 for country-specific 
requirements.
Figure 1
Study Design
Abbreviations: BICR = blinded independent central review; IMDC = International Metastatic Renal Cell Carcinoma 
Database Consortium; QD = once daily; RCC = renal cell carcinoma; VEGF = vascular endothelial growth factor.
a. Participants who discontinue study treatment for reasons other than BICR-verified disease progression should continue 
with imaging assessments per the protocol-defined schedule until disease progression is BICR-verified, initiation of a 
new anticancer treatment, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first.
b. [Cella, D. 2011] [Heng, D. Y., et al 2013].
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1.3
Schedule of Activities
Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
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.
Inclusion/
exclusion criteria
X
Participant ID card
X
X
At Week 1, site personnel 
should add the allocation 
number to the Participant ID 
card.
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Demographics and 
medical history
X
Medical history includes 
smoking, alcohol, and 
surgical history.
Cancer history
X
Prior/concomitant 
medication review
X
X
X
X
X
Q4W
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 should be 
recorded for SAEs as 
outlined for AE monitoring 
timeframes below.
Randomization
X
Participants may be 
randomized up to 3 days 
prior to initiation of study 
interventiona and after 
confirmation of eligibility. 
All procedures and 
assessments performed on 
Week 1 Day 1 should be 
performed after 
randomization.
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Subsequent 
antineoplastic 
therapy status
X
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.
Survival status
X
Continued after investigator 
determined disease 
progression or start of new 
anticancer treatment. In 
addition, on Sponsor 
request, participants may be 
contacted for survival status 
at any time during the study.
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Administration of Study Intervention
Belzutifan 
dispensing
X
X
X
Q4W
Participants will hold dosing 
of belzutifan on regularly 
scheduled clinic visit days 
until after completion of 
blood collection. The time of 
ingestion of belzutifan will 
be recorded and subsequent 
time-dependent procedures 
should be performed relative 
to the ingestion time.
Everolimus 
dispensing
X
X
X
Q4W
Review study 
intervention 
compliance
X
X
X
Q4W
X
At Week 3 Day 1, a tablet 
count will not be performed. 
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Efficacy Procedures
Imaging should continue to 
be performed until disease 
progression is documented 
by the investigator and 
verified by BICR, 
initiation of new 
anticancer treatment, 
withdrawal of consent, 
pregnancy, death, or the 
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 
prior to randomization. First 
on-study imaging should be 
performed at 8 weeks from 
randomization (±7 days) 
then Q8W through Week 49 
then Q12W (±7 days) 
thereafter (Section 8.2.1.2). 
All imaging visits on study 
will have a visit window of 
±7 days (± 14 days after 
Week 109) Refer to Section 
8.2.1.2.
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Bone imaginge
Xe
Xe
Xe
Xe
Screening images are to be 
captured within 28 days 
prior to randomizatione. All 
imaging visits on study will 
have a visit window of ±7 
days.
Brain imagingf
Xf
Xf
Xf
Screening images are to be 
captured within 28 days 
prior to 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. 
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Safety Procedures
AE monitoring
X
X
X
X
X
Q4W
X
X
X
Any AEs noted prior to ICF 
should be recorded as 
medical history. AEs that 
occur within 30 days of the 
end of treatment or before 
initiation of a new 
anticancer treatment should 
be followed and recorded. 
SAEs should be reported 
from the time of intervention 
allocation through 90 days 
after cessation of study 
intervention or 30 days 
following 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.
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Directed physical 
examination
X
X
X
X
Q4W
X
Directed physical 
examination performed as 
clinically indicated prior to 
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
Q4W
X
X
Vital signs will be obtained 
prior to study intervention 
administration on Week 1 
Day 1. Pulse oximetry will 
be measured each time vital 
signs are taken, using a 
Sponsor supplied pulse 
oximeter. If Sponsor-
provided pulse oximeter is 
unavailable, a local device 
may be used. All blood 
pressure measurements 
should be taken after the 
participant has rested in a 
seated position for at least 
3 minutes.
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
12-lead ECG
X
X
X
X
X
Q8W
X
X
Single 12-lead ECG. 
Participants must be in the 
recumbent position for a 
period of 5 minutes prior to 
the ECG. All ECGs should 
be prior to or no less than 60 
minutes after blood draw. 
Additional assessments 
should be performed if 
clinically indicated.
EPO
X
EPO levels will be measured 
≤10 days prior to 
randomization in all 
participants and should be 
measured prior to initiating 
EPO replacement therapy. 
EPO level to be measured by 
local laboratory.
Hematology
X
X
X
X
X
Q4W
X
X
All screening laboratory 
tests should be performed 
within 10 days prior to 
randomization. All tests 
should be performed by the 
central laboratory. 
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Chemistry
X*
X*
X
X
X*
Q4W
X
X
All screening laboratory 
tests should be performed 
within 10 days prior to 
randomization. All tests 
should be performed by the 
central laboratory.
*Fasting for ≥8 hours at 
screening, Week 1 Day 1, 
and every 8 weeks 
thereafter. There are no 
fasting restrictions for 
assessments at other time 
points.
Urinalysis
X
X
Q8W
X
X
To be performed locally.
Karnofsky 
performance status
X
KPS performance status is 
collected at screening only 
and should be within 10 
days prior to randomization.
ECOG performance 
status
X
X
X
X
X
Q4W
X
X
ECOG performance status at 
screening should be within 
10 days prior to 
randomization.
HBV, HCV, and 
HIV testing
X
Not required unless 
mandated by local health 
authorities. If mandated, 
conduct locally.
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Urine or serum
β-hCG - WOCBP 
only
X
X
X
X
Q4W
X
X
Female participants of 
childbearing potential will 
have a serum or highly 
sensitive urine pregnancy 
test within 1 day prior to 
randomization. If more than 
1 day has elapsed between 
the screening pregnancy test 
and the first dose of study 
intervention, another 
pregnancy test (urine or 
serum) must be performed 
within 24 hours of first dose 
and must be negative in 
order for the participant to 
start receiving study 
medication. Pregnancy tests 
will be conducted locally. 
PT or INR and 
aPTT
X
X
X
X
Q4W
X
X
Screening samples will be 
collected within 10 days 
prior to randomization. All 
tests should be performed by 
the central laboratory.
Additional testing to be 
conducted as clinically 
indicated for participants 
taking anticoagulant therapy. 
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Patient-reported Outcomes
PROs are to be 
administered in the order 
listed, prior to all 
assessments/procedures
FKSI-DRS
X
X
X
X
Q4W
X
X
Every effort should be made 
to administer PRO surveys 
on site prior to dosing and 
before other assessments and 
procedures.
As of 15-APR-2024, PROs 
will no longer be required.
EORTC QLQ-C30
X
X
X
X
Q4W
X
X
EuroQoL EQ-5D-
5L
X
X
X
X
Q4W
X
X
Pharmacokinetics/ Pharmacodynamics/ Biomarkers
CCI
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
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Study Period
Screening
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screeninga
Wk 1
Day 
1a
Wk 3
Day 1
Wk 5
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
±5
At 
time 
of 
DC
30 Days 
After 
Last 
Dose 
(+7 days)
Q8W or 
Q12W
(±7 days)
Q12W 
(±7 days)
Refer to Appendix 7 for 
country-specific 
requirements
Archival or newly 
obtained tissue 
collection
X
Tumor tissue (archival or 
newly acquired core or 
excisional biopsy) will be 
obtained at screening. 
Tumor blocks are preferred 
over cut slides (refer to the 
study laboratory manual for 
important details regarding 
tumor tissue submission 
time window and process). 
If submitting unstained cut 
slides, newly cut slides will 
be submitted to the testing 
laboratory (details pertaining 
to tumor tissue submission 
can be found in the study 
laboratory manual).
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Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; β-hCG = β-human chorionic gonadotropin; BICR = blinded independent central review; 
CBC = complete blood count; CR = complete response; CT = computed tomography; 
; DC = discontinuation; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for the Research and Treatment of Cancer Quality of Life 
Questionnaire 30; EOT = end-of-treatment; EQ-5D-5L = EuroQoL-5 dimensions-5 levels; FKSI-DRS = Functional Assessment of Cancer Therapy – Kidney Symptom 
Index-disease-related symptoms; 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; PRO = patient-reported outcome; PT = prothrombin 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 treatment, which should be on the date of randomization, but can be within 3 days following 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, contact, medical record review, etc. Participant status information includes survival 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 verified by BICR. 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 verified by BICR should continue with 
imaging assessments per the protocol-defined schedule until: 1) disease progression is verified by BICR, 2) initiation of a new anticancer treatment, 3) pregnancy, 4) 
death, 5) withdrawal of consent, or 6) the end of the study, whichever occurs first.
e.
Baseline bone scan is required for all participants at screening. Bone scans are not required to be repeated at screening if performed within 42 days prior to 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) until disease progression is verified by BICR. 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.
Samples for PK analyses will be collected only from participants randomized to belzutifan. The Week 1 Day 1 dose should be taken fasted (minimum of 2 hours fasting 
predose); food should be withheld for 1-hour postdose. A window of 30 minutes is permitted for all time points at which samples are collected.
A blood sample for PK assessments will be obtained on:
•
Week 1 Day 1: at predose, 1, 2 and 4 hours postdose.
•
On Week 3 Day 1, and Week 5 Day 1: participants will hold dosing of belzutifan tablets, until taken in the clinic.
o
A blood sample will be collected predose.
o
If a participant has a treatment interruption or discontinues treatment prior to 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.
A blood sample for pharmacodynamic assessments will be obtained on:
•
Week 1 Day 1 at predose, 1, 2 and 4 hours postdose (Postdose collections should only be from participants randomized to belzutifan); a window of 30 minutes is 
permitted.
•
Week 3 Day 1, and Week 5 Day 1, participants will hold dosing of belzutifan tablets, until taken in the clinic.
o
Week 3 and Week 5 Day 1, a blood sample will be collected predose. If a participant has a treatment interruption or discontinues treatment prior to 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.
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2
INTRODUCTION
This study will evaluate the efficacy and safety of the HIF-2α inhibitor, belzutifan, versus 
everolimus in participants with advanced RCC after prior therapy.
2.1
Study Rationale
2.1.1
Rationale for the Study of Belzutifan in Renal Cell Carcinoma
The hypoxia-inducible factor, HIF-2α, is believed to play a critical role in tumorigenesis and 
tumor progression in RCC. Belzutifan (MK-6482, formerly known as PT 2977) 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 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].
2.2
Background
2.2.1
Renal Cell Carcinoma
Renal cancers will be diagnosed in an estimated 400,000 patients worldwide each year and 
approximately 175,000 patients are expected to die of the disease [Bray, F., et al 2018]. RCC, 
an aggressive cancer, accounts for approximately 85% of all kidney cancers [National 
Comprehensive Cancer Network 2019]. RCC is a heterogeneous disease and comprises many 
distinct histologies with ccRCC, accounting for approximately 80% of all cases[Leibovich, 
B. C., et al 2010].
A substantial proportion of patients with RCC progress to advanced stage disease; about 
one-third of patients with RCC present with unresectable disease or metastases at diagnosis, 
and 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%. Prognostic factors for survival among RCC patients 
include tumor stage, grade, presence of regional or nodal metastases, and evidence of 
metastases at presentation [National Comprehensive Cancer Network 2019]. Common 
metastatic sites among patients with RCC include lung, lymph nodes, bone, liver, adrenal 
gland, and brain [Bianchi, M., et al 2012].
2.2.2
Hypoxia-inducible Factor and Renal Cell Carcinoma
HIF-2α is a transcription factor that regulates the body’s response to diminished availability 
of oxygen. HIF-2α activity is mediated by the activity of prolyl hydroxylase enzymes, which 
use oxygen to add hydroxyl groups to HIF-2α when oxygen availability is high 
(“normoxia”). The VHL tumor suppressor protein recognizes this modified form of HIF-2α, 
binds to it and targets it for degradation. Due to its efficient degradation, HIF-2α protein and 
activity levels are typically low under normoxia. Under hypoxia, the degradation system is 
inactive, and HIF-2α transcriptional activity is enhanced. This leads to the expression of a 
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variety of proteins, including factors associated with the production of new RBCs and the 
formation of new blood vessels.
In RCC, the VHL tumor suppressor is inactivated in the vast majority of patients. This defect 
in the ubiquitin-proteasome system results in the abnormal over accumulation and activation 
of HIF-2α. The aberrant activation of HIF-2α is a key oncogenic driver in RCC as it leads to 
excessive blood vessel growth, cell proliferation and other ill effects.
Refer to the IB for detailed background information on belzutifan.
2.2.3
Current Treatment Options
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 commonly 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. 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.
2.2.4
Pharmaceutical and Therapeutic Background
Belzutifan is a small molecule inhibitor of HIF-2α.
2.2.4.1
Pharmacology
Belzutifan is a potent and selective inhibitor of HIF-2α both in vitro and in vivo. HIF-2α is 
known to form a heterodimeric complex with HIF-1β, which is also referred to as ARNT; the 
heterodimer can then bind to hypoxic response elements in target genes and induce their 
transcription. The PAS domains of HIF are essential for heterodimerization of the HIF-
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2α:HIF-1β subunits, a prerequisite for target gene induction. A unique ligand-binding pocket 
has been identified in the PAS-B domain of HIF-2α [Scheuermann, T. H., et al 2013]. 
Belzutifan binds in this pocket, thereby disrupting HIF-2α:HIF-1β heterodimerization and 
directly inhibiting the function of HIF-2α.
In tumor cells in which HIF-2α is activated, belzutifan blocks the transcription of several 
genes involved in oncogenesis, including cyclin D1, VEGF-A, and the glucose transporter 
SLC2A1. 
 
2.2.5
Preclinical Studies
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2.2.5.2
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.
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.
A summary of belzutifan nonclinical toxicology is contained in the IB. The IB should be 
reviewed in conjunction with this study protocol.
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2.2.6
Clinical Studies
As of 06-SEP-2019, a total of 34 healthy volunteers and 185 patients had been treated with 
belzutifan in 5 ongoing 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 and 9 patients with GBM in the dose 
expansion cohort (Part 1B) 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. 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, 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 15.4 hours, resulting in 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 
estimated Vz/F was 106 to 266 L, which suggests extensive distribution to peripheral tissues. 
The CV was 32 to 59% for Cmax and 24 to 48% for AUC after a single dose, and 27 to 56% 
for Cmax and 30 to 64% for AUC at steady state. 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 11 
participants (20%) with PR and 32 participants (58%) with SD as assessed by RECIST v1.1.
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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.
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Preclinical toxicology results for belzutifan are summarized in Section 2.2.5.2. Recent 
preclinical findings in rats suggest that belzutifan may cause embryo-fetal lethality in 
humans. 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 in Section 10.5 through 10.5.2 (Appendix 5).
The proposed study will enroll participants with advanced RCC who have progressed after 
prior therapy. As described in Section 2.2.4.1, belzutifan is a potent and selective inhibitor of
HIF-2α in preclinical studies and clinical data as described in Section 2.2.6 show antitumor 
activity of belzutifan, which warrants further investigation. As described in Section 2.2.6, the 
most common AE of ≥Grade 3 toxicity occurring in 5% or more of the participants studied 
have been fatigue, anemia, and hypoxia. These AEs have frequently occurred in conjunction 
with acute comorbid conditions such as pneumonia, pleural effusion, etc. and have responded 
to appropriate management. Further guidance on the management of these AEs and dosing is 
provided in Sections 6.6.1, 6.6.1.1, and 6.6.1.2.
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.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
This study will be conducted in male and female participants with advanced clear cell RCC.
Primary Objectives
Primary Endpoints
To compare belzutifan to everolimus with 
respect to PFS per RECIST 1.1 as assessed 
by BICR.
Hypothesis (H1): Belzutifan is superior to 
everolimus with respect to PFS per 
RECIST 1.1 by BICR.
PFS: the time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first
Objective: To compare belzutifan to 
everolimus with respect to OS.
Hypothesis (H2): Belzutifan is superior to 
everolimus with respect to OS.
OS: the time from randomization to death 
due to any cause
Secondary Objectives
Secondary Endpoints
Objective: To compare belzutifan to 
everolimus with respect to ORR based on 
RECIST 1.1 as assessed by BICR.
Hypothesis (H3): Belzutifan increases ORR 
according to RECIST 1.1 by BICR 
compared to everolimus.
OR: CR or PR
Objective: To evaluate the 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 safety and 
tolerability of belzutifan compared to 
everolimus.
•
AEs
•
Study intervention discontinuation due 
to AEs
Objective: To evaluate TTD and change 
from baseline in HRQoL using the EORTC 
QLQ-C30 and the FKSI-DRS.
PRO scores for the following domains:
•
EORTC QLQ-C30 global health 
status/HRQoL (Items 29 and 30)
•
EORTC QLQ-C30 physical functioning 
(Items 1-5)
•
FKSI-DRS Subscale (Items 1-9)
Objective: To characterize health utility as 
measured using the EuroQoL EQ-5D-5L.
Health utility scores from the EQ-5D-5L
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, open-label, multicenter, randomized, active-controlled study to compare 
the efficacy and safety of belzutifan with that of everolimus in participants with advanced 
RCC that has progressed after prior PD-1/L1 and VEGF-targeted therapies.
Approximately 736 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 belzutifan or 
everolimus (~368 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 within 28 days before randomization, 
but can occur earlier unless otherwise specified. Potential participants will be screened to 
determine if they meet the required eligibility criteria.
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 VEGF/VEGF receptor targeted therapies for advanced RCC: 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 48 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 BICR-verified 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 
confirmed disease progression will continue with all protocol-required assessments and 
procedures.
Crossover between treatment arms is not planned.
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 following 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 following cessation of study intervention or 30 days 
following cessation of study intervention if the participant initiates new anticancer therapy, 
whichever is earlier.
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Study intervention will continue until documented disease progression (BICR-verified 
disease progression), unacceptable AEs, intercurrent illness that prevents further 
administration of study intervention, investigator’s decision to discontinue the participant, 
participant withdrawal of consent, pregnancy of the participant, 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 BICR-verified disease progression should 
continue with imaging assessments as described in the SoA and Section 8.2.2. Following 
verification of disease progression, all participants will be followed for survival (in-person 
visit, telephone contact, medical record review, etc.) until death, withdrawal of consent, lost 
to follow-up, or until the study is concluded or terminated early, whichever occurs first.
Two IAs are planned in addition to the FA for this study. The analyses planned, endpoints 
evaluated, and drivers of timing are summarized in Section 9.7.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
Refer to Appendix 7 for country-specific requirements.
4.2
Scientific Rationale for Study Design
This study uses an open-label design similar to what has been used in 2 pivotal randomized 
Phase 3 studies in advanced RCC, which compared axitinib to sorafenib (AXIS) and 
cabozantinib to everolimus (METEOR) [Rini, B. I., et al 2011] [Choueiri, T. K., et al 2016].
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. Investigators 
are to continue study treatment, to repeat radiographic studies at the next scheduled time, and 
to delay determination of progression until the findings indicating progression are 
unequivocal per BICR assessment.
Belzutifan and everolimus each have unique safety profiles that may result in the participants 
experiencing different AEs that may disclose the treatment invention received if the study 
was blinded.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The dual primary objectives of this study are to evaluate the efficacy of belzutifan compared 
with everolimus for the treatment of advanced RCC as assessed by PFS as determined by 
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BICR and by OS. A meta-analysis of 31 studies including 10,943 patients that studied the 
relationship between PFS and OS in metastatic RCC concluded that in RCC, the treatment 
effects on PFS are strongly associated with treatment effects on OS [Delea, T. E., et al 2012]. 
To ensure that PFS is rigorously evaluated, PFS will be determined by a BICR that will 
review all radiographic studies. The BICR will be blinded to study treatment.
This study will also use ORR and DOR as secondary endpoints. Efficacy will be evaluated 
using RECIST 1.1 for PFS, ORR, and DOR, determined by BICR.
PFS and ORR are acceptable measures of clinical benefit for a late stage 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 PFS and ORR 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. In 
addition, the final determination of radiologic progression will be based on the central 
assessment of progression, rather than a local site investigator/radiology assessment. 
Expedited verification of radiologic progression as determined by central review will be 
communicated to the site.
OS is standardly used to show benefit in oncology clinical studies.
DOR is considered an acceptable measure of clinical benefit when considered with ORR.
4.2.1.2
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the investigator when determining eligibility and for all protocol guidelines related to disease 
status (eg, discontinuation of study intervention). The RECIST 1.1 assessment of disease 
progression is used as a basis for discontinuation of treatment.
4.2.1.3
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version [5.0].
4.2.1.4
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention. As part of the 
analyses for this study, HRQoL and disease-related symptoms will be investigated among all 
participants via the FKSI-DRS, EORTC QLQ-C30, and EuroQoL EQ-5D-5L questionnaires. 
These measures are not pure efficacy or safety endpoints because they are affected by both 
disease progression and study intervention tolerability. The EQ-5D-5L will also be used to 
calculate health utilities for health economic models.
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FKSI-DRS
The FKSI-DRS is a patient-reported instrument that measures whether the patient has 
experienced any of the following 9 kidney cancer-related symptoms: lack of energy, fatigue, 
weight loss, pain (general), bone pain, shortness of breath, cough, fever, or blood in the urine 
[Cella, D., et al 2007]. Each item is scored by using the following 5 response categories: 0, 
not at all; 1, a little bit; 2, somewhat; 3, quite a bit; and 4, very much. All 9 questions are 
negatively stated items; according to the scoring manual, the score for each item must be 
reversed by subtracting the response from “4”. Participant responses to all FKSI-DRS items 
are summed to generate a summary symptom score ranging from 0 to 36, with higher scores 
indicating improved (more favorable) symptom status. The FKSI-DRS is a reliable, valid, 
and responsive brief index of the most important symptoms associated with advanced kidney 
cancer.
EORTC QLQ-C30
The EORTC QLQ-C30 was developed to assess the QoL of participants with cancer. It has 
been translated and validated in over 100 languages and used in more than 3000 studies 
worldwide. It contains 5 functional scales (physical, role, cognitive, emotional, and social), 
3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single symptom items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact) 
[Aaronson, N. K., et al 1993]. It is scored on a 4-point scale (1=not at all, 2=a little, 3=quite a 
bit, 4=very much). The EORTC QLQ-C30 instrument also contains 1 global health 
status/QoL scale that uses a 7-point scale scoring with anchors (1=very poor and 
7=excellent).
EuroQoL EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. The 
EQ-5D-5L will provide data for use in economic models and analyses including developing 
health utilities or quality-adjusted life-years [Rabin, R. and de Charro, F. 2001]. The 5 health 
state dimensions addressed in this instrument are mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The EuroQoL EQ-
5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant 
rates his or her general state of health at the time of the assessment. This instrument has been 
used extensively in cancer studies and published results from these studies support its 
validity and reliability [Pickard, A. S., et al 2007].
4.2.1.5
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 steady state Ctrough values. 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.
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4.2.1.6
Pharmacodynamic Endpoints
Assessment of serum EPO levels and other pharmacodynamic markers will be performed by 
the Sponsor or designee using a validated method.
4.2.1.7
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 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. Ct DNA and/or RNA may also be evaluated from 
blood samples.
CCI
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Tumor and blood RNA analyses
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 only from participants randomized to belzutifan. 
Pharmacodynamic biomarkers to be assessed include, but are not limited to, levels of EPO.
4.2.1.8
Future Biomedical Research
The Sponsor will conduct FBR 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 FBR.
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 
FBR 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 FBR research are 
presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator
Everolimus is indicated for advanced RCC after failure of treatment with sunitinib or 
sorafenib. In the Phase 3 randomized RECORD-1 study comparing everolimus or placebo in 
participants with metastatic RCC after treatment with sunitinib and/or sorafenib, everolimus 
was superior for PFS (4.9 months for everolimus vs 1.9 for placebo); there was no significant 
difference in OS between treatments. An analysis of data from an international consortium of 
25 cancer centers that provided data on 1,012 patients who had received third-line targeted 
therapy showed that, although a wide spectrum of targeted therapies was used in the third-
line setting, everolimus was the most prevalent third-line therapy used in 28% of patients 
[Wells, J. C., et al 2017]. Other agents included sunitinib, sorafenib, pazopanib, 
CCI
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temsirolimus, and axitinib, which were used in between 9% and 13% of patients. Based on 
the findings that everolimus is frequently used in late-line settings including the intended 
patient population for this study, everolimus was chosen as the appropriate comparator in this 
Phase 3 study. Use of everolimus as the comparator allows treatment by agents with different 
therapeutic targets (ie, HIF-2α or mTOR) than the patient’s prior therapies that have targeted 
the immune system and VEGF/VEGF receptor. The use of everolimus in this study’s 
participant population is in accordance with established clinical practice guidelines 
[Escudier, B., et al 2019] [National Comprehensive Cancer Network 2019].
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
The dose of belzutifan used in this study is 120 mg QD and is the optimum dose based on 
previous clinical study experience as described in Section 2.2.6.
The dose of everolimus used in this study is 10 mg QD and is the current approved dose.
4.3.2
Maximum Dose Exposure for This Study
There is no maximum duration of exposure for belzutifan or everolimus.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3), or the last participant on active treatment is consented in an extension study. For
purposes of analysis and reporting, the overall study ends when the Sponsor receives the last 
laboratory test result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
Male and female participants with advanced RCC 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. Has unresectable, locally advanced or metastatic clear cell RCC.
2. Has measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology. Lesions situated in a previously irradiated area are considered 
measurable if progression has been shown in such lesions.
Prior Therapy
3. Has had disease progression on or after having received systemic treatment for locally 
advanced or metastatic RCC with both: PD-1/L1 checkpoint inhibitor and VEGF-TKI in 
sequence or in combination.
-
PD-1/L1 checkpoint inhibitor treatment progression is defined by meeting ALL of the 
following criteria:
◦
Has received at least 2 doses of an anti-PD-1/L1 mAb
◦
Has demonstrated radiographic PD during or after an anti-PD-1/L1 mAb
-
VEGF-TKI treatment progression is defined by meeting the following criteria:
◦
Has demonstrated radiographic PD during or after a treatment with a VEGF-TKI
4. Has received no more than 3 prior systemic regimens for locally advanced or metastatic 
RCC.
5. For the most recently received regimen, has demonstrated radiographic disease 
progression.
Demographics
6. Is male or female, who is at least 18 years of age at the time of signing the informed 
consent.
7. Has a KPS score of at least 70% assessed within 10 days prior to randomization.
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
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8. 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
-
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.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
9. 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 for those 
randomized to the belzutifan study intervention and for at least 8 weeks after last 
dose of study intervention for those randomized to the everolimus arm. 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) 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 test is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
in the Schedule of Activities.
•
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.
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Informed Consent
10. The participant (or legally acceptable representative) has provided documented informed
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the main study without participating in FBR. Refer to 
Appendix 7 for country-specific requirements.
Additional Categories
11. Has adequate organ function, as detailed in Table 1; all screening laboratory tests should 
be performed within 10 days prior to randomization. Screening laboratory tests should be 
fasting for >8 hours. Note: Participant cannot have received colony-stimulating factors 
(eg, G-CSF, GM-CSF or recombinant EPO) or packed RBC transfusion ≤28 days prior to 
hemoglobin assessment. Refer to Appendix 7 for country-specific requirements.
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/L
Renal
Serum creatinine or estimated CrCl using the 
Cockcroft-Gault equation, or based on a 24-hour 
urine testa (GFR can also be used in place of 
creatinine or CrCl)
≤1.5 × ULN OR
≥51 mL/min for participants with creatinine levels 
>1.5 x 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
Fasting serum triglycerides and total cholesterol
≤2.5 x ULN AND total cholesterol ≤300 mg/dL 
(≤7.75 mmol/L). Lipid-lowering medication is 
allowed
Fasting Glucose
a fasting glucose ≤160 mg/dL (≤8.9 mmol/L) is 
required
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.
Estimated creatinine clearance using Cockcroft-Gault:
(140-age [years] × weight (kg)
(×F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for females and F = 1 for males
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.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. A WOCBP who has a positive urine pregnancy test within 24 hours prior to 
randomization (see Appendix 5). If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.
Note: If more than 1 day has elapsed between the screening pregnancy test and the first 
dose of study intervention, another pregnancy test (urine or serum) must be performed 
within 24 hours before the first dose of study intervention and must be negative in order 
for the participant to start receiving study medication.
2. Has any of the following:
-
Hypoxia as defined by pulse oximeter reading <92% at rest, OR
-
Requires intermittent supplemental oxygen, OR
-
Requires chronic supplemental oxygen.
3. 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.
4. 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 randomization.
5. Has clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months from Day 1 of study medication administration, or New York 
Heart Association Class III or IV congestive heart failure. Medically controlled 
arrhythmia stable on medication is permitted.
6. Has poorly controlled hypertension defined as SBP ≥150 mm Hg and/or DBP ≥90 mm 
Hg.
7. Has moderate to severe hepatic impairment (Child-Pugh B or C).
8. Received colony-stimulating factors (eg, G-CSF, GM-CSF or recombinant EPO) within 
28 days prior to randomization.
9. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the study.
10. Is unable to swallow orally administered medication or has a gastrointestinal disorder 
affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption).
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11. Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any 
component of the study intervention (belzutifan or everolimus) formulations.
Prior/Concomitant Therapy
12. Has received prior treatment with belzutifan or another HIF-2α inhibitor.
13. Has received any prior treatment with everolimus or any other specific or selective 
TORC1/PI3K/AKT inhibitor (eg, temsirolimus) in the advanced disease setting.
14. Has received any type of small molecule kinase inhibitor (including investigational 
kinase inhibitor) within 2 weeks before randomization.
15. Has received any type of systemic anticancer antibody (including investigational 
antibody) within 4 weeks before randomization.
16. Has received prior radiotherapy within 2 weeks prior to randomization. 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.
17. Has had major surgery within 3 weeks prior to randomization. Note: Adequate wound 
healing after major surgery must be assessed clinically, independent of time elapsed for 
eligibility.
18. Has received a live vaccine within 30 days prior to the randomization of study 
medication. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®/Fluenz 
Tetra) are live attenuated vaccines and are not allowed.
19. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, 
protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, 
boceprevir, telaprevir) or moderate (eg, ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil) inhibitors of CYP3A4 that cannot be discontinued for the 
duration of the study.
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
20. 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
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21. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
22. Is currently receiving a drug that is an inhibitor of P-gp (eg, cyclosporin, elacridar, 
ketoconazole, quinidine, reserpine, ritonavir, tacrolimus, valspodar, verapamil, 
zosuquidar) that cannot be discontinued for the duration of the study.
Note: A current list of inhibitors of P-gp can be found at the following website:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm
Prior/Concurrent Clinical Study Experience
23. 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 or 5 half-lives, whichever is longer (investigational antibody only 
requires 4 weeks after last dose).
Diagnostic Assessments
24. Has an active infection requiring systemic therapy.
25. Has active TB.
26. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior randomization. Exception: Replacement 
corticosteroid therapy for adrenal or pituitary insufficiency is allowed.
27. Has a known history of HIV infection.
Note: Testing for HIV at screening is only required if mandated by local health authority. 
Refer to Appendix 7 for country-specific requirements.
28. 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. 
Refer to Appendix 7 for country-specific requirements.
5.3
Lifestyle Considerations
5.3.1
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.
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
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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.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention(s) provided by the Sponsor; local supply as needed) 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 interventions to be used in this study are outlined in Table 2.
Country-specific requirements are noted in Appendix 7.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Levels
Route of 
Administration
Regimen/
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Belzutifan
Experimental Belzutifan
Drug
Tablet
40 mg 
tablet
120 mg
Oral
QD
Test 
Product
IMP
Central
Everolimus Active 
Comparator
Everolimus
Drug
Tablet
10 mg 
tablet
10 mg
Oral
QD
Comparator IMP
Central; 
local 
supply as 
needed
Abbreviations: EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; QD=once daily.
Belzutifan: 120 mg dose should be made up of 3 × 40 mg tablets.
Everolimus: 2.5 mg and 5 mg tablets are provided for dose reductions as outlined in Section 6.6.2.
Note: The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences 
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All 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
6.2.1
Dose Preparation
6.2.1.1
Belzutifan
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. Each bottle of study intervention will contain 90 tablets of a single 
strength of belzutifan (40 mg) and a desiccant insert.
The Pharmacy Manual contains additional information.
6.2.1.2
Everolimus
Everolimus will be available as 10-mg, 5-mg, and 2.5-mg tablets. Refer to the package insert 
for additional information. Everolimus is to be administered as the tablet formulation only; 
the suspension formulation is not to be used.
All dosages of everolimus (10-mg, 5-mg, and 2.5-mg) will be available in commercial 
packaging if locally sourced.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
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For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment allocation will occur centrally using an IRT system. There are 2 study intervention 
treatment groups. Participants will be assigned randomly in a 1:1 ratio to belzutifan study 
intervention or everolimus study intervention.
6.3.2
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 VEGF/VEGF receptor targeted therapies for advanced RCC: 1 vs 2-3
The IMDC prognostic factors are the following:
•
Clinical Risk Factors
-
Low KPS score (<80%)
-
Time from diagnosis to initiation of first-line treatment <1 year
•
Laboratory Risk Factors
-
Low hemoglobin (<LLN)
-
High corrected serum calcium (>ULN)
-
High neutrophils (>ULN)
-
High levels of platelets (>ULN)
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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, and only results from central laboratory testing will be 
considered for the laboratory factors.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
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 his/her designated and qualified representatives will dispense study 
intervention (except locally sourced everolimus) 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 Weeks 1, 3, and 5 when 
belzutifan dosing will occur during the clinic visit.
All participants must bring back to the clinic their bottle(s)/packages of 
belzutifan/everolimus at the appropriate scheduled visit. 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 (if 
permitted) until reconciliation is completed by the study monitor, if possible.
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.
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6.5
Concomitant Therapy
All concomitant medications received within 28 days prior to randomization and up to 30 
days after the last dose of study intervention should be recorded. Concomitant medications 
administered >30 days after the last dose of study intervention should be recorded for SAEs 
as 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 should also be included on the eCRF.
In vitro and physiologically based PK modeling results indicated that belzutifan is a weak 
inducer of CYP3A4. Belzutifan may, therefore, decrease the exposure of concomitant 
medications that are mainly metabolized by CYP3A4, including hormonal contraceptives; 
however, the clinical relevance of these effects is not clear. Inhibitors of UGT2B17 or 
CYP2C19 may increase plasma exposure of belzutifan, which may increase the incidence 
and/or severity of adverse reactions.
Everolimus is a substrate of CYP3A4 and of the multidrug efflux pump P-gp. Refer to the 
most current everolimus prescribing information about potential drug interactions and 
appropriate dosage adjustments.
6.5.1
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 symptomatic lesions or to the brain is allowed 
following Sponsor consultation.
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4. Live vaccines while participating in the study. Refer to Appendix 7 for country-specific 
requirements.
•
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chickenpox, yellow fever, intranasal seasonal influenza, rabies, 
BCG, and typhoid (oral).
Note: Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed
5. Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE. 
Corticosteroid replacement therapy for participants with adrenal or pituitary insufficiency 
is permitted. Note: Inhaled, intranasal, ophthalmologic, intra-articular or intrathecal 
steroid injections are permitted.
6. Use of strong inhibitors of CYP3A4 is not allowed on treatment. If a moderate CYP3A4 
inhibitor or a moderate/strong CYP3A4 inducer is required during the study intervention 
treatment period for participants randomized to belzutifan consult with the Sponsor 
Clinical Director; for participants randomized to everolimus, refer to the everolimus 
package insert for guidance.
•
Note: a current list of strong/moderate inducers/inhibitors of CYP3A4 can be found 
at the following website:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/D
rugInteractionsLabeling/ucm093664.htm
7. P-gp inhibitors are not prohibited during the study intervention treatment period for 
participants randomized to belzutifan. If a P-gp inhibitor is required during the study 
intervention treatment period for participants randomized to everolimus, refer to the 
everolimus package insert for guidance.
•
Note: a current list of P-gp inhibitors 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
8. ACE inhibitors are prohibited for those participants receiving everolimus, however, are 
not prohibited for participants receiving belzutifan.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from treatment, but 
continue in study for assessment of disease status and survival.
There are no prohibited therapies during the Survival Follow-up Phase.
6.5.2
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
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6.6
Dose Modification
6.6.1
Belzutifan Dosing Modifications
Guidelines for dose modification for belzutifan are listed in Table 3. Specific dose reduction 
levels are listed in Table 4.
The following should be considered in decisions regarding dose modifications:
•
As a general approach, all AEs should be managed with supportive care at the earliest 
signs of toxicity considered related to belzutifan treatment. Should this be ineffective, 
dose reductions or interruptions should 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 of study treatment for >28 days will require Sponsor 
consultation.
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. Refer to the ECI Guidance 
(Appendix 8) for additional practice guidelines and management recommendations for AEs 
potentially related to belzutifan treatment.
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Table 3
Dose Modification Guidelines for Belzutifan-related Toxicities
Belzutifan-related Toxicity
Action
Anemia
Grade 4 anemia
First episode: Hold belzutifan. Once 
toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by one 
level.
Second 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 one 
hour,) or
Grade 4 neutropenia for >5 
days
First and second episodes: Hold belzutifan. 
Once toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by one 
level.
Third episode: Permanently discontinue 
belzutifan.
Grade 4 febrile neutropenia
Permanently discontinue belzutifan.
Thrombocytopenia
Grade 3 thrombocytopenia 
with bleeding
First and second episodes: Hold belzutifan. 
Once toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by one 
level.
Third episode: Permanently discontinue 
belzutifan.
Grade 4 thrombocytopenia
First episode: Hold belzutifan. Once 
toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by one 
level.
Second 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)
First and second episodes: Hold belzutifan. 
Once toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by one 
level.
Third episode: Permanently discontinue 
belzutifan.
Grade 4 dyspnea
Grade 4 hypoxia
Permanently Discontinue belzutifan.
Gastrointestinal
Grade 3 or 4 nausea, 
vomiting, or diarrhea if 
persistent for >48 hours 
despite optimal antiemetic or 
antidiarrheal therapy
First and second episodes: Hold belzutifan. 
Once toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by one 
level.
Third episode: Permanently discontinue 
belzutifan.
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Belzutifan-related Toxicity
Action
Hepatic
Grade 3 increase in AST 
and/or ALT levels, if 
confirmed upon repeat testing 
within 48 hours
First episode: Hold belzutifan. Once 
toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by one 
level.
Second episode: Permanently discontinue 
belzutifan.
Grade 4 increase in AST 
and/or ALT levels, if 
confirmed upon 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 Nonlaboratory 
Toxicities
Any other nonlaboratory 
Grade 3 toxicity (excluding 
weight increased)
First and second episodes: Hold belzutifan. 
Once toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by one 
level.
Third 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; ULN = upper limit of normal; AST = aspartate aminotransferase; ALT 
= alanine aminotransferase.
Re-escalation to the next higher dose level may be permitted after Sponsor Consultation for a participant that 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 one dose level” and participant is already at dose level -2 when a toxicity occurred, belzutifan 
should be permanently discontinued.
Table 4
Belzutifan Dose Levels
Dose Level 
Dose 
Starting Dose 
120 mg QD
-1 
80 mg QD
-2 
40 mg QD
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6.6.1.1
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. Transfusion 
can also be used to manage anemia in patients receiving belzutifan.
6.6.1.2
Management of Hypoxia
Participants enrolled in the study will have a baseline pulse oximetry of at least 92% at rest, 
nor require 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. Diagnosis of hypoxia is to follow 
CTCAE v5 and management to follow the dose modification Table 3 and ECI guidance in 
Appendix 8.
6.6.2
Everolimus Dosing Modifications
For participants on the everolimus arm, dose adjustments and the management of AEs should 
be made as described in the everolimus package insert.
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 (belzutifan and everolimus) 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.
6.9.1
Study Site Retention Samples
Not applicable
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention 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 
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.
•
Radiographic disease progression outlined in Section 8.2.1 (exception if the Sponsor 
approves treatment continuation following BICR-verified disease progression per 
RECIST [Section 4.1]).
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires treatment.
•
Unacceptable AEs or toxicities (Section 6.6).
•
The participant interrupts study intervention administration for >28 consecutive days 
without Sponsor consultation.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum or highly sensitive urine pregnancy test.
•
Sponsor discontinuation of study.
As described in Section 4.1, treatment may continue beyond BICR-verified disease 
progression, but requires Sponsor consultation and approval. If approved by the Sponsor, 
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continued participation requires additional consent (Section 8.1.1). Participants who continue 
treatment beyond confirmed 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.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. 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.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within 
the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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 
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protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
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The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically significant. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history. Investigator will discuss use of tobacco or any inhaled agents 
(vaping) with study participants as it is important to understand the pulmonary and cardiac 
health of study participants. It is not known whether prior use of these agents will impact the 
incidence of hypoxia, an ECI for this study. Refer to Appendix 7 for country-specific 
requirements.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication/vaccination use, 
including any protocol-specified washout requirement, and record prior 
medication/vaccination taken by the participant within 28 days before randomization.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
treatment allocation. Once a 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 randomization number.
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8.1.8
Study Intervention Administration
Study intervention should begin on the date of randomization, but can be within 3 days 
following randomization. Every effort should be made to ensure the participants receive the 
first dose of study intervention on the day of randomization.
8.1.8.1
Belzutifan
Study intervention may be administered at home except on clinic visit days on Day 1 of 
Weeks 1, 3, 5, and 9. Study intervention on these days will occur in the clinic after 
completion of blood collection.
8.1.8.2
Everolimus
Study intervention may be administered at home except on clinic visit days of Week 1, 3, 5, 
and 9.
8.1.8.3
Timing of Dose Administration
Participants should be given clear instructions on how and when to take their study 
intervention. Three 40-mg tablets of belzutifan or everolimus 10mg will be taken orally QD, 
with doses taken at approximately the same time of day. Study medication can be taken 
without regard to food.
Missed doses may be made up if taken within 6 hours after the scheduled administration 
time. In the event of a missed everolimus dose, refer to the package insert or SmPC. 
Participants who vomit after study medication administration should not retake that study 
medication dose but should resume taking study medication with the next scheduled dose.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention 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 FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. The participant’s data will be included in any analyses that are in 
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progress at the time of the request for withdrawal or that have already been performed before 
the request being received by the Sponsor. The participant’s data will not be included in any 
new analyses generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding in this study.
8.1.11
Tissue Collection
A tumor specimen for biomarker assessment will be provided or collected prior to 
randomization in the study. A new tumor specimen, if obtained as part of normal clinical 
practice (not solely for the purpose of screening for randomization in this study) is preferred 
to archival samples.
A core or excision biopsy of a tumor lesion 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 prior to 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.
8.1.12
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.
CCI
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8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the iCRO can be found in the SIM. In 
general, imaging should include the chest, abdomen, and pelvis. Tumor imaging 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 imaging the brain. 
Imaging of any anatomy that shows disease either at screening or in subsequent evaluations 
will be required and should be submitted to the iCRO. The same imaging 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 imaging.
Note: for the purposes of assessing tumor imaging, 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 images for all study participants from the sites will be submitted to the iCRO. 
In addition, images (including via other modalities) that are obtained at an unscheduled time 
point to determine disease progression, as well as imaging obtained for other reasons, but 
which captures radiologic progression based on investigator assessment, should also be 
submitted to the iCRO.
When the investigator identifies radiographic progression per RECIST 1.1, the BICR will 
perform expedited verification of radiologic disease progression and the results will be 
communicated to the study site and the Sponsor via email. In clinically stable participants, 
imaging should continue until disease progression has been verified by BICR (if initial site-
assessed disease progression was not verified by BICR, each subsequent scan, if indicating 
progression, must be submitted to the iCRO with a verification of disease progression request 
until disease progression has been verified by BICR).
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
randomization. The site study team must review screening images to confirm the participant 
has measurable disease per RECIST 1.1.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality, performed within 28 days prior to the 
date of randomization and can be assessed by the iCRO.
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Tumor imaging 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 within 42 days prior to randomization.
•
Brain imaging is required at screening for those participants with brain metastases at 
baseline (ie, to confirm stability) or 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 imaging assessment should be performed at Week 9 Day 1 (±7 days) from 
the date of randomization. Subsequent tumor imaging 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 imaging performed Q12W 
(±7 days). The imaging visit window is ±14 days after Week 109. Imaging timing should 
follow the imaging scheduling calculator from the date of randomization and should not be 
adjusted for delays in study intervention. Imaging should continue to be performed until 
disease progression is BICR-verified (unless the investigator elects to continue treatment 
following Sponsor approval [Section 7.1]), or until any of the following conditions are met, 
whichever occurs first:
•
Initiation of new anticancer treatment
•
Withdrawal of consent
•
Pregnancy
•
Death
•
The end of the study
All supplemental imaging must be submitted to the iCRO.
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) until disease progression is 
verified by BICR. 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.
After randomization, brain imaging should be performed as clinically indicated and to 
confirm a CR in participants with brain metastases at baseline.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks (at least 28 days) after the first 
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indication of a response is observed. Participants will then return to regular scheduled 
imaging, starting with the next scheduled imaging time point. Participants who receive 
additional imaging for confirmation do not need to undergo the next scheduled tumor 
imaging if it is less than 4 weeks (<28 days) later; tumor imaging may resume at the 
subsequent scheduled imaging time point. Note: Response does not typically need to be 
verified in real time by BICR.
On investigator-assessed disease progression, the indicative scan(s) is to be submitted 
immediately to the iCRO for BICR verification of progression. After submission of the 
scan(s), the iCRO will email the assessment to the site and the Sponsor. Participants who 
have unverified disease progression should continue on treatment at the discretion of the 
investigator until disease progression is BICR-verified provided they are clinically stable. In 
clinically stable participants, imaging should continue until disease progression has been 
verified by BICR (if initial site-assessed disease progression was not verified by BICR, each 
subsequent scan, if indicating progression, must be submitted to the iCRO with a verification 
of disease progression request until disease progression has been verified by BICR).
If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
-
Resume imaging per protocol schedule (Q8W until Week 49, then Q12W)
-
Send scans to iCRO
-
Continue local assessment
-
Do not change investigator assessment of disease progression
-
If subsequent scan(s) indicate progression, submit scan(s) to iCRO to request 
verification
•
If the participant is not clinically stable, best medical practice is to be applied.
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
If disease progression is verified, the process continues as follows:
•
Investigator 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.
-
Obtain scans locally per original protocol schedule
-
Do not send scans to iCRO.
Figure 2 illustrates the study intervention decision process involving verification of disease 
progression for participants.
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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.
Figure 2
Decision-Making Process When Progression Observed by Investigator
iCRO=imaging contract research organization; RECIST=Response Evaluation Criteria in Solid Tumors; VOP=verification 
of progression.
Participants who continue treatment beyond verified disease progression must sign a separate 
ICF and will continue with all protocol-specified assessments and procedures.
8.2.1.3
End-of-treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window from treatment discontinuation). If 
previous imaging was obtained within 4 weeks (28 days) prior to the date of discontinuation, 
then imaging at treatment discontinuation is not mandatory. For participants who discontinue 
study intervention due to documented disease progression (BICR-verified disease 
progression), this is the final required tumor imaging.
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Participants who discontinue study treatment for reasons other than disease progression, that 
is BICR-verified, should continue with imaging assessments per the protocol-defined 
schedule until one of the following conditions are met:
•
Disease progression is BICR-verified
•
Start of a new anticancer treatment
•
Pregnancy
•
Death
•
Withdrawal of consent
•
End of the study, whichever occurs first.
For participants who discontinue for reasons other than disease progression, imaging 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 is verified by BICR.
8.2.2
Quality of Life Assessments
The PROs will be completed on Day 1 of Weeks 1, 3, 5, and 9, Q4W thereafter, at the 
treatment discontinuation visit, and at the 30-day Posttreatment Safety Follow-Up Visit. It is 
estimated that the assessments will take approximately 10 minutes. The FKSI-DRS, EORTC 
QLQ-C30, and EQ-5D-5L questionnaires will be administered by trained study-site 
personnel and completed by the participants themselves.
It is strongly recommended that PROs are administered prior to other study procedures and 
assessments including drug administration, AE evaluation, and disease status notification. 
The PROs are to be completed in the following order: FKSI-DRS, then EORTC QLQ-C30, 
then EQ-5D-5L at the time points specified in Section 1.3.
As of 15-APR-2024, PROs will no longer be required.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided throughout Section 8.3. The total amount of blood/tissue to be drawn/collected over 
the course of the study (from prestudy to poststudy visits), including approximate 
blood/tissue volumes drawn/collected by visit and by sample type per participant, can be 
found in the laboratory manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard and at the time points 
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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.
8.3.2
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.
8.3.3
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 using Fridericia’s formula locally. Additional ECGs should be 
performed when clinically necessary.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
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.
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8.3.5
KPS and ECOG Performance Status
The investigator or qualified designee will assess KPS and ECOG performance status at 
screening (within 10 days prior to randomization). The investigator or qualified designee will 
assess ECOG performance status on Day 1 of Weeks 1, 3, 5, 9, and Q4W thereafter (Section 
1.3). ECOG performance status will also be assessed at the treatment discontinuation visit, 
and at the 30-day Posttreatment Safety Follow-Up Visit. ECOG performance status [Oken, 
M. M., et al 1982] will be assessed prior to 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 need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention randomization through 30 days after cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days after cessation of study intervention or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
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•
All pregnancies and exposure during breastfeeding, from the time of intervention 
randomization through 30 days for belzutifan or 8 weeks for everolimus following 
cessation of study intervention, or 30 days after cessation of study intervention if the 
participant initiates new anticancer therapy must be reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5.
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Table 5
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
Nonserious Adverse 
Event (NSAE)
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
– due to 
intervention
– causes exclusion
Report all
Previously reported 
– Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
– due to 
intervention
– causes exclusion
Report
– potential 
drug-induced 
liver injury 
(DILI)
– require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (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
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. 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). The investigator will also make every attempt to 
follow nonserious AEs that occur in randomized participants for outcome. Further 
information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Note: To meet EU CTR requirements, the Sponsor will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR form in compliance with CTR 536/2014.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of 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.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as 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.
8.4.7
Events of Clinical Interest
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
ECIs that are not SAEs should be collected through 30 days following cessation of study 
intervention and must be reported by the investigator. ECIs that are SAEs should be collected 
through 90 following cessation of study intervention and must be reported by the 
investigator.
Events of clinical interest for this study include:
a.
An overdose of Sponsor’s product, as defined in Section 8.5.
b. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3X the upper limit of normal and an elevated total bilirubin laboratory 
value that is greater than or equal to 2X the upper limit of normal and, at the same time, 
an alkaline phosphatase laboratory 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).
c.
Any ≥Grade 3 anemia
d. Any ≥Grade 3 hypoxia
e.
Any ≥Grade 3 AE deemed related to belzutifan by the investigator, including laboratory 
abnormalities
8.5
Treatment of Overdose
Overdose will be defined as any dose greater than 240 mg QD of belzutifan. No specific 
information is available on the treatment of overdose of belzutifan. In the event of overdose
the participant should be observed closely for signs of toxicity. Appropriate supportive 
treatment should be provided if clinically indicated. Overdose is defined as any dose 
exceeding the prescribed dose of everolimus. No specific information is available on the 
treatment of overdose of everolimus. In the event of overdose, everolimus should be 
interrupted and the participant should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
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8.6
Pharmacokinetics
8.7
Pharmacodynamics
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.
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8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover specimens as listed in Section 8.8.
8.10
Medical Resource Utilization and Health Economics
Medical resource utilization and health economic data, associated with medical encounters, 
will be collected in the eCRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
•
All-cause hospitalizations and emergency department visits, from the time of treatment 
allocation through 90 days following cessation of study intervention, or 30 days 
following cessation of study intervention, if the participant initiates new anticancer 
therapy, whichever is earlier.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
From -28 days to -1 day prior to randomization, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.
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Written 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 specified time 
frame.
Screening procedures are to be completed within 28 days before randomization except for the 
following:
•
Laboratory tests are to be performed within 10 days prior to randomization. An exception 
is HIV (if required by local health authority) and hepatitis testing which may be 
conducted up to 28 days prior to randomization. Refer to Appendix 7 for country-specific 
requirements.
•
Evaluation of KPS and ECOG is to be performed within 10 days prior to randomization.
•
For WOCBP, a urine pregnancy test will be performed within 24 hours prior to 
randomization. If greater than 1 day has elapsed between the screening pregnancy test 
and the first dose of study intervention, another pregnancy test (urine or serum) must be 
performed within 24 hours of first dose and must be negative in order for participants to 
start receiving study medication. 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 prior to randomization.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.11.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1. Assessments/procedures should be performed, prior to the 
administration of study intervention.
8.11.3
Posttreatment
8.11.3.1
Posttreatment Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
8.11.3.2
Imaging Follow-up
Participants who discontinue study treatment for reasons other than BICR-verified disease 
progression should continue with imaging assessments per the protocol-defined schedule 
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until: 1) disease progression is BICR-verified, 2) initiation of a new anticancer treatment, 3) 
death, 4) pregnancy, 5) withdrawal of consent, or 6) the end of the study, whichever occurs 
first. Tumor imaging 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 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 should be followed for survival 
(in-person visit, telephone contact, medical record review, etc.) approximately Q12W. Every 
effort should be made to assess for survival 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.
The first survival follow-up assessment should be scheduled as described below:
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
For participants who completed assessments in Efficacy Follow-up, the first survival follow-
up contact will be scheduled 12 weeks after the last efficacy assessment follow-up visit has 
been performed.
To ensure current and complete survival data are available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to, 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 
survival status.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to these hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to the exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a sSAP and referenced in the CSR for the study. Posthoc exploratory analyses 
will be clearly identified in the CSR. The PRO analysis plan will be included in the sSAP. A 
separate biomarker analysis plan may be provided as appropriate in the sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A randomized, open-label, Phase 3 controlled study of the HIF-2α 
inhibitor, belzutifan, versus everolimus in participants with advanced 
renal cell carcinoma after prior therapy
Treatment Assignment
Participants will be randomly assigned in a 1:1 ratio to receive either 
belzutifan at 120 mg QD or everolimus at 10 mg QD.
Stratification factors are as follows:
IMDC prognostic scores: 0 vs 1-2 vs 3-6
Number of prior VEGF/VEGF receptor targeted therapies for 
advanced RCC: 1 vs 2-3
Analysis Populations
Efficacy: ITT
Safety: APaT
Primary Endpoints
PFS
OS
Secondary Endpoints
ORR
DOR
PRO assessment
AEs and discontinuations due to AEs
Statistical Methods for
Key Efficacy Analyses
The primary hypotheses comparing belzutifan to everolimus with 
respect to PFS and OS will be evaluated using a stratified log-rank test. 
The hazard ratio will be estimated using a stratified Cox regression 
model. Event rates over time will be estimated within each treatment 
group using the Kaplan-Meier method. The stratified Miettinen and 
Nurminen method with strata weighted by sample size will be used for 
analysis of ORR.
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].
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Interim Analyses
Two IAs are planned for the study. Results will be reviewed by an 
external DMC. Details are provided in Section 9.7.
Primary purpose: efficacy analyses for PFS, OS, and ORR.
Second IA (IA2):
Primary purpose: efficacy analysis for OS and PFS (final analysis).
FA:
Primary purpose: efficacy analysis for OS.
Multiplicity
The overall Type I error rate over the primary and secondary 
hypotheses is strongly controlled at 2.5% (1-sided), with 0.5% initially 
allocated to PFS (H1), 1.9% initially allocated to OS (H2) and 0.1% 
initially allocated to ORR (H3). By using the graphical approach of 
Maurer and Bretz, if one hypothesis is rejected, the alpha will be 
shifted to other hypotheses [Maurer, W. and Bretz, F. 2013].
Sample Size and Power
The planned sample size is approximately 736 participants.
There will be ~483 deaths at the final OS analysis. With 483 deaths, 
the study has ~85.4% power for detecting a HR of 0.75 at an initially 
assigned 0.019 (1-sided) significance level.
It is estimated that there will be ~626 events at the final PFS analysis 
(ie, the second IA of the study). With 626 PFS events, the study has 
~96.9% power for detecting a HR of 0.70 at an initially assigned 0.005 
(1-sided) significance level.
Based on all randomized participants, the power of the ORR testing at 
the allocated α=0.001 is approximately 99.9% to detect a 15-
percentage point difference between an underlying 5% response rate in 
the control arm and a 20% response rate in the experimental arm.
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.
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9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Primary:
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.
OS – OS is defined as the time from randomization to death due to any cause.
Secondary:
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.
DOR – For participants who demonstrated confirmed 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.
9.4.2
Safety Endpoints
A description of safety endpoint assessment is provided in Section 4.2.1.3. Assessments 
include, but not limited to, the incidence of, causality of, and outcome of AEs/SAEs; and 
changes in laboratory values.
9.4.3
Patient-reported Outcome Endpoints
As described in Section 4.2.1.4, the following PRO assessments will be evaluated:
•
Scores from the EORTC QLQ-C30:
-
Global health status/QoL scale (items 29 and 30)
-
Physical functioning scale (items 1-5)
•
Scores from the FKSI-DRS
•
Health Utility Scores from the EQ-5D-5L
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The ITT population will serve as the population for primary efficacy analysis. All 
randomized participants will be included in this population. Participants will be included in 
the treatment arm to which they are randomized. The same population will be used for all 
efficacy analyses unless otherwise specified in the sSAP.
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9.5.2
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. 
For most participants this will be the treatment group to which they are randomized. 
Participants who take incorrect study treatment for the entire treatment period will be 
included in the treatment group corresponding to the study treatment actually received.
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.
9.5.3
Patient-reported Outcome Analysis Population
The PRO analyses are based on the PRO FAS population, defined as randomized participants 
who have at least 1 PRO assessment available and have received at least 1 dose of study 
treatment.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
9.6.1.1
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, 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 both the stratified log-rank test and the 
stratified Cox model.
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9.6.1.2
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, the HR). The HR and its 95% CI from the stratified 
Cox model with a single treatment covariate will be reported. The stratification factors used 
for randomization (Section 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model. Participants without documented death at the time of analysis will be 
censored at the date the participant was last known to be alive.
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9.6.1.3
Objective Response Rate
The stratified Miettinen and Nurminen’s method will be used for comparison of the ORR 
between 2 treatment groups. The difference in ORR and its 95% confidence interval 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.
9.6.1.4
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 subjects still in response 
and 95% CIs at specific duration time points will be provided.
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 8.
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Table 8
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Hypothesis 1 
PFS as assessed by BICR 
according to RECIST 1.1 
Test: Stratified log-rank test
Estimation: Stratified Cox
model with Efron’s tie
handling method
ITT
Primary censoring rule
• Sensitivity analysis 1
• Sensitivity analysis 2
(More details are in Table 6)
Primary Hypothesis 2
OS 
Test: stratified log-rank test
Estimation: stratified Cox model 
with Efron’s tie handling method
ITT
Censored at last known alive 
date
Key Secondary Hypothesis 3
ORR as assessed by 
BICR according to 
RECIST 1.1 
Testing and estimation:
stratified Miettinen and 
Nurminen method
ITT
Participants with missing 
data are considered 
nonresponders
Abbreviations: BICR = blinded independent central review; ITT = intent-to-treat; ORR = objective response rate; 
OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors Version 1.1.
Note: Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization will be used as stratification factors for analysis.
9.6.2
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.
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 exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
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of at least 10% of participants was chosen for Tier 2 events because the population enrolled 
in this study is in critical condition and usually experiences various AEs of similar types 
regardless of treatment; events reported less frequently than 10% of participants would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of 
participants in 1 of the treatment groups) and SAEs (≥5% of participants in 1 of the treatment 
groups) will be considered Tier 2 endpoints. Because many 95% CIs may be provided 
without adjustment for multiplicity, the CIs should be regarded as a helpful descriptive 
measure to be used in safety review, not as a formal method for assessing the statistical 
significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. 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.
Table 9
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
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
Abbreviations: AE = adverse event; SOC = system organ class; X = results will be provided.
9.6.3
Statistical Methods for Patient-reported Outcome Analyses
Details of PRO analyses will be included in the sSAP.
9.6.4
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 
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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.
9.7.1
Efficacy Interim Analyses
Two IAs are planned in addition to the FA for this study. For the IAs and FAs, all 
randomized participants will be included. Results of the IAs will be reviewed by the DMC. 
 
 
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9.7.2
Safety Interim Analyses
The DMC will be responsible for periodic interim safety reviews, as specified in the DMC 
charter. Interim safety analyses will also be performed at the time of interim efficacy 
analyses.
9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W., et al 2011] to control 
multiplicity for multiple hypotheses as well as IAs. According to this approach, study 
hypotheses may be tested more than once, and when a particular null hypothesis is rejected, 
the α allocated to that hypothesis can be reallocated to other hypothesis tests. Figure 3 shows 
the initial 1-sided α allocation for each hypothesis in the ellipse representing the hypothesis. 
The weights for reallocation from each hypothesis to the others are shown in the boxes on the 
lines connecting hypotheses.
Initial α assigned to OS, PFS and ORR will be 0.019, 0.005 and 0.001, respectively. If any 
hypothesis is rejected, α will be reallocated to the other hypotheses.
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Figure 3
Multiplicity Diagram for Type I Error Control (One-Sided)
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9.9
Sample Size and Power Calculations
The study will randomize approximately 736 participants in a 1:1 ratio to the belzutifan and 
everolimus arms. PFS and OS are primary endpoints for the study, with ORR as the key 
secondary endpoint.
Based on all randomized participants, the power of the ORR testing at the allocated α=0.001 
is approximately 99.9% to detect a 15-percentage point difference between an underlying 5% 
response rate in the control arm and a 20% response rate in the experimental arm.
For the PFS endpoint, based on an expected number of 626 events at the final analysis and 
one interim analysis at 90% of the final target number of events, the study has approximately 
96.9% power to demonstrate an HR of 0.7 at an overall α level of 0.005 (1 sided), 99.3% 
power at an α level of 0.024 (1-sided), and 99.3% power at an α level of 0.025 (1-sided).
For the OS endpoint, based on a target number of 483 events at the final analysis and 2 
interim analyses at approximately 62% and 85% of the final target number of events, the 
study has approximately 85.4% power to detect an HR of 0.75 at an overall α level of 0.019 
(1-sided), 85.8% power at an α level of 0.020 (1-sided), 87.4% power at an α level of 0.024 
(1-sided), and 87.7% power at an α level of 0.025 (1-sided).
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the 
safety and effectiveness of our products. As such, we are committed to designing, 
implementing, conducting, analyzing, and reporting these trials in compliance with 
the highest ethical and scientific standards. Protection of participants in clinical trials 
is the overriding concern in the design and conduct of clinical trials. In all cases, 
MSD clinical trials will be conducted in compliance with local and/or national 
regulations (including all applicable data protection 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 (eg, 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.
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The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial. 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 source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
fraud, scientific/research misconduct or serious GCP-non-compliance is 
suspected, the issues are investigated. When necessary, the clinical site will be 
closed, the responsible regulatory authorities and ethics review committees 
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.
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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. Unless required by law, only the investigator, Sponsor (or individuals acting 
on behalf of MSD), ethics committee, and/or regulatory authorities will have access 
to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on chart review and medical evaluation to identify 
potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, 
investigator meetings, etc.) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
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10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee
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.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor senior management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study. Additional 
details regarding the EOC can be found in the DMC charter.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued integrity of the study. Also, the DMC will review interim study 
results, consider the overall risk and benefit to study participants (Section 9.7), and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the protocol team, meeting facilitation, the 
minutes, and recommendations will be described in the DMC charter that is reviewed and 
approved by all DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
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If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP 
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
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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.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period 
(eg, EU CTR: 25 years after the end of the study). No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred 
to another location or party without written notification to the Sponsor.
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10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 14 will be performed by the central laboratory.
If local laboratory results are used to make either a study intervention decision or response 
evaluation, the results must be entered into the CRF.
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 at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1. The length of time required 
to continue pregnancy testing for study intervention is as follows:
◦
Belzutifan: at least 30 days after the last dose of study intervention
◦
Everolimus: at least 8 weeks 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.
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Table 14
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
% Reticulocytes
WBC count with 
differentiala
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN or ureab
Potassium
Aspartate 
Aminotransferase 
(AST) / Serum 
Glutamic-
oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
ULN)
Albumin
CO2 or 
bicarbonatec
Chloride
Phosphorous
Creatinine or CrCld
Sodium
Alanine 
Aminotransferase 
(ALT) / Serum 
Glutamic-pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucosee
Calcium
Alkaline 
phosphatase
Triglycerides and 
total cholesterol 
(fasting ≥8 hours)
Routine 
Urinalysisf
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
Serum or urine β-hCG pregnancy test (as needed for WOCBP)f.
Serology (HIV, HBsAg and HCV antibody) as required by local health authority or 
institutional regulationsf.
Coagulation factors (PT or INR, and aPTT). Additional testing to be conducted as 
clinically indicated for participants taking anticoagulation therapy.
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.
At baseline, the participant should be in the fasted state for glucose measurement.
f.
To be performed locally. Urine β-hCG pregnancy test will additionally be performed monthly, at EOT, and at 
30 days after last dose of study intervention.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Refer to Appendix 7 for country-specific requirements.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported 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).
•
Is associated with an overdose.
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life-threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
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Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the study 
intervention and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the study intervention 
caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
etc), expected pharmacologic effect, or measurement of drug/metabolite in bodily 
specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
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TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
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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.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
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•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable for this study, except as described in Section 10.7.6.
10.4.1
Definition of Device Event
Not applicable for this study, except as described in Section 10.7.6.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
WOCBP
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
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, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with 2 FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Table 15
Highly Effective Contraception Methods

Contraceptives allowed during the studya
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
●Progestogen-only contraceptive implantb,c
●IUSc,d
●Nonhormonal 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.
Notes:
a Contraceptive use by men and women should be consistent with local regulations regarding the use of 
contraceptive methods for participants in clinical studies.
b If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
hormonal contraceptives are limited to those which inhibit ovulation.
c Male condoms must be used in addition to hormonal contraception.
d IUS is a progestin-releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
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will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
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identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Germany
Section 1.3 Schedule of Activities
Study Period
Screening
Treatment Period
EOT
Notes
Week
Screeninga
(Visit 1)
1
4
8
12
16
20+b
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 prior to treatment allocation, unless otherwise noted.
b.
Following Week 20, visits are to occur approximately every 4 weeks (~28 days) until documented PD, death, 
withdrawal of consent, or the end of the study, whichever occurs first.
Section 5.1 Inclusion Criteria
10. The participant provides written informed consent for the study. The participant may also 
provide consent for FBR. However, the participant may participate in the main study without 
participating in FBR.
Section 5.2 Exclusion Criteria
27. 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 prior to the first dose of study 
intervention randomization. An exception is HIV and hepatitis testing which may be done 
up to 42 days prior to the first dose of study intervention randomization.
Appendix 2 Clinical Laboratory Tests
Other Screening Tests: Serology (HIV RNA)
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10.7.2
United Kingdom
Section 1.3 Schedule of Activities
Study Period
Screening
Treatment Period
EOT
Notes
Week
Screeninga
(Visit 1)
1
4
8
12
16
20+b
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 prior to treatment allocation, unless otherwise noted.
b.
Following Week 20, visits are to occur approximately every 4 weeks (~28 days) until documented PD, death, 
withdrawal of consent, or the end of the study, whichever occurs first.
Section 5.2 Exclusion Criteria
27.
Participant has a known history of human immunodeficiency virus (HIV) infection. 
Testing for HIV is required at screening.
Section 6.5.1 Prohibited Concomitant Medications
•
Live vaccines while participating in the study, and within 90 days of the last dose of 
study intervention.
Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chickenpox, yellow fever, intranasal seasonal influenza, rabies, BCG, and 
typhoid (oral).
Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed.
Section 8.11.1 Screening
•
Laboratory tests are to be performed within 10 days prior to the first dose of study 
intervention randomization. An exception is HIV and hepatitis testing which may be done 
up to 42 days prior to the first dose of study intervention randomization.
Appendix 2 Clinical Laboratory Tests
Other Screening Tests: Serology (HIV antibody).
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10.7.3
Ireland
Section 1.3 Schedule of Activities
Study Period
Screening
Treatment Period
EOT
Notes
Week
Screeninga
(Visit 1)
1
4
8
12
16
20+b
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 prior to treatment allocation, unless otherwise noted.
b.
Following Week 20, visits are to occur approximately every 4 weeks (~28 days) until documented PD, death, 
withdrawal of consent, or the end of the study, whichever occurs first.
Section 5.2 Exclusion Criteria
27. Participant has a known history of human immunodeficiency virus (HIV) infection. 
Testing for HIV is required at screening.
Section 6.5.1 Prohibited Concomitant Medications
•
Live vaccines while participating in the study, and within 90 days of the last dose of 
study intervention.
Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chickenpox, yellow fever, intranasal seasonal influenza, rabies, BCG, and 
typhoid (oral).
Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and, 
once confirmed, are allowed.
Section 8.1.4 Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed that the investigator 
considers to be clinically significant. Details regarding the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as medical history.
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Section 8.11.1 Screening
•
Laboratory tests are to be performed within 10 days prior to the first dose of study 
intervention randomization. An exception is HIV and hepatitis testing which may be done 
up to 42 days prior to the first dose of study intervention randomization.
Appendix 2 Clinical Laboratory Tests
Other Screening Tests: Serology (HIV antibody).
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10.7.4
Norway
Section 1.3 Schedule of Activities
Study 
Period
Screen-
ing
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screen-
inga
Wk 1
Day 1a
Wk 3
Day 1
Wk 5
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety Follow-up
Imaging
Follow-
up Visits
Survival
Follow-
upc
Schedul-
ing 
Window 
(Days):
–28 to –1
+3
±3
±3
±3
±5
At 
time 
of 
DC
30 Days 
After 
Last Dose 
(+7 days)
56 Days 
After 
Last Dose 
(+7 days)
Q8W
or
Q12W
(±7 days)
Q12W
(±7 days)
Urine or 
serum
β-hCG -
WOCBP 
only
X
X
X
X
Q4W
X
X
X*
Female participants of 
childbearing potential 
will have a serum or 
highly sensitive urine 
pregnancy test within 
1 day prior to 
randomization. If 
more than 1 day has 
elapsed between the 
screening pregnancy 
test and the first dose 
of study intervention, 
another pregnancy test 
(urine or serum) must 
be performed within 
24 hours of first dose 
and must be negative 
in order for the 
participant to start 
receiving study 
medication. Pregnancy 
tests will be conducted 
locally.
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Study 
Period
Screen-
ing
Treatment Period
EOT
Posttreatment
Notes
Visit:
Screen-
inga
Wk 1
Day 1a
Wk 3
Day 1
Wk 5
Day 1
Wk 9
Day 1
Wk 13+
Day 1b
DC
Safety Follow-up
Imaging
Follow-
up Visits
Survival
Follow-
upc
Schedul-
ing 
Window 
(Days):
–28 to –1
+3
±3
±3
±3
±5
At 
time 
of 
DC
30 Days 
After 
Last Dose 
(+7 days)
56 Days 
After 
Last Dose 
(+7 days)
Q8W
or
Q12W
(±7 days)
Q12W
(±7 days)
*Pregnancy testing at 56 days post EOT is only required for WOCBP on the everolimus treatment arm.
a.
Week 1 Day 1 denotes the first dose of study treatment, which should be on the date of randomization, but can be within 3 days following 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, contact, medical record review, etc. Participant status information includes survival status and 
subsequent antineoplastic therapies for RCC.
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10.7.5
Czech Republic
Section 1.3 Schedule of Activities
Study Period
Screening
Treatment Period
EOT
Notes
Week
Screeninga (Visit 
1)
1
4
8
12
16
20+b
DC
Visit Number
1
2
3
4
5
6
7+
Scheduling Window 
(Days):
–28 to –1
±3
±3
±3
±3
±3
±3
At time 
of DC
Safety Procedures
HIV testing
X
Testing is required.
HBV testing
X
Testing is required.
HBC testing
X
Testing is required.
a.
All screening procedures should be performed within 28 days prior to treatment allocation, unless otherwise noted.
b.
Following Week 20, visits are to occur approximately every 4 weeks (~28 days) until documented PD, death, withdrawal of consent, or the end of the study, 
whichever occurs first.
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Section 5.2 Exclusion Criteria
27.
Has a known history of HIV infection.
Note: Testing for HIV at screening will be performed up to 28 days prior to randomization.
28.
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 will be performed up to 28 days prior to randomization.
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 16 will be performed by the central laboratory.
•
If local laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be entered into the CRF.
•
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.
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Table 16
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differentiala
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN or ureab
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above the 
ULN)
Albumin
CO2 or bicarbonate
Chloride
Phosphorous
Creatinine or CrClc
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucosed
Calcium
Alkaline 
phosphatase
Triglycerides and 
total cholesterol 
(fasting ≥ 8 hours)
Routine 
Urinalysise
•
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

Serum or urine β-hCG pregnancy test (as needed for WOCBP)e.

Serology (HIV, HBsAg and HCV antibody)e.

Coagulation factors (PT or INR, and aPTT). Additional testing to be conducted as 
clinically indicated for participants taking anticoagulation therapy.
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.
GFR (measured or calculated) or CrCl can be used in place of creatinine.
d.
At baseline, the participant should be in the fasted state for glucose measurement.
e.
To be performed locally.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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10.7.6.3
Use of Erythropoiesis-stimulating Agents
Background and Overview
ESAs are not approved in Japan for chemotherapy-induced anemia and the Sponsor considers 
that ESA use for belzutifan-induced anemia is off-label use in Japan. 
 
 
CCI
CCI
CCI
CCI
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Study Interventions Administered
In addition to the study intervention described in Table 2, the study intervention to be used in 
this study specific for Japan is outlined in Table 18.
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Table 18
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
Belzut
ifan
Experi-
mental
M-darbe
Combination 
Product
Sterile 
Solution
180 µg 
prefilled 
syringe
360 µg
SC
Refer to 
ESA dose 
for 
belzutifan-
induced 
anemia
Test 
Product
IMP
Central
Abbreviations: EEA = European economic area; IMP = Investigational Medicinal Product; M-darbe = darbepoetin alfa; NIMP/AxMP = Noninvestigational/Auxiliary Medicinal 
Product; SC = subcutaneously.
According to hemoglobin level, dosage levels is to be reduced as outlined in the ESA dose for belzutifan-induced anemia.
The participants who are assigned to the belzutifan arm will be administered M-darbe according to hemoglobin level.
M-darbe will be provided as a single-dose prefilled syringe, which is defined as a combination product (syringe device and M-darbe).
Note: The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country 
differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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Evaluation of M-darbe for Belzutifan-induced Anemia in Japanese Participants
All Japanese participants, including the participants in the safety run-in cohort, who receive 
at least 1 dose of belzutifan and receive at least 1 dose of M-darbe after experiencing 
belzutifan-induced anemia (hemoglobin <10.0 g/dL), will be evaluated to assess the 
effectiveness of M-darbe in the treatment of belzutifan-induced anemia. The following 
endpoints will be evaluated and reported for Japanese participants:
•
Percentage of participants with change from baseline in hemoglobin ≥2.0 g/dL
CCI
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Percentage of participants with change from baseline in hemoglobin ≥2.0 g/dL will be 
calculated. Baseline measurement is defined as the last value measured between start date of 
the AE of anemia and before the first M-darbe administration for each participant. The 
postbaseline measurements are defined as the values measured after the start date of 
receiving M-darbe, and before the earliest date of 12 weeks after receiving M-darbe, the date 
of discontinuation of belzutifan, and the start date of blood transfusion. Change from baseline 
in hemoglobin will be calculated as the maximum value of postbaseline measurements minus 
the value of baseline measurement.
•
Percentage of avoidance of a blood transfusion
Percentage of avoidance of a blood transfusion will be calculated and is defined as the 
percentage of participants who did not receive a blood transfusion.
•
The percentage of participants whose minimum value of post-baseline measurements of 
hemoglobin ≥7.0 g/dL
•
The percentage of participants whose minimum value of post-baseline measurements of 
hemoglobin ≥8.0 g/dL
In addition, AEs will also be summarized for all participants included in this evaluation of 
M-darbe.
AE Monitoring and Reporting Related to M-darbe
Based on Sections 1.3 and 8.4, AE monitoring of administration of M-darbe, which is 
considered as an IMP in Japan, will also be performed. Treatment with M-darbe is 
considered as study intervention, and therefore, the time period for collecting AE, SAE, and 
other reportable safety event information will be as described in Section 8.4.1.
Concomitant Therapy
Based on Section 6.5, all concomitant medications received within 28 days before 
randomization and up to 30 days after the last dose of study intervention, defined by the last 
dose of belzutifan, everolimus, or M-darbe should be recorded. Concomitant medications 
administered >30 days after the last dose of study intervention defined by the last dose of 
belzutifan, everolimus, or M-darbe should be recorded for SAEs as defined in Section 8.4.
Serious Syringe Device Events (Incidents)
M-darbe will be provided as a single-dose prefilled syringe, which is defined as a 
combination product (syringe device and M-darbe). A syringe device corresponds to a 
medical device, and serious syringe device events (incidents) must be reported to the 
Sponsor.
Instructions for medical device use are provided in the Pharmacy Manual.
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Definition of Serious Syringe Device Events (Incidents)
A serious syringe device event (incident) is any malfunction or deterioration in the 
characteristics and/or performance of the device, as well as any inadequacy in the labeling or 
the instructions for use that, directly or indirectly, led to the death of a participant or user, or 
of other persons, or to a serious deterioration in their state of health.
A serious deterioration in the state of health can include:
1. Life-threatening illness;
2. Permanent impairment of a body function or permanent damage to a body structure;
3. A condition necessitating medical or surgical intervention to prevent 1 or 2;
4. A condition that requires hospitalization or significant prolongation of existing 
hospitalization; or
5. Fetal distress, fetal death, or any congenital abnormalities or birth defects.
Definition of Malfunction Which may Lead to Serious Adverse Events - Any malfunction 
of a medical device which might have led to the death of a participant and/or the associated 
person or to a serious deterioration in his/her state of health. “Which might have led to” 
means that there is the possibility that death or a serious deterioration might have occurred in 
a participant and/or the associated person, although these cases have not actually occurred.
Monitoring, Reporting, and Follow-up of Serious Syringe Device Events (Incidents)
For the time period beginning when the consent form is signed through the duration of the 
participant’s study participation, any serious syringe device event (incident), including 
follow-up to an incident and death due to any cause, that occurs to any participant must be 
reported within 24 hours to the Sponsor both by paper reporting for the event (incident) and 
electronic reporting for SAEs. Malfunction which may lead to SAEs will be reported to the 
Sponsor within 5 calendar days of learning of the information via a paper reporting form.
Any serious syringe device event (incident) that occurs in study personnel must be reported 
within 24 hours to the Sponsor both by paper reporting for the event (incident) and 
spontaneous reporting to the Sponsor.
Paper reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious syringe device event (incident) considered by an investigator who 
is a qualified physician to be related to the Sponsor's product that is brought to the attention 
of the investigator at any time outside of the time period specified above must be reported 
immediately to the Sponsor.
All participants involved with serious syringe device events (incidents) must be followed up 
for outcome.
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South Korea
Section 5.1 Inclusion Criterion 11
Table 19
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/L
Renal
Serum creatinine or estimated CrCl using the 
Cockcroft-Gault equation, or based on a 24-hour 
urine testa (GFR can also be used in place of 
creatinine or CrCl)
≤1.5 × ULN OR
≥51 mL/min for participants with creatinine levels 
>1.5 x 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
Fasting serum triglycerides and total cholesterol
≤2.5 x ULN AND total cholesterol ≤300 mg/dL 
(≤7.75 mmol/L). Lipid-lowering medication is 
allowed
Fasting glucose
A fasting glucose ≤125 mg/dL (≤6.9 mmol/L) is 
required.
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.
Estimated creatinine clearance using Cockcroft-Gault:
(140-age [years] × weight (kg)
(×F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for females and F = 1 for males
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.
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10.8
Appendix 8: Belzutifan ECI Guidance
10.8.1
Belzutifan ECI Criteria
Anemia: Any ≥Grade 3 anemia/decreased hemoglobin event 
Anemia
Decreased hemoglobin
Hypoxia: Any ≥Grade 3 hypoxia
Hypoxia
Any ≥Grade 3 SAE/AE deemed related to belzutifan by the investigator, including laboratory 
abnormalities.
≥ Grade 3 belzutifan-related clinical AEs
≥ Grade 3 belzutifan-related laboratory AEs
Common Terminology Criteria for Adverse Events (CTCAE) Version 5 will be used.
10.8.2
Anemia/Decreased Hemoglobin ECI Reporting
The following AE terms are considered ECIs and should be reported to the Sponsor within 
5 calendar days of learning of the event if the event is non-serious or within 24 hours if the 
event is an SAE:
•
≥Grade 3 anemia
•
≥Grade 3 decreased hemoglobin
Definition: A disorder characterized by a reduction in the amount of hemoglobin in 100 mL
of blood. Signs and symptoms of anemia may include pallor of the skin and mucous 
membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, 
and fatigability.
CTCAE Version 5 definition of Anemia Grades: 
•
Grade 1:  Hemoglobin <LLN - 10.0 g/dL; <LLN - 6.2 mmol/L; <LLN - 100 g/L
•
Grade 2:  Hemoglobin <10.0 - 8.0 g/dL; <6.2 - 4.9 mmol/L; <100 - 80 g/L 
•
Grade 3: Hemoglobin <8.0 g/dL; <4.9 mmol/L; <80 g/L; transfusion indicated 
•
Grade 4: Life-threatening consequences; urgent intervention indicated 
•
Grade 5: Death 
10.8.3
Anemia Management 
Decreased EPO is the potential etiology of anemia with belzutifan treatment. EPO 
replacement is an effective management strategy for participants who may develop and 
subsequently require intervention for belzutifan-induced anemia. Transfusion can also be 
used to manage anemia in patients receiving belzutifan.
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Grade 3 events (report as ECI):
•
Dose Modification not required
Grade 4 events (report as ECI):
•
First episode: Hold belzutifan. Once toxicity has resolved to ≤Grade 2 or baseline, dose 
reduce belzutifan by 1 level
•
Second episode: Permanently discontinue belzutifan
All attempts should be made to rule out other causes of anemia. Relevant diagnostic studies 
may include peripheral blood smear, reticulocyte count, LDH, haptoglobin, Coomb’s test, 
blood levels of vitamin B12, folate, iron studies, etc. 
While dose interruption is not required, the investigator may elect to hold belzutifan for 
participants who develop anemia Grade 1-3. If belzutifan is held for anemia Grade 1-3, the 
participant can be re-challenged with belzutifan at the same dose. 
10.8.4
Hypoxia ECI Reporting
The following AE terms are considered ECIs and should be reported to the Sponsor within 5 
calendar days of learning of the event if the event is non-serious or within 24 hours if the 
event is an SAE:
•
≥ Grade 3 hypoxia
Definition: A disorder characterized by a decrease in the level of oxygen in the body.
CTCAE Version 5 definition of Hypoxia Grades:
•
Grade 1: Not Applicable
•
Grade 2: Decreased oxygen saturation with exercise (eg, pulse oximeter <88%); 
intermittent supplemental oxygen
•
Grade 3: Decreased oxygen saturation at rest (eg, pulse oximeter <88% or PaO2 <=55 
mm Hg)
•
Grade 4: Life-threatening airway compromise; urgent intervention indicated (eg, 
tracheotomy or intubation)
•
Grade 5: Death
[National Cancer Institute 2017]
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10.8.5
Hypoxia Management 
Grade 3 events (report as ECI):
•
Consult pulmonology
•
Provide supplemental oxygen
•
Consider appropriate clinical work-up including chest x-ray/CT and ECG to evaluate for 
potential concomitant/underlying etiologies
•
First and second episodes: Hold belzutifan. Once toxicity has resolved to ≤Grade 2 or 
baseline, dose reduce belzutifan by 1 level (Grade 3 hypoxia [asymptomatic], belzutifan 
may be continued at the discretion of the investigator) 
•
Third episode: Permanently discontinue belzutifan
Grade 4 events (report as ECI):
•
Consult pulmonology
•
Provide supplemental oxygen and endotracheal intubation if indicated
•
Consider appropriate clinical work-up including chest x-ray/CT and ECG to evaluate for 
potential concomitant/underlying etiologies
•
Permanently discontinue belzutifan
All attempts should be made to characterize the etiology of the events associated with 
hypoxia such as heart disease, pulmonary infection, pulmonary metastasis, chronic 
obstructive pulmonary disease, interstitial lung disease, pulmonary embolism, acute 
respiratory distress syndrome, chronic liver disease, etc. 
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10.9
Appendix 9: Abbreviations
Abbreviation
Definition
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event 
AEOSI
Adverse events of special interest
ALP 
Alkaline phosphatase
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
BCG
Bacillus Calmette–Guérin
BCRP
Breast cancer resistance protein
BCS
Biopharmaceutics Classification System
β-hCG
β-human chorionic gonadotropin
BICR
Blinded independent central review
BID
Twice daily
BUN
Blood urea nitrogen
Ca
Calcium
CBC
Complete blood count
ccRCC
Clear cell renal cell carcinoma
CI
Confidence interval
Cl
Chloride
cLDA
Constrained longitudinal data analysis
CL/F
Clearance
Cmax
Maximum concentration
CNS
Central nervous system
CO2
Carbon dioxide
CONSORT
Consolidated Standards of Reporting Trials
CR
Complete response
CrCl
Creatinine clearance
CRF
Case Report Form 
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
Ctrough
Trough concentration
CV
Variability
CYP
Cytochrome P450
D
De-escalate to the next lower dose; 
DBP
Diastolic blood pressure
DC
Discontinuation
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee 
DNA
Deoxyribonucleic acid 
DOR
Duration of response
DU
Current dose is unacceptably toxic
E
Escalate to the next higher dose
ECG
Electrocardiogram 
CCI
CCI
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Abbreviation
Definition
ECI
Event of clinical interest
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic data collection 
ELISA
Enzyme-linked immunosorbent assay
EOC
Executive Oversight Committee 
EORTC QLQ-C30
European Organisation for the Research and Treatment of Cancer Quality of Life 
Questionnaire 30
EOT
End-of-treatment
EPO
Erythropoietin
ESA
Erythropoiesis-stimulating agents
ESMO
European Society for medical Oncology
EuroQoL EQ-5D-
5L
European Quality of Life (EuroQoL)-5 dimensions-5 levels
Exp
Experimental
FA
Final analysis
FAS
Full Analysis Set
FBR
Future biomedical research
FDAAA
Food and Drug Administration Amendments Act
FFPE
Formalin-fixed, paraffin embedded
FKSI-DRS
Functional Assessment of Cancer Therapy – Kidney Symptom Index-disease-related 
symptoms 
FSH
Follicle-stimulating hormone 
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
HA
Health authority
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
High-density polyethylene
HIF-1β
Hypoxia-inducible factor 1β
HIF-2α
Hypoxia-inducible factor 2α
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health-related quality of life
HRT
Hormone replacement therapy
IA
Interim analysis
IB
Investigator’s Brochure 
IC50
Half-maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ICMJE
International Committee of Medical Journal Editors
iCRO
Imaging contract research organization
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
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Abbreviation
Definition
IRB
Institutional Review Board
IRT
Interactive response technology
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous(ly)
IVD
In vitro diagnostic
K
Potassium
KPS
Karnofsky performance status
LAM
Lactational amenorrhea method
LLN
Lower limit of normal
M-darbe
NESP; darbepoetin alfa
Mg
Magnesium
MRI
Magnetic resonance imaging
mRNA
Messenger RNA
MTD
Maximum tolerated dose 
mTPI
Modified toxicity probability interval
Na
Sodium
NCCN
The National Comprehensive Cancer Network
NCI
National Cancer Institute
NIMP
Non-investigational Medicinal Product
OR
Objective response
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PAS
Per-ARNT-Sim
PD-1
Programmed cell death 1
PD-L1
Programmed cell death 1 ligand 1
pEFD
Preliminary embryo-fetal toxicity
PFS
Progression-free survival
P-gp
P-glycoprotein
PK
Pharmacokinetic
PO4
Phosphate
PR
Partial response
pRBC
Packed red blood cells
PRO
Patient-reported outcome
PT
Prothrombin time
Q3W
Every 3 weeks
Q4W
Every 4 weeks
Q8W
Every 8 weeks
Q12W
Every 12 weeks
Q16W
Every 16 weeks
Q24W
Every 24 weeks
QD
Once daily
QoL
Quality of life
RBC
Red blood cell
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
S
Stay at the current dose
SAC
Scientific Advisory Committee
SAE
Serious adverse event 
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Abbreviation
Definition
SBP
Systolic blood pressure
SC
Subcutaneously
SD
Stable disease
SIM
Site Imaging Manual
SLC2A1
Solute carrier family 2 member 1
SoA
Schedule of activities
SOC
System organ class
sSAP
Supplemental Statistical Analysis Plan
SUSAR
Suspected unexpected serious adverse reaction
TB
Bacillus tuberculosis
TK
Toxicokinetic
TKI
Tyrosine kinase inhibitor
tmax
Time to maximum concentration
TTD
Time to deterioration
UGT
Uridine 5’-diphospho-glucuronosyltrasnferase
ULN
Upper limit of normal
VAS
Visual Analog Scale
VEGF
Vascular endothelial growth factor
VEGF-A
Vascular endothelial growth factor-A
VHL
Von Hippel Lindau
VZ/F
Apparent volume of distribution
WBC
White blood cell
Wk
Week
WOCBP
Woman/women of childbearing potential 
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REFERENCES
[Aaronson, N. K., et al 
1993]
Aaronson NK, Ahmedzai S, Bergman B, 
Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life 
instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst 1993;85(5):365-76.
[03Q3QL]
[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 Nov-
Dec;68(6):394-424.
[054JFN]
[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]
[Cella, D., et al 2007]
Cella D, Yount S, Brucker PS, Du H, Bukowski 
R, Vogelzang N, et al. Development and 
validation of a scale to measure disease-related 
symptoms of kidney cancer. Value Health. 2007 
Jul-Aug;10(4):285-93.
[04FLVV]
[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]
[Delea, T. E., et al 2012]
Delea TE, Khuu A, Heng DYC, Haas T, 
Soulieres D. Association between treatment 
effects on disease progression end points and 
overall survival in clinical studies of patients with 
metastatic renal cell carcinoma. Br J Cancer. 
2012;107:1059-68.
[059L95]
08RD3B

PRODUCT: MK-6482
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PROTOCOL/AMENDMENT NO.: 005-09
MK-6482-005-09 FINAL PROTOCOL
14-NOV-2024
[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]
[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]
[Ji, Y. and Wang, S.-J. 
2013]
Ji Y and Wang S-J. Modified toxicity probability 
interval design: a safer and more reliable method 
than the 3 + 3 design for practical phase I trials. J 
Clin Oncol 2013;31:1-12.
[03FL3C]
[Ji, Y., et al 2007]
Ji Y, Li Y, Bekele BN. Dose-finding in phase l 
clinical trials based on toxicity probability 
intervals. Clin Trials 2007;4:235-44.
[03TFYL]
[Ji, Y., et al 2010]
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity 
probability interval method for dose-finding 
trials. Clin Trials. 2010;7:653-63.
[04WC92]
[Jonasch, E., et al 2019]
Jonasch E, Plimack ER, Bauer TM, Merchan JR, 
Papadopoulos KP, McDermott DF, et al. A first-
in-human phase 1/2 trial of the oral HIF-2alpha 
inhibitor PT2977 in patients with advanced RCC 
[abstract]. To be presented at: European Society 
for Medical Oncology (ESMO); 2019 Sep 27-Oct 
1; Barcelona (Spain).
[05BD7M]
[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]
[Maurer, W. and Bretz, F. 
2013]
Maurer W and Bretz F. Multiple testing in group 
sequential trials using graphical approaches. Stat 
Biopharm Res 2013;5(4):311-20.
[03XQVB]
08RD3B

PRODUCT: MK-6482
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PROTOCOL/AMENDMENT NO.: 005-09
MK-6482-005-09 FINAL PROTOCOL
14-NOV-2024
[Maurer, W., et al 2011]
Maurer W, Glimm E, Bretz F. Multiple and 
repeated testing of primary, coprimary, and 
secondary hypotheses. Stat Biopharm Res. 
2011;3(2):336-52.
[045MYM]
[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 and Nurminen M. Comparative 
analysis of two rates. Stat Med 1985;4:213-26.
[00VMQY]
[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 
2017]
National Cancer Institute. Common terminology 
criteria for adverse events (CTCAE): version 5.0. 
U.S. Bethesda (MD): National Cancer Institute 
(NCI); 2017 Nov 27. 147 p.
[05JJSW]
[National Comprehensive 
Cancer Network 2019]
National Comprehensive Cancer Network. NCCN 
clinical practice guidelines in oncology: kidney 
cancer; version 1.2020. Plymouth Meeting (PA): 
National Comprehensive Cancer Network 
(NCCN); 2019. 64 p.
[058BHB]
[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(6):649-55.
[03Q3F0]
[Pickard, A. S., et al 2007]
Pickard AS, Wilke CT, Lin H-W, Lloyd A. 
Health utilities using the EQ-5D in studies of 
cancer. Pharmacoeconomics 2007;25(5):365-84.
[03RLHG]
08RD3B

PRODUCT: MK-6482
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PROTOCOL/AMENDMENT NO.: 005-09
MK-6482-005-09 FINAL PROTOCOL
14-NOV-2024
[Rabin, R. and de Charro, 
F. 2001]
Rabin R, de Charro F. EQ-5D: a measure of 
health status from the EuroQol Group. Ann Med 
2001;33:337-43.
[03XLS2]
[Rini, B. I., et al 2011]
Rini BI, Escudier B, Tomczak P, Kaprin A, 
Szczylik C, Hutson TE, et al. Comparative 
effectiveness of axitinib versus sorafenib in 
advanced renal cell carcinoma (AXIS): a 
randomised phase 3 trial. Lancet. 2011 Dec 
3;378(9807):1931-9.
[04TSWS]
[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]
[Scheuermann, T. H., et al 
2013]
Scheuermann TH, Li Q, Ma HW, Key J, Zhang 
L, Chen R, et al. Allosteric inhibition of hypoxia 
inducible factor-2 with small molecules. Nat 
Chem Biol. 2013 Apr;9:271-6.
[059L97]
[Wells, J. C., et al 2017]
Wells JC, Stukalin I, Norton C, Srinivas S, Lee 
JL, Donskov F, et al. Third-line targeted therapy 
in metastatic renal cell carcinoma: results from 
the International Metastatic Renal Cell 
Carcinoma Database Consortium. Eur Urol. 
2017;71:204-9.
[059L98]
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