Clinical trial NCT02212730
Conditions: Renal Cell Cancer
Sponsor: Merck Sharp & Dohme LLC
Start date: 2014-12-03; Completion date: 2019-07-05
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will examine the effect of treatment with the neoadjuvant antibody pembrolizumab (MK-3475) on tumors of participants with renal cell cancer (RCC). The primary hypotheses are that pembrolizumab is well tolerated in participants undergoing RCC tumor resection; and that pembrolizumab will stimulate a 2-fold or greater increase in intratumoral lymphocytic infiltration in at least 30% of participants with RCC.

Detailed description:

Arms: arm 1: Participants received pembrolizumab, 200 mg intravenously (IV) once every 3-week cycle for up to 2 cycles followed by standard of care (SOC) renal cell carcinoma (RCC) surgical resection; and then received post-resection pembrolizumab 200 mg IV once every 3 week cycle for up to approximately 1 year (17 cycles). Post-resection pembrolizumab was only administered to participants who enrolled after Protocol Amendment 04. arm 2: Participants received SOC renal cell carcinoma (RCC) surgical resection; and then may have received post-resection pembrolizumab 200 mg IV once every 3 week cycle for up to approximately 1 year (17 cycles). Post-resection pembrolizumab was only administered to participants who enrolled under Protocol Amendment 04.
Interventions: intervention 1: Pembrolizumab Pre-Resection intervention 2: Surgical Resection intervention 3: Pembrolizumab Post-Resection
Intervention descriptions: intervention 1: 200 mg administered by IV, once every 3-week cycle for a maximum of 2 cycles intervention 2: Standard of care surgical resection of RCC tumor intervention 3: 200 mg administered by IV, once every 3-week cycle for a maximum of 17 cycles

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02212730
13-Sep-2018
Document Date: 
A Clinical Trial to Evaluate the Effect of Neoadjuvant MK-3475 
(Pembrolizumab) Therapy on Intratumoral Immune Infiltrates in 
Renal Cell Cancer (RCC) Patients Undergoing Surgical Resection


Product:  MK-3475 
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Clinical Trial to Evaluate the Effect of Neoadjuvant MK-3475 (Pembrolizumab) Therapy 
on Intratumoral Immune Infiltrates in Renal Cell Cancer (RCC) Patients Undergoing 
Surgical Resection
IND NUMBER:  Not applicable
EudraCT NUMBER:  2014-002526-12
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 11
2.0
TRIAL DESIGN........................................................................................................ 12
Trial Design ........................................................................................................... 12
2.1
Trial Diagram........................................................................................................ 14
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 15
Primary Objective(s) & Hypothesis(es) .............................................................. 15
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 15
3.2
Tertiary Objectives............................................................................................... 16
3.3
Exploratory Objectives......................................................................................... 17
3.4
4.0
BACKGROUND & RATIONALE.......................................................................... 17
Background ........................................................................................................... 17
4.1
Pharmaceutical and Therapeutic Background .................................................... 17
4.1.1
Pre-clinical and Clinical Trials ........................................................................... 19
4.1.2
Ongoing Clinical Trials....................................................................................... 19
4.1.3
Rationale................................................................................................................ 20
4.2
Rationale for the Trial and Selected Subject Population .................................... 20
4.2.1
4.2.1.1
Rationale for the Trial.................................................................................. 20
4.2.1.1.1
Rationale for Neoadjuvant MK-3475 in RCC ...................................... 20
4.2.1.1.2
Rationale for Post-Resection MK-3475 in RCC................................... 21
Rationale for Adjuvant MK-3475 in Subjects with Fully 
4.2.1.1.2.1
Resected RCC ......................................................................................... 21
Rationale for Post-Resection MK-3475 in Patients with 
4.2.1.1.2.2
Metastatic Disease at the Time of RCC Resection ................................. 22
4.2.1.2
Rationale for Selected Study Population ..................................................... 23
4.2.1.3
Rationale for Sample Collection in This Trial............................................. 23
4.2.1.4
Rationale for Intraoperative Core Needle Biopsies in This Trial ................ 24
4.2.1.5
Rationale for Key Hypothesis...................................................................... 25
Rationale for Dose Selection/Regimen/Modification ......................................... 28
4.2.2
4.2.2.1
Rationale for the Use of Comparator/Placebo ............................................. 29
 
 
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4.2.2.2
Starting Dose for This Trial ......................................................................... 29
4.2.2.3
Maximum Dose/Exposure for This Trial..................................................... 29
4.2.2.4
Rationale for Dose Interval and Trial Design .............................................. 30
Rationale for Endpoints ...................................................................................... 31
4.2.3
4.2.3.1
Safety Endpoints.......................................................................................... 31
4.2.3.2
Efficacy Endpoints....................................................................................... 32
4.2.3.3
Planned Exploratory Biomarker Research................................................... 33
Exploratory Biomarker Objectives..................................................................... 35
4.3
Future Biomedical Research ............................................................................... 37
4.3.1
Benefit/Risk ........................................................................................................... 38
4.4
5.0
METHODOLOGY ................................................................................................... 38
Entry Criteria........................................................................................................ 38
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 38
5.1.1
Subject Inclusion Criteria.................................................................................... 38
5.1.2
Subject Exclusion Criteria .................................................................................. 40
5.1.3
Trial Treatment(s) ................................................................................................ 41
5.2
Dose Selection/Modification .............................................................................. 42
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 42
5.2.1.2
Dose Modification and Toxicity Management 
Guidelines for 
Pembrolizumab............................................................................................ 42
Neoadjuvant MK-3475................................................................... 42
5.2.1.2.1.1
Post-Resection MK-3475 ............................................................... 43
5.2.1.2.1.2
Timing of Dose Administration .......................................................................... 47
5.2.2
Trial Blinding/Masking....................................................................................... 47
5.2.3
Randomization or Treatment Allocation............................................................ 47
5.3
Stratification.......................................................................................................... 47
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 48
5.5
Acceptable Concomitant Medications ................................................................ 48
5.5.1
Rescue Medications & Supportive Care............................................................. 50
5.6
Supportive Care Guidelines During the Neoadjuvant Portion of this Trial........ 50
5.6.1
5.6.1.1
Supportive Care Guidelines for Events of Clinical Interest (ECIs) and 
Immune-Related Adverse Events (irAEs) During Neoadjuvant MK-
3475 Only .................................................................................................... 52
 
 
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5.6.1.2
Supportive Care Guidelines for Pneumonitis- Neoadjuvant MK-3475 
Only ............................................................................................................. 53
Supportive Care Guidelines During Post-Resection MK-3475 Treatment for 
5.6.2
this Trial.............................................................................................................. 53
Diet/Activity/Other Considerations..................................................................... 55
5.7
Diet...................................................................................................................... 55
5.7.1
Contraception...................................................................................................... 55
5.7.2
Use in Pregnancy ................................................................................................ 56
5.7.3
Use in Nursing Women....................................................................................... 56
5.7.4
Subject Withdrawal/Discontinuation Criteria................................................... 57
5.8
Treatment 
after 
Initial 
Radiologic 
Progression 
(irRECIST-based 
5.8.1
Management) ...................................................................................................... 59
Subject Replacement Strategy............................................................................. 61
5.9
Beginning and End of the Trial ........................................................................... 61
5.10
Clinical Criteria for Early Trial Termination ................................................... 62
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 63
Trial Flow Chart - Patients Randomized to Neoadjuvant MK-3475............... 63
6.1
Trial Flow Chart - Patients Randomized to No Treatment Control Group ... 67
6.2
Trial Flow Chart - Patients Randomized to Neoadjuvant MK-3475 (3 
6.3
DOSE REGIMEN)................................................................................................ 70
Trial Flow Chart – Post-Resection MK-3475 Treatment (All Subjects) ......... 74
6.4
7.0
TRIAL PROCEDURES ........................................................................................... 75
Trial Procedures ................................................................................................... 75
7.1
Administrative Procedures.................................................................................. 75
7.1.1
7.1.1.1
Informed Consent......................................................................................... 75
7.1.1.1.1
General Informed Consent.................................................................... 75
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 76
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 76
7.1.1.3
Subject Identification Card .......................................................................... 76
7.1.1.4
Medical History ........................................................................................... 76
7.1.1.5
Prior and Concomitant Medications Review ............................................... 76
7.1.1.5.1
Prior Medications.................................................................................. 76
 
 
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7.1.1.5.2
Concomitant Medications..................................................................... 76
7.1.1.6
Assignment of Screening Number............................................................... 76
7.1.1.7
Assignment of Randomization Number....................................................... 77
7.1.1.8
Trial Compliance (Medication).................................................................... 77
Clinical Procedures/Assessments........................................................................ 77
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 77
7.1.2.2
Physical Exam.............................................................................................. 77
7.1.2.2.1
Full Physical Exam ............................................................................... 77
7.1.2.2.2
Directed Physical Exam........................................................................ 78
7.1.2.3
Vital Signs.................................................................................................... 78
7.1.2.4
Electrocardiogram (ECG) ............................................................................ 78
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 78
7.1.2.6
Tumor Imaging and Assessment of Disease................................................ 78
7.1.2.7
Assessment of Disease................................................................................. 78
Laboratory Procedures/Assessments .................................................................. 78
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 79
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 80
7.1.3.2.1
Protocol Specific Specimen Collection ................................................ 80
Tumor Tissue Collection................................................................ 80
7.1.3.2.1.1
Blood Collection ............................................................................ 81
7.1.3.2.1.2
Urine Collection ............................................................................. 81
7.1.3.2.1.3
7.1.3.3
Future Biomedical Research........................................................................ 81
Other Procedures................................................................................................. 81
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 81
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 82
7.1.4.2
Blinding/Unblinding .................................................................................... 82
7.1.4.3
Domiciling ................................................................................................... 82
7.1.4.4
Calibration of Critical Equipment................................................................ 82
Visit Requirements.............................................................................................. 83
7.1.5
7.1.5.1
Screening...................................................................................................... 83
7.1.5.2
Image-guided Percutaneous Tumor Core Needle Biopsy............................ 83
7.1.5.3
Neoadjuvant MK-3475 Treatment............................................................... 84
 
 
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7.1.5.4
SOC Surgical RCC Resection...................................................................... 84
7.1.5.5
Follow-up After Surgical RCC Resection ................................................... 84
7.1.5.6
Post-Resection MK-3475 Treatment ........................................................... 85
7.1.5.7
Follow-up After Post-resection MK-3475 Treatment.................................. 85
7.1.5.8
Critical Procedures Based on Trial Objectives: Timing of Procedure......... 85
7.1.5.9
Trial 
Design/Dosing/Procedures Modifications Permitted 
within 
Protocol Parameters ..................................................................................... 86
Assessing and Recording Adverse Events .......................................................... 87
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 88
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 88
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 89
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 89
7.2.3.2
Events of Clinical Interest............................................................................ 89
7.2.3.3
Surgical complications................................................................................. 90
Evaluating Adverse Events ................................................................................. 91
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 94
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 94
Statistical Analysis Plan Summary ..................................................................... 94
8.1
Statistical Analysis Plan ....................................................................................... 95
8.2
Hypotheses.......................................................................................................... 95
8.2.1
Analysis Endpoints ............................................................................................. 96
8.2.2
Approaches to Analyses...................................................................................... 97
8.2.3
Statistical Methods.............................................................................................. 98
8.2.4
Multiplicity ....................................................................................................... 100
8.2.5
Interim Analysis................................................................................................ 101
8.2.6
Power ................................................................................................................ 102
8.2.7
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 104
Investigational Product ...................................................................................... 104
9.1
Packaging and Labeling Information ............................................................... 104
9.2
Clinical Supplies Disclosure............................................................................... 104
9.3
Storage and Handling Requirements................................................................ 104
9.4
 
 
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Returns and Reconciliation................................................................................ 105
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 105
Confidentiality..................................................................................................... 105
10.1
Confidentiality of Data ..................................................................................... 105
10.1.1
Confidentiality of Subject Records ................................................................... 105
10.1.2
Confidentiality of Investigator Information...................................................... 105
10.1.3
Confidentiality of IRB/IEC Information........................................................... 106
10.1.4
Compliance with Financial Disclosure Requirements..................................... 106
10.2
Compliance with Law, Audit and Debarment ................................................. 106
10.3
Compliance with Trial Registration and Results Posting Requirements ...... 108
10.4
Quality Management System............................................................................. 109
10.5
Data Management............................................................................................... 109
10.6
Publications ......................................................................................................... 109
10.7
11.0
LIST OF REFERENCES....................................................................................... 111
12.0
APPENDICES......................................................................................................... 118
Merck Code of Conduct for Clinical Trials...................................................... 118
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 120
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 126
Approximate Blood/Tissue/Urine Volumes Drawn/Collected by Trial Visit 
12.4
and by Sample Types.......................................................................................... 137
List of Abbreviations and Definitions ............................................................... 142
12.5
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 144
12.6
Eastern Cooperative Oncology Group (ECOG) Performance Scale ............. 145
12.7
Algorithm for Assessing Out-of-Range Laboratory Values ........................... 146
12.8
13.0
SIGNATURES......................................................................................................... 147
Sponsor's Representative ................................................................................... 147
13.1
Investigator.......................................................................................................... 147
13.2
 
 
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LIST OF TABLES
    
Table 1
Adequate Organ Function Laboratory Values........................................................ 39
Table 2
Trial Treatment ....................................................................................................... 41
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab (During Post-Resection Phase ONLY)...... 44
Table 4
Sample Allocation Schedule................................................................................... 47
Table 5
Infusion Reaction Treatment Guidelines-Neoadjuvant MK-3475 Only .............. 51
Table 6
General Approach to Handling irAEs- Neoadjuvant Phase Only........................ 53
Table 7
Recommended Approach for Handling Pneumonitis- Neoadjuvant Phase Only... 53
Table 8
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines-Post-Resection Phase Only.................................................................. 54
Table 9
Imaging and Treatment after First Radiologic Evidence of PD (irRESIST-
based Management) (Post-Resection MK-3475 Only) .......................................... 61
Table 10 Laboratory Tests..................................................................................................... 79
Table 11 Evaluating Adverse Events .................................................................................... 92
Table 12 First Interim Analysis Outcome Scenarios........................................................... 101
Table 13 Probability of Observing Serious Grade 3 or Grade 4 Adverse Experience for 
Various AE Rates ................................................................................................. 102
Table 14 Cumulative Probabilities of Stopping and Declaring Success After Each 
Interim Analysis Assuming Various True Immune Cell Infiltration Response 
Rates ..................................................................................................................... 103
Table 15 Product Description.............................................................................................. 104
Table 16 Estimated Blood Sample Volumes - Patients Randomized to Neoadjuvant 
MK-3475 .............................................................................................................. 137
Table 17 Estimated Blood Sample Volumes - Patients Randomized to No Treatment 
Control Group....................................................................................................... 138
Table 18 Estimated Tissue Sample Volumes - Patients Randomized to Neoadjuvant 
MK-3475 .............................................................................................................. 139
Table 19 Estimated Tissue Sample Volumes - Patients Randomized to No Treatment 
Control Group....................................................................................................... 140
Table 20 Estimated Urine Sample Volumes - Patients Randomized to Patients 
Randomized to Neoadjuvant MK-3475 ............................................................... 140
Table 21 Estimated Urine Sample Volumes – Patients Randomized to No Treatment 
Control Group....................................................................................................... 141
 
 
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LIST OF FIGURES
Figure 1 MK-3475-031 Trial Design.................................................................................... 14
Figure 2 Relationship Between AEs and Time on Pembrolizumab (MK-3475) Therapy.... 25
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.2/5.2.1.2.1.2
Dose 
Modification 
and 
toxicity 
Management 
Guidelines 
for 
Pembrolizumab/Post-
Resection MK-3475
Replaced the Dose Modification 
Guidelines Table.
Table now 
includes added guidelines for dose 
modification in the event of 
myocarditis 
and 
updated 
guidelines 
for 
several 
other 
conditions.
To align with the most current label 
and 
safety 
information 
for 
pembrolizumab. 
5.6.2
Supportive Care Guidelines 
During Post-Resection
MK-
3475 Treatment for this Trial
Updated the risk language and 
replaced the Infusion Reaction 
Treatment Guidelines Table. 
To align with the most current safety 
information for pembrolizumab
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Neoadjuvant MK-3475 (pembrolizumab) RCC Study
Trial Phase
Phase I
Clinical Indication
Neoadjuvant treatment of RCC (≥T1b)
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Neoadjuvant MK-3475, then standard-of-care (SOC) surgical RCC 
resection
vs.
No neoadjuvant therapy, with SOC surgical RCC resection;
Followed by post-resection MK-3475 for all subjects.
Number of trial subjects
Approximately 36 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 36 months
from the time the first subject signs the informed consent until the last 
subject’s last visit.
Duration of Participation
After a screening phase of 1-2 weeks, each subject assigned neoadjuvant 
MK-3475 will receive 2 (possibly 3) Q3 week cycles of treatment
followed by surgical RCC resection, while subjects not assigned to 
neoadjuvant treatment will proceed directly to RCC resection. Following 
recovery from surgery, all subjects will receive MK-3475 Q3 weeks for 
up to one year.  After the final dose of MK-3475 each subject will be 
followed for 30 days for adverse event (AE) assessment. Serious adverse 
events (SAEs) and events of clinical interest (ECIs) will be collected for 
90 days or until the initiation of new anti-cancer therapy, whichever
comes first.  Each subject will participate in the trial for up to 
approximately 18 months from the time the subject signs the Informed 
Consent Form (ICF) through the final Adverse Event Review.     
Randomization Ratio
Initial randomization of 2:1 for neoadjuvant MK-3475 vs. untreated 
controls, with interim analysis influencing further randomization (see 
Sections 7.1.5.5 and 8.0).
A list of abbreviations used in this document can be found in Section 12.6.
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a Phase I, randomized, no treatment controlled trial of neoadjuvant administration of 
MK-3475 (also known as pembrolizumab) in subjects with newly diagnosed RCC, ≥T1b (>4 
cm diameter), to be conducted in conformance with Good Clinical Practices.  Initially, 
subjects will be randomized 2:1 to receive either neoadjuvant MK-3475 or serve as untreated 
controls.  Those to receive neoadjuvant MK-3475 will undergo image-guided core needle 
biopsy of their tumor with collection of a minimum of three cores of tumor tissue.  Tissue 
from this block will be used by the local pathologist to confirm the diagnosis of RCC prior to 
the administration of MK-3475, and remaining tissue will be used for study analyses. Blood 
and urine samples for biomarker analysis will also be collected at the time of core biopsy in 
patients randomized to receive neoadjuvant MK-3475. Two to 3 weeks after the final
neoadjuvant dose of MK-3475 (administered at a dose of 200 mg IV Q3 weeks), additional 
blood and urine will be collected for biomarker analysis and patients will undergo SOC RCC 
surgical tumor resection. 
Control patients will proceed to surgery, without receiving 
neoadjuvant MK-3475, with the collection of blood and urine samples for biomarker analysis 
on the day of surgery.  In the operating room, three or more core needle biopsy specimens of 
the RCC may be collected before tumor removal and prior to renal artery cross-clamping 
under direct vision, at the discretion of the operating surgeon and subject to local institutional 
review board approval.  Upon surgical removal of the tumor, a minimum of 10 cm3 of non-
necrotic resected tumor tissue will be collected and shipped as fresh tissue to Merck Research 
Laboratories for analyses.  From the remaining resected tumor tissue, additional research 
samples will be collected for formalin fixation, snap freezing, and placement in RNAlater 
solution, while the remaining tumor tissue will be used by the local clinical site pathologist 
for routine clinical diagnostic purposes. Additional blood and urine samples for biomarker 
analyses will be collected from all subjects during post-operative follow up.  
Following recovery from surgery, each subject may receive post-resection MK-3475.  During 
this phase of the trial, subjects should be evaluated by SOC radiologic imaging at intervals to 
be selected by their treating physicians. The physician should utilize RECIST 1.1 and/or 
irRECIST for making clinical management decisions.  AEs should be monitored throughout 
the trial and graded in severity according to the guidelines outlined in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0.
Treatment with post-resection MK-3475 may continue until documented disease progression
or recurrence, unacceptable AE(s), intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw the subject, consent withdrawn by subject, 
start of new anti-cancer treatment, subject is lost to follow up, pregnancy of the subject, 
noncompliance with trial treatment or procedure requirements, completion of 17 
administrations of post-resection MK-3475 (approximately 1 year of treatment), or 
discontinuation for administrative reasons. 
 
 
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After the final study visit, routine SOC clinical follow up will continue.  Since the majority 
of recurrences (83%) after surgical resection in RCC occur within 2 years of surgery [1], the 
clinical outcome will be queried for each subject 1 and 2 years following surgical tumor
resection. 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
This trial will use an adaptive design based on pre-specified criteria. There will be up to three 
formal interim analyses.  The first interim analysis will be conducted after 9 subjects have 
entered the trial and the immune cell infiltrates in their surgically resected RCC specimens
have been assessed.  The second interim analysis will be conducted after 9 additional 
subjects have entered the trial and the immune cell infiltrates in their surgically resected RCC 
specimens have been assessed.  The third interim analysis may be conducted when 9 
additional subjects have entered the trial and the immune cell infiltrates in their surgically 
resected RCC specimens have been assessed.  See section 8.0 – Statistical Analysis Plan, for 
additional details regarding sample size determination.
The interim analyses will include re-estimations of the sample size required to maintain 
power in the trial. If results of the interim analyses indicate that a larger sample size is 
necessary, subject enrollment may be extended. Details are described in Section 8.0 –
Statistical Analysis Plan.  If further extension of enrollment beyond the 36 subjects proposed 
in this protocol is needed, a protocol amendment will be filed. 
Results of the first interim analysis will be used to determine if subsequent patients recruited 
to participate in the study will continue to be randomized to the untreated control group that 
does not receive neoadjuvant MK-3475 or whether subsequent patients enrolled in the study 
will all receive neoadjuvant MK-3475. This determination will be made according to the pre-
specified algorithm described in detail in Section 8.0 - Statistical Analysis Plan.
Results from the first interim analysis will also be used to determine if the two dose regimen 
for neoadjuvant MK-3475 should be increased to 3 doses, according to the pre-specified 
algorithm described in detail in Section 8.0 – Statistical Analysis Plan.  
 
 
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Trial Diagram
2.2
The trial design is depicted in Figure 1. 
  
Figure 1
MK-3475-031 Trial Design
Patients with newly diagnosed RCC (≥T1b (>4 cm diameter)) will be screened for trial 
participation, and after informed consent is obtained will be assigned to either undergo 
percutaneous image-guided core needle tumor biopsy followed by neoadjuvant MK-3475 and 
then SOC surgical RCC resection (top arrow) or proceed directly to SOC surgical RCC
resection (bottom arrow). After recovery from surgery, all subjects may receive post-
resection MK-3475.
*Initially, patients will be randomized 2:1 to neoadjuvant MK-3475 vs. untreated control, but 
based on prespecified interim analysis endpoints, continued randomization to the control 
group may be discontinued. 
†An additional study-prescribed pretreatment core needle biopsy is not required if a 
diagnostic biopsy has been performed per local SOC (and within 45 days prior to the first 
dose of MK-3475) and sufficient tissue is available from such a specimen for the study-
related analyses specified for the pretreatment core biopsy.   
‡If RCC immune cell infiltrates are not increased by at least two-fold in more than one of the 
initial 6 patients receiving 2 doses of neoadjuvant MK-3475, all subsequently enrolled 
subjects may receive 3 doses of neoadjuvant MK-3475.
#Upon recovery from surgery, all subjects may receive post-resection MK-3475, 200 mg IV, 
Q3W, for up to one year (17 doses).




-2
-1
1
4
7
week


12

1

6
week
week
2:1
#Post-Resection Treatment 
(for up to 1 year)
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
(1) Objective: To assess the safety of neoadjuvant MK-3475 therapy in patients undergoing 
surgical resection for the treatment of RCC
Hypothesis: Neoadjuvant MK-3475 treatment will be well tolerated in patients 
undergoing subsequent surgical RCC tumor resection.  
(2) Objective: To assess the effect of neoadjuvant MK-3475 therapy on immune cell 
infiltration in RCC
Hypothesis: Neoadjuvant MK-3475 therapy will stimulate a 2-fold or greater increase in 
intratumoral lymphocytic infiltration in at least 30% of patients with RCC.
Secondary Objective(s) & Hypothesis(es)
3.2
 
 
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Tertiary Objectives 
3.3
 
 
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Exploratory Objectives 
3.4
(8) Objective:  To assess the effect of neoadjuvant MK-3475 therapy on IMR ligand 
expression by tumor cells in RCC
(9) Objective:  To assess the ability of neoadjuvant MK-3475 to stimulate antigen-specific 
anti-tumor immune responses in patients with RCC
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-3475.
Pharmaceutical and Therapeutic Background
4.1.1
MK-3475 is a highly selective humanized mAb designed to block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 thus exerts an immunomodulatory 
function by affecting the PD-1 pathway that regulates peripheral immune tolerance.
 
 
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The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [2].  Accumulating evidence shows a correlation 
between TILs in cancer tissue and favorable prognosis in various malignancies [3-7].  In 
particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ 
regulatory T-cells seems to correlate with improved prognosis and long-term survival in solid 
malignancies such as ovarian, colorectal and pancreatic cancer, hepatocellular carcinoma, 
malignant melanoma (MEL) and RCC.  TILs can be expanded ex vivo and re-infused, 
inducing durable objective tumor responses in cancers such as MEL and RCC [8, 9]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement with its ligands (PD-L1 and/or PD-L2) 
[10,11].  PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) 
and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, 
PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ 
and ZAP70 which are involved in the CD3 T-cell signaling cascade [10; 12-14].  The 
mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from 
that of Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) as both molecules regulate an 
overlapping set of signaling proteins [15, 16].  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, Tregs and NK cells [17,
18].  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors [15, 
19-22].  Both ligands are type I transmembrane receptors containing both IgV- and IgC-like 
domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered 
through the T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic 
tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably 
expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments.  PD-L2 is thought to control immune T-cell activation in lymphoid organs, 
whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues [15].  
Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  High expression of PD-L1 
(and to a lesser extent of PD-L2) on tumor cells has been found to correlate with poor 
prognosis and survival in various cancer types, including RCC [23], pancreatic carcinoma 
[24], hepatocellular carcinoma [25], and ovarian carcinoma [26]. Furthermore, PD-1 also 
appears to regulate tumor-specific T-cell expansion in subjects with MEL [27].  This 
 
 
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suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention.
RCC is the seventh most common cancer among US men and ninth among US women.  
Twenty percent of people present with advanced disease, and an additional 30% of those who 
present with localized disease will eventually develop distant metastases and become largely 
incurable.  Surgical resection of the primary tumor, even in the face of metastatic disease, 
remains SOC for treatment of RCC.  In addition, systemic treatment using agents that target 
the vascular endothelial growth factor and its receptor as well as therapies against the 
mammalian target of rapamycin are standard options for metastatic disease. Cytokine-based 
treatment with interleukin-2 (IL-2) or interferon-α (IFN-α) were previously the mainstay of 
therapy for RCC and still benefit a small proportion of subjects. Despite seven new 
treatments being approved for treatment of metastatic RCC in last decade, there has been 
only a modest improvement in overall survival [28, 29].  Of particular relevance to this 
protocol, to date neoadjuvant therapy has not been shown to improve clinical outcome in 
RCC.  
Pre-clinical and Clinical Trials
4.1.2
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a mono-therapy or in combination with other 
treatment modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a monotherapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [27, 30-34].  Experiments have confirmed the in vivo efficacy 
of PD-1 blockade as a mono-therapy as well as in combination with chemotherapy in 
syngeneic mouse tumor models (see the Investigator’s Brochure [IB]).
Ongoing Clinical Trials
4.1.3
Ongoing clinical trials are being conducted in advanced MEL, non-small cell lung cancer, 
RCC, head and neck cancer, triple negative breast cancer, gastric cancer, bladder cancer and 
hematologic malignancies, as well as a variety of other cancer types.  For trial details please 
refer to the IB.
 
 
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Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
4.2.1.1
Rationale for the Trial
4.2.1.1.1 Rationale for Neoadjuvant MK-3475 in RCC
RCC is considered an immunogenic tumor, with reported episodes of spontaneous immune-
mediated tumor regression, and as such is a logic candidate for immunotherapy.  Immune 
modulation with high dose IL-2, a multitude of tumor vaccine approaches, as well as 
blockade of the CTLA-4 IMR using the mAb Ipilimumab have all shown clinical activity, 
further supporting the concept that RCC can respond to immune manipulation.   
The expression of PD-L1, the primary ligand for PD-1, by RCC cells also supports the 
administration of MK-3475 in RCC to block this interaction and release intratumoral immune 
cells from PD-1 mediated suppression.  In one study, increased expression of PD-L1 was 
found in 44% of primary RCCs and in 54% of metastatic RCC lesions.   Importantly, RCC 
patients with high levels of tumor PD-L1 expression were more likely to die [35, 36].  Of 
note, RCC infiltration by NK cells, as detected using molecular profiling of NK cell 
associated genes, has also been shown to correlate with survival [37].  As PD-1 has been 
found to be expressed by NK cells, and blockade of PD-1 has been shown to augment NK 
activity [38], PD-1 blockade by MK-3475 could therefore potentially restore NK-mediated 
anti-tumor immunity in RCC patients.  
The strongest rationale for administering MK-3475 in RCC is provided by the results of 
studies in which patients with RCC were treated with mAbs that block either PD-1 or its 
primary ligand PD-L1.  In a phase I study in 32 patients with metastatic RCC treated with
anti-PD-1 mAb (nivolumab) at IV doses of either 1 mg/kg or 10 mg/kg Q2weeks, the overall 
clinical response rate was 31%, with an overall duration of response of more than one year in 
4/5 patients treated with the 10 mg/kg dose [39].  Grade 3-4 AEs were observed in 12% of 
subjects. Using an anti-PD-L1 mAb to block the interaction between PD-1 and its primary 
(but not only) ligand PD-L1, Cho treated patients with metastatic RCC, observing 
progression free survival of 50% at 24 weeks, with Grade 3-4 AEs attributable to the study 
drug occurring in 13% of patients [40].    
While the use of neoadjuvant PD-1 blockade in RCC has not yet been reported, neoadjuvant 
therapy of RCC using targeted antiangiogenic drugs has been reported.  Such therapy has not 
been associated with an increase in overall complications from surgical RCC resection, but 
was noted to be an independent risk factor for the development of postoperative wound 
infection [41].  As anti-PD-1 mAb functions to enhance immune responses and does not 
appear to have an inhibitory effect on angiogenesis (a process critical for wound healing), 
such an increase in wound complications would not be expected with neoadjuvant
administration of MK-3475.  
 
 
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4.2.1.1.2 Rationale for Post-Resection MK-3475 in RCC
Rationale for Adjuvant MK-3475 in Subjects with Fully Resected RCC
4.2.1.1.2.1
Patients with RCC and no evidence of metastatic disease at diagnosis have a risk of relapse 
as high as 35% or 40% [42-44].
For patients with a partial or radical nephrectomy, the risk or recurrence largely depends on 
tumor size, grade, stage, histology, performance status, and completeness of resection [45-
47]. Currently, pathologic tumor stage is the single most important prognostic factor in 
resected RCC but does not fully explain disparities in survival among stages [48]. Some 
other histologic features, such as Fuhrman grade, histologic subtype, and presence of 
necrosis or sarcomatoid component have been linked with a poorer prognosis [49].
Regarding histologic subtypes, chromophobe and papillary type I seem to have a more 
indolent clinical course, and papillary type II and clear-cell RCC show a more aggressive 
behavior [47].
A systematic review with meta-analysis of adjuvant therapies for locally advanced renal cell 
cancer was published in 2011 [50]; it concluded that there was no support for using systemic 
therapy in the adjuvant setting, as there was no evidence of any benefit and there was 
evidence of substantial toxicity. The therapeutic modalities included in that study were 
mainly chemotherapy, immune therapies, and hormonal treatments, since no trial with 
targeted therapies had been completed at that time.
Immunotherapy was one of the standard options for metastatic RCC before the advent of 
targeted therapies. Interleukin-2 and interferon (IFN) were commonly used in that setting but 
with poor results, achieving a response rate of 6% to 10% with some durable responses, and a 
median OS of 12 to 15 months [51]. Nevertheless, none of the adjuvant trials with such 
immune therapies has been successful.  Two trials compared IFN with placebo in T3 to T4 
and/or node-positive patients, without improvements in DFS or OS [52, 53].
Two other 
small trials that explored the role of IL-2, whether in monotherapy as a single-dose treatment 
[54] or combined with IFN [55], also had negative results. A triple combination of IL-2, IFN, 
and 5-fluorouracil also failed to show an improvement in DFS compared with placebo and 
was associated with significant toxicity [56]. This same schedule was tested in a different 
trial, showing no differences in DFS but a worse OS for the treatment arm [57]. Some other 
trials have explored the potential role in the adjuvant setting of therapeutic vaccines.
Therefore, until October of 2016, no treatment had demonstrated substantial and consistent 
benefit in the adjuvant setting for RCC, whether using immunotherapy, radiotherapy, 
hormonal therapy, or chemotherapy. Trials testing targeted therapies such as sunitinib, 
sorafenib, pazopanib, and axitinib have either failed or are ongoing, but appear to cause
significant toxicities in patients with no existing disease burden during treatment [42, 43].
In October 2016, results from a Phase III randomized, placebo-controlled study in patients 
with high-risk clear-cell RCC who had undergone nephrectomy (S-TRAC) showed a median 
duration of DFS that was significantly longer in the sunitinib group (6.8 years; 95%
 
 
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confidence interval [CI]: 5.8 to NR) compared with the placebo group (5.6 years; 95% CI: 
3.8 to 6.6), with a hazard ratio (HR) of 0.76 for blinded independent radiologic review. 
Overall survival data were not available at the reported data cutoff. Dose reductions due to 
AEs were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as 
were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 
and 4 AEs were more frequent in the sunitinib group (48.4% and 12.1%, respectively) than in 
the placebo group (15.8% and 3.6%, respectively). The incidence of SAEs in the groups was 
similar (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects 
related to study treatment [58].
These recent data are encouraging, as technically this is the first study to show a positive 
DFS in this patient population; however, the treatment discontinuation rate remained high 
and the main AEs were the primary driver for limited treatment duration.
Given recent preliminary signs of both clinical activity and tolerability of checkpoint 
inhibitors in clinical trials in the adjuvant setting of RCC treatment, pembrolizumab may be 
expected to demonstrate a similar efficacy and safety profile in this setting. 
Rationale for Post-Resection MK-3475 in Patients with Metastatic Disease 
4.2.1.1.2.2
at the Time of RCC Resection
The anti-PD-1 mAb nivolumab has subsequently received FDA approval for the treatment of 
patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic 
therapy, based on a Phase III randomized, open-label study in patients with advanced RCC 
who had experienced disease progression during or after one or two prior anti-angiogenic 
therapy regimens. In that study, patients were randomized to nivolumab (n=410) 
administered intravenously at 3 mg/kg every 2 weeks or everolimus (n=411) administered 
orally 10 mg daily. The trial demonstrated a statistically significant improvement in OS for 
patients randomized to nivolumab as compared with everolimus (median survival of 25 
months vs 19.6 months, respectively (p=0.0018).
Of note, nivolumab as well as 
pembrolizumab (MK-3475) are both currently being evaluated in clinical trials in the first-
line setting for the treatment of metastatic RCC.
Even though the successful clinical development of VEGF/VEGFR targeting anti-angiogenic 
agents, such as sunitinib, pazopanib, axitinib, and bevacizumab plus IFNα, have collectively 
made improvements in the outcome of advanced RCC, most patients will progress within 2 
years following a standard first-line treatment.  As of now, the best median overall survival 
seen with the first-line advanced RCC treatments in a population with good and intermediate 
prognosis was approximately 28 to 29 months, as shown in the Phase III sunitinib vs 
pazopanib trial [59].  In a meta-analysis by Heng et al. on 645 patients who received first-line 
anti-VEGF/VEGFR agents including sunitinib, sorafenib, and bevacizumab in the US and 
Canada, the median survival was 22 months [60].  Based on Surveillance, Epidemiology, and 
End Results (SEER) data from 2004-2010, the 5-year survival rate of advanced RCC was 
only 12% [61].  Therefore, further development of novel agents, such as MK-3475, with 
durable clinical benefit and curative effect is still highly needed for advanced RCC. This low 
survival rate and lack of a durable response in patients with advanced RCC treated with the 
 
 
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available SOC agents (i.e. antiangiogenic agents) provides a strong rationale for moving to 
MK-3475 treatment in the post-resection Phase of this study without requiring patient with 
metastatic RCC at the time of RCC resection to fail post-resection anti-angiogenic therapy 
before initiating MK-3475 treatment.
4.2.1.2
Rationale for Selected Study Population 
Patients with RCC have been selected for this study for a variety of reasons.  First, renal 
tumors are amenable to percutaneous core needle biopsy, allowing collection of tumor tissue 
for confirmation of the diagnosis of RCC prior to MK-3475 administration and for critical 
baseline analyses, with minimal potential morbidity.  Secondly, there is no standard of care 
neoadjuvant therapy for RCC, and as such, the administration of MK-3475 in a neoadjuvant 
setting will not displace a SOC therapy.  Third, RCC has been shown to be immunogenic and 
some cases of RCC have responded to immunotherapy.  As such, the immune-stimulatory 
effects of PD-1 blockade using MK-3475 might be expected to enhance anti-RCC immune 
responses.  
Patients with metastatic RCC are specifically not excluded from participating in this study, 
because surgical resection of the primary tumor is the first line of treatment, even in those 
patients with metastatic disease, provided the primary tumor is amenable to resection.  In a 
prospective randomized study, Flanigan, et al, found that in patients with metastatic RCC, 
nephrectomy followed by systemic interferon -2b therapy significantly prolonged survival 
when compared to interferon therapy alone [62].  In a similar trial in metastatic RCC, 
Mickinsch, et al, also found that surgical resection of the primary tumor provided a 
statistically significant survival benefit over therapy with interferon -2b alone [63].  For 
patients with metastatic RCC, cytoreductive nephrectomy prior to any systemic therapy is 
supported by results from two prospective randomized phase 3 trials comparing nephrectomy 
followed by IFN-therapy vs IFN-therapy alone.  In both those studies, significantly 
improved overall survival was observed in patients receiving cytoreductive nephrectomy 
followed by IFN-[41].  Until ongoing trials evaluating the utility of cytoreductive 
nephrectomy prior to anti-angiogenic therapy are completed, the current standard of care for 
patients with metastatic RCC who are operative candidates remains surgical removal of the 
primary tumor [41].
4.2.1.3
Rationale for Sample Collection in This Trial 
Discovery Sciences at Merck has a critical unmet need for clinical specimens from patients 
being treated with MK-3475 to help elucidate the mechanism of action of PD-1 blockade and 
to both identify new targets for immune modulation and guide the selection of IMRs for 
blockade in combination with MK-3475.  This study is designed specifically to collect these 
critical specimens in RCC patients receiving MK-3475 in a neoadjuvant setting.  Upon 
completion of this study, we will more fully understand the mechanism of action by which 
MK-3475 stimulates anti-tumor immunity, we will more clearly understand the changes in 
IMR expression profiles of immune cells within RCC tumors that occur during MK-3475 
treatment, we will have identified numerous biomarkers potentially predictive of immune 
 
 
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responses stimulated by MK-3475, and we will have identified new IMR targets for 
Discovery Sciences to further interrogate.
4.2.1.4
Rationale for Intraoperative Core Needle Biopsies in This Trial
As presented at the 2014 American Society of Clinical Oncology (ASCO) meeting, Geyde, et 
al, noted that in RCC, gene expression profiles in biopsy tissue are significantly altered by 
warm ischemia [64].  Specifically, they found that gene expression profile of RCC tissue 
obtained by intraoperative core needle biopsy immediate prior to renal artery cross-clamping 
differed markedly from that obtained from analysis of RCC tissue collected after the tumor 
was resected, due to warm ischemia of the non-perfused tumor after renal artery cross-
clamping.  Based on this data, it is imperative that to most accurately compare gene 
expression profiles between RCC tissue collected pre-treatment by percutaneous core needle 
biopsy (of the normally perfused tumor in vivo) and RCC tissue collected at the time of 
surgery, such post-treatment RCC tissue should ideally be collected intraoperatively prior to 
renal artery cross-clamping in order to avoid RCC tissue ischemia-related gene expression 
changes that would be unrelated to MK-3475 treatment.  
Based on anecdotal reports, some urologists may be concerned that such intraoperative core 
needle biopsies could “violate” the renal capsule and spill tumor cells, leading to delayed 
local tumor recurrences.  However, the risk of this occurring is minimal, based on two 
perspectives; from the perspective of needle tract seedling during radiologically guided 
biopsies and from the perspective of intraabdominal seeding during surgery.
Percutaneous biopsy seeding is so rare that as of 2012 approximately 5 such problematic 
cases had been described [65, 66]. Port site seeding after laparoscopic RCC resection is also 
rare, even when the tumor is morcellated prior to removal, further supporting the concept that 
RCC does not readily metastasize in this fashion [67, 68]. Importantly, RCC enucleation has 
been promoted as a safe alternative to resection with margins, suggesting that the invasive 
edge of RCC is not at the physical boundary of the tumour [69]. Finally, even large RCC 
tumors that extend through the capsule of the kidney clinically do not lead to omental 
metastatic disease or cause ascites, again suggesting that RCC does not readily spread to the 
peritoneal cavity by tumor cell leakage.  
For these reasons, we conclude that intraoperative core needle RCC biopsies obtained 
immediately prior to renal artery crossclamping are not only safe, but are also critical for 
obtaining accurate intratumoral gene expression profiling information for this study.  Such 
accurate information will help to better inform on MK-3475 mechanism of action, better 
identify biomarkers of response to MK-3475 treatment, and better identify new targets for 
cancer immunotherapy, all of which will contribute to improved treatments for patients with 
RCC as well as other malignancies. It is understood that intra-operative core needle biopsy 
will be performed at the discretion of the operating surgeon and subject to local IRB 
approval.
 
 
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4.2.1.5
Rationale for Key Hypothesis
Primary hypothesis (1) Neoadjuvant MK-3475 treatment will be well tolerated in patients 
undergoing subsequent surgical RCC tumor resection.  MK-3475 therapy has been safe and 
effective in patients with a variety of different cancer types in the metastatic disease setting, 
including in patients with RCC, and none of the adverse effect observed to date should 
significantly impact patients undergoing surgical tumor resection.  
The administration of only a limited course (two or three doses) of MK-3475 in the 
neoadjuvant setting as proposed in this protocol may lead to a lower incidence of treatment-
associated SAEs than has been observed when patients with metastatic disease received 
extended (up to two years of) treatment with MK-3475.  As shown in Figure 2, for patients 
with metastatic melanoma receiving MK-3475 every two or three weeks until disease 
progression, the overall incidence of AEs increased over the cumulative time of therapy, with 
approximately 47% of subjects experiencing serious (Grade 3-5) AEs after 300+ days of 
MK-3475 treatment.  As can also be seen in Figure 2, at the times corresponding to the 
length of exposure that subjects in this trial will experience after 2 or 3 doses of neoadjuvant 
MK-3475 administered Q3W, the incidences of Grade 3-5 AEs were approximately 11% and 
18%, respectively.  Thus, during the administration of this limited course of neoadjuvant 
MK-3475 in this trial, the incidence of SAEs is expected to be markedly lower than has been 
reported to date with MK-3475 treatment.  
Figure 2
Relationship Between AEs and Time on Pembrolizumab (MK-3475) Therapy
 
 
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Kaplan-Meier estimates of time to first adverse event of Grade 3, 4, or 5 severity, regardless 
of attribution to study treatment, in the all-patients-as-treated population in a clinical study in 
patients with metastatic melanoma (adapted from Figure S2 [70]).
Once this proposed study demonstrates the safety of neoadjuvant MK-3475, larger clinical 
studies assessing changes in survival and recurrence rates after neoadjuvant PD-1 blockade 
with MK-3475 in patients with RCC, as well as other malignancies, can be performed.
Primary hypothesis (2) Neoadjuvant MK-3475 therapy will stimulate a 2-fold or greater 
increase in intratumoral lymphocytic infiltration in at least 30% of patients with RCC. Based 
on preclinical studies using PD-1 blockade in in vitro models, studies using PD-1 blockade in 
in vivo tumor models, and clinical studies using MK-3475 in a variety of human 
malignancies, blockade of PD-1 is expected to enhance anti-tumor immunity and stimulate 
immune cell infiltration into RCC tumor tissue.  Prior human studies have demonstrated that 
approximately 30% patients with metastatic RCC will clinically respond to therapy with 
mAbs that block PD-1.  In addition, in a clinical study in MEL, MK-3475 treatment 
stimulated a more than 2-fold increase in CD8+ T cell infiltrates within metastatic tumors in 
a majority of patients with clinical responses [71].  In contrast, in none of the MEL patients
with progressive disease during MK-3475 treatment did CD8+ T cell infiltrates increase.  
This suggests that an increase of at least 2-fold in RCC immune cell infiltrates will be 
observed in approximately 30% of RCC patients receiving MK-3475 in this study.  
 
 
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Rationale for Dose Selection/Regimen/Modification
4.2.2
Modifications to the dose or dosing regimen may be required to achieve the scientific goals 
of the trial objectives and/or to ensure appropriate safety monitoring of the trial subjects.  
Details 
of 
allowed 
modifications 
are 
provided 
in 
Section 
7.1.5.8
-
Trial 
Design/Dosing/Procedures Modifications Permitted within Protocol Parameters.
The safety and efficacy of multiple different dose/schedules combinations have been 
explored in multiple clinical trials. Extensive data support a fixed MK-3475 dose of 200 mg 
IV Q3 weeks. The discussion below provides justification for this dosing in this protocol.   
In the first in human study (Protocol number 001, refer to IB), which treated a variety of 
tumor types, MK-3475 showed evidence of target engagement and objective evidence of 
tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). The dose 
level of 10 mg/kg Q3W was evaluated in previously treated subjects with NSCLC in Part C 
of Protocol 001.
PK data analysis of MK-3475 administered Q2W showed slow systemic clearance, limited 
volume of distribution, and a long half-life (refer to IB). PD data (IL-2 release assay) 
suggested that peripheral target engagement is durable (>21 days). This early PK and PD 
data provided scientific rationale for testing Q2W vs. Q3W dosing schedules. Previously 
 
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treated subjects with NSCLC in PN001 Part C have experienced durable objective responses 
with acceptable toxicity when treated with MK-3475 at 10 mg/kg Q3W.
Data both from subjects with MEL and with NSCLC demonstrates objective responses to 
MK-3475 administered at the 2 mg/kg Q3W dose and schedule.  In addition, given the lack 
of a dose response to date, modeling and simulation data indicate that a fixed dose of 200 mg 
provides adequate exposure for the largest sized subjects while not exceeding the exposure 
seen at 10 mg every 3 weeks in the smallest sized subjects. A population PK analysis has 
been performed using serum concentration time data from 476 subjects. Within the resulting 
population PK model, clearance and volume parameters of MK-3475 were found to be 
dependent on body weight. The relationship between clearance and body weight, with an 
allometric exponent of 0.59, is within the range observed for other antibodies and would 
support both body weight normalized dosing or a fixed dose across all body weights. 
Simulations were performed on the basis of the population PK model, using a distribution of 
body weight reflective of the general population obtained from the National Health and 
Nutrition Examination Survey (NHANES) 2009-2010 database. Differences in exposure for 
a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 
in the MEL indication. The population PK evaluation also revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between
the NSCLC and MEL indications.  Therefore, there are no anticipated changes in exposure 
between different indication settings, including RCC.  Thus, a fixed dose of 200 mg Q3W 
will result in adequate exposure to MK-3475 across all body weights, similar to the 
exposures obtained with a 2 mg/kg Q3W regimen.
4.2.2.1
Rationale for the Use of Comparator/Placebo
Because the use of a placebo would entail an added delay of more than 5 weeks between 
diagnosis of RCC and SOC surgical tumor resection, with no potential for any clinical 
benefit, this study will not utilize a placebo control.
4.2.2.2
Starting Dose for This Trial
The starting dose of MK-3475, 200 mg IV, is based on extensive clinical data (see above).  
The 200 mg fixed dose is identical to that selected for FDA filings for MK-3475 approval in 
a variety of cancers.  
4.2.2.3
Maximum Dose/Exposure for This Trial
The dosage of MK-3475 for this trial is fixed at 200 mg IV Q3W.  Initial plans are to 
administer a total of two neoadjuvant doses to each subject, but this may be increased to 
three total doses, based on the first interim analysis (See Section 8.0- Statistical Analysis 
Plan) as stipulated in Section 7.1.5.8- Trial Design/Dosing/Procedures Modifications 
Permitted within Protocol Parameters. Therefore the maximum exposure prior to surgical 
RCC resection in those subjects randomized to neoadjuvant MK-3475 will be 600 mg per 
subject.  Following RCC resection and recovery from surgery, all subjects may receive MK-
 
 
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3475, 200 mg IV, Q3W, for up to 1 year (17 doses), for a maximal exposure in the post-
operative period of 3.4 gm.  The maximal total exposure on trial will therefore be 4 gm per 
subject.
4.2.2.4
Rationale for Dose Interval and Trial Design
The dosing interval (Q3W) and number of doses (2) for MK-3475 (200 mg dose) in the 
neoadjuvant portion of this study is based on several considerations.  The Q3W interval is 
based on the results of clinical MK-3475 studies comparing Q2W with Q3W dosing intervals 
in which no difference in clinical efficacy was observed.  Secondly, the decision to 
administer two (possibly three) neoadjuvant doses of MK-3475 is based on clinical 
considerations.  
MK-3475 will be administered during a 5-6 week interval prior to surgery, which is 
considered clinically acceptable in the RCC neoadjuvant context for a drug with a proven 
mechanism of action.  While this 5-6 week delay may cause potential anxiety for the patient 
and/or the physicians treating the patient, this relatively short delay should have no clinical 
impact.  Based on a 2006 report, the average size of renal cell cancers is approximately 6 cm 
in diameter [72].  With the growth rate of RCCs of between 0.1 to 1.35 cm/year [73], the 
average lesion has been present for over 4 years if one assumes the highest rate of growth in 
this range.  A 6 week interval in such an instance corresponds to at most a 2.5% increase in 
the time from initial renal cell malignant transformation to surgical resection.  As such, a 6 
week interval between diagnosis and surgical resection is clinically insignificant.  In addition, 
all patients in this trial who will be experiencing this interval between diagnosis and SOC 
surgical RCC resection will be receiving MK-3475 during this period, with the potential for 
clinical benefit.  Of note, this study does not include placebo administration in the control 
patients in order to avoid any delay between diagnosis and SOC surgical RCC resection in 
subjects not receiving neoadjuvant MK-3475.   
It is also highly likely that a period of time of at least 5-6 weeks will be necessary for MK-
3475 to stimulate an anti-tumor response that manifests as an immune cell infiltration of the 
primary tumor. In a study in patients with metastatic melanoma, significant increases in 
CD8+ T cell infiltrates were observed in tumor biopsies collected after 3-8 weeks of MK-
3475 therapy in the majority of patients who responded clinically to therapy [71].  
Importantly, in four of five patients with delayed clinical responses to therapy, increases in 
tumor TIL’s were not observed in tumor biopsies collected 3-8 weeks following initiation of 
MK-3475 therapy but were later observed in biopsies collected 80-120+ days following 
treatment initiation.  The variability of the time interval between the initiation of MK-3475 
therapy and tumor biopsy in that melanoma study precludes a precise estimation of length of 
time needed for MK-3475 to augment anti-tumor responses and stimulate infiltration of the 
tumor with immune cells.  We anticipate that immunologically, the tumor, present during this 
period of neoadjuvant therapy with MK-3475, will serve as an important source of both RCC 
antigen-specific T cells and tumor antigens for stimulating anti-tumor immune responses in 
this setting, and that without the presence of the tumor, MK-3475 might not be able to 
stimulate an effective anti-tumor immune response.  As discussed in Section 8.2.6 (Interim 
Analysis), if at least a 2-fold increase in immune cell infiltrates is not seen in more than one 
 
 
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of the first 6 subjects that receive 2 Q3W doses of MK-3475, we may increase to three the 
number of Q3W doses that subsequent subjects receive, primarily to allow more time for the 
tumor to be exposed to MK-3475 and therefore facilitate the stimulation of anti-tumor 
immunity and immune cell infiltration of the primary tumor.  
This increase in the number of doses would lengthen the delay time to surgery from 5-6 
weeks (2 doses) to 8-9 weeks (3 doses).  This slightly increased delay remains clinically 
insignificant for the same reasons that a 5-6 week delay is clinically insignificant, as 
described above.  Specifically, for an 8-9 week delay, with the growth rate of RCCs of 
between 0.1 to 1.35 cm/year [73], the average RCC lesion has been present for over 4 years if 
one assumes the highest rate of growth in this range. A 9 week interval in such an instance 
corresponds to at most a 4.3% increase in the time from initial renal cell malignant 
transformation to surgical resection. As such, a 9 week interval between diagnosis and 
surgical resection remains clinically insignificant. In addition, all patients in this trial who 
will be experiencing this interval between diagnosis and SOC surgical RCC resection will be 
receiving MK-3475 during this period, with the potential for clinical benefit.
In this protocol, all subjects may receive up to 1 year of post-resection MK-3475 at a dose of 
200 mg Q3W once they have recovered from surgery.  As discussed previously (Section 
4.2.2), this dosing regimen is supported by extensive clinical data.
Rationale for Endpoints
4.2.3
4.2.3.1
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of MK -
3475 administered in a neoadjuvant setting in patients with RCC.  The primary safety 
analysis will be based on subjects who experienced toxicities as defined by CTCAE criteria.  
Safety will be assessed by quantifying the toxicities and grades, including serious adverse 
events (SAEs) and events of clinical interest (ECIs), experienced by all subjects who have 
received MK-3475.  
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded.  AEs to be analyzed will include but will not be 
limited to all AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, potential immune-
related adverse events (irAEs) will be collected and designated as immune-related events of 
clinical interest (ECIs) as described in Section 7.2.3.2.
Because all patients with RCC treated with neoadjuvant MK-3475 in this trial will undergo 
subsequent SOC operative tumor resection, surgical complications will be assessed.  The 
following information related to surgery will be recorded: blood transfusions in the 
perioperative period, length of hospital stay, readmission, and surgical complications 
including the need for surgical re-exploration, thromboembolic events, cardiovascular events, 
pulmonary complications, gastrointestinal complications, postoperative infection, and 
incision-related complications.  
 
 
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4.2.3.2
Efficacy Endpoints
Immune cell infiltration of RCC.  The primary efficacy objective of this trial is to determine
the effect of neoadjuvant MK-3475 on intratumoral immune cell infiltration in patients with
RCC.  In order to assess changes in tumor immune cell infiltrates, each subject randomized 
to receive neoadjuvant MK-3475 must either undergo a study-prescribed pretreatment image-
guided percutaneous RCC biopsy or have already undergone a diagnostic core-needle biopsy 
performed as per local SOC (and within 45 days prior to the first dose of MK-3475) from 
which sufficient tissue is available and will be provided for the study-related analyses
specified for the pretreatment core biopsy.  Tissue from either such biopsy will be used to 
confirm the diagnosis of RCC prior to the administration of MK-3475 and for assessment of 
baseline immune cell infiltration of each subject’s RCC prior to MK-3475 treatment. At the 
time of SOC surgical tumor resection, RCC tissue will also be collected for analysis of 
immune cell infiltrates, both from control patients and those receiving a full course of 
neoadjuvant MK-3475.
Immune cell infiltration into RCC tissue will be assessed using three methods.  First, IHC of 
sections of FFPE tissues will be utilized to enumerate specific lymphocyte populations 
infiltrating the tumor, with markers to include CD3, CD8, and FoxP3.  Secondly, DNA will 
be extracted from the FFPE core biopsy tissue as well as from FFPE and frozen resected 
tumor specimens and promoter methylation analysis will be performed to quantitate T cell
infiltrates [74].  Third, the same DNA will be subjected to TCR sequencing analysis for 
quantitating T cell infiltration and for determining clonality of the tumor infiltrating T cells.  
Alterations in TIL IMR expression.  This trial is also designed to assess changes in IMR 
expression by TILs in response to therapy with MK-3475.  Fresh RCC tumor tissue will be 
collected from each patient (controls and those receiving neoadjuvant MK-3475) at the time 
of SOC RCC surgical resection.  In the operating room immediately after the tumor specimen 
is removed from the patient, a minimum of 10 cm3 of resected RCC tumor tissue will be 
collected as fresh tissue, placed in transport medium, and shipped overnight to the Merck 
laboratories.  Once received in the laboratory, fresh tumor tissue will be enzymatically 
digested and the phenotype and IMR expression profiles of the TILs will be assessed using a 
panel of mAbs and flow cytometry.  
Clinical Efficacy.  This trial is not designed to assess clinical efficacy, and this study is not 
powered to detect an effect of neoadjuvant and/or post-resection MK-3475 treatment on 
clinical outcome measures.  Because all subjects may receive additional MK-3475 after they 
have recovered from surgery, the impact of neoadjuvant therapy on response also cannot be 
assessed in this trial.
The pre-operative imaging studies on which the diagnosis of RCC was based for each study 
participant as well as postoperative scans for those subjects with metastatic disease at the 
time of enrollment may be requested and held for possible further analysis.  Supportive 
retrospective central review of imaging studies may be performed for this study using 
RECIST 1.1 and volumetric analysis. 
 
 
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RCC recurrence and patient survival will be queried at 1 and 2 years after surgical RCC 
resection. Patient survival and RECIST-based responses will be queried, but again, this study 
is not powered to detect an effect either neoadjuvant or post-resection treatment with MK-
3475 treatment on any clinical outcome measure.  
4.2.3.3
Planned Exploratory Biomarker Research
Biomarker research to identify factors important for MK-3475 treatment responses will be 
pursued. Tissues to be collected and assays to be performed include but are not limited to the 
following:
Gene expression profiling
RNA extracted from FFPE core biopsy tissue, FFPE resected RCC specimens, fresh resected 
RCC tissue in RNAlater solution, and whole blood will be utilized for gene profiling. 
Pretreatment gene expression profiles may predict which RCC tumors are infiltrated by 
immune cells in response to MK-3475 therapy.  By comparing profiles in tumor tissues and 
whole blood collected before and after neoadjuvant MK-3475, changes in gene expression 
induced during MK-3475 treatment will be identified and will be used to more fully 
understand the mechanism of action of MK-3475.  
Blood collection for genomic, genetic, and proteomic analysis
Blood will be collected at the time of biopsy (baseline), at the time of surgical tumor 
resection, and one month postoperatively.  Blood collected in Paxgene tubes will also be used 
for DNA extraction and subsequent sequencing-based TCR utilization analysis (for 
correlation with intratumoral TCR utilization).  Additional blood collected in Paxgene tubes 
will be used for RNA extraction and subsequent gene profiling for comparison to and 
correlation with tumor gene profiles.  Whole blood samples will be analyzed by flow 
 
 
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cytometry to determine the phenotype of PBMC, and for subject that are HLA-A2+, 
pentamer staining will be performed (see below).  PBMC will also be isolated from whole 
blood and then cryopreserved for later functional analysis.  
Plasma and serum will also be collected and frozen for later analysis.  Assays to be 
performed using plasma or serum may include but will not be limited to measurement of 
sPD-L1 levels using an ELISA assay recently developed at Merck, protein profiling, miRNA 
profiling, exosome isolation and analysis, assessment of serum antibodies, and circulating 
tumor DNA analysis.  A recent study suggested that miRNAs 21 and 378 levels in plasma
were predictive of response in patients with metastatic RCC treated with everolimus [78].
Determining the influence of tumor tissue source (FFPE vs frozen tissues) on DNA-
based methods for quantitating RCC T cell infiltration
In addition to fresh tumor tissue, additional RCC tumor tissue samples will be collected at the 
time of nephrectomy.  Tumor tissue will be fixed in formalin and then paraffin embedded, 
while additional pieces of tumor tissue will be snap frozen and used for DNA extraction and 
additional pieces will be placed in RNAlater solution for RNA extraction.  As described 
above for the analysis of the core biopsy tissue, infiltration by T cells will be assessed using 
three approaches.  In addition, DNA extracted from frozen tumor tissue may be analyzed 
using the two DNA-based T cell infiltration assessment approaches described above.  This 
will allow a comparison of molecular T cell analysis using formalin fixed vs fresh frozen 
tissue and inform on the need for collection of frozen tumor tissue in subsequent studies 
using these DNA-based approaches.  As formalin fixation and paraffin embedding has a 
variable effect on the integrity of DNA extracted from such tissues, comparing results 
derived from the analysis of DNA extracted from FFPE vs frozen tissues should also allow 
us to assess the accuracy of performing these types of assays using DNA extracted from 
archived FFPE tissues.  
PBMC Phenotypic Assessment
Whole blood will be collected at the time of pretreatment core needle biopsy (for those 
patients randomized to receive neoadjuvant MK-3475), perioperatively, and in follow up for 
assessment of phenotype using flow cytometry.  Expression of lineage markers, activation 
markers, and IMRs will be assessed.  In addition, when a given patient is HLA-A2+, tetramer 
staining will be performed to characterize the phenotype of RCC antigen-specific T cells in 
the blood.  
Measurement of Tumor miRNA levels
miRNA profiling may be performed using RNA extracted from RCC tumor tissue.
Urine Exosome Analysis
Urine will be collected at the time of pretreatment core needle biopsy (for those patients 
randomized to receive neoadjuvant MK-3475), perioperatively, and in follow up, and will be 
frozen.  Exosome analysis may subsequently be performed.  
 
 
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Tumor histoculture
A portion of fresh resected RCC tissue may be used for histoculture.  Briefly, this unique 
approach developed by our discovery scientists entails incubating thin tumor tissue slices in 
medium, modulating IMRs with mAbs added to the medium, and measuring the secretion of 
cytokines by T cells residing within the tumor.
Assessment of IMR Expression by RCC tumor cells
Digested tumor cells may be analyzed for expression of PD-L1 and PD-L2 using specific 
fluorochrome-labeled Abs and flow cytometry.  Expression of other IMR ligands may also be 
assessed. Digested tumor tissue cells in suspension may also be cryopreserved after TIL and 
tumor cell analysis.  These RCC cells may later be used as targets for immune-based assays 
to measure tumor-specific responses in cryopreserved PBMCs.
Isolation and cloning of intratumoral B cells secreting anti-RCC Abs
B cells isolated from peripheral blood may be transformed and cloned and the Abs secreted 
will be screened for reactivity against RCC cells.  
Induction of RCC antigen-specific T cells in peripheral blood in response to MK-3475 
treatment
PBMC isolated from peripheral blood may be assessed for antigen specificity using an IFN-
ELISpot assay and stimulation with overlapping pools of peptides from known RCC 
antigenic proteins.  Other approaches for measuring immune reactivity of these PBMCs may 
also be utilized.  
Exploratory Biomarker Objectives 
4.3
(1)
Objective:  To evaluate the differences in the IMR expression profiles between RCC 
tumor antigen-specific CD8+ T cells and unselected TILs in patients that are HLA-A2+ 
using tetramers
Purpose: When compared to bulk TILs, tumor antigen-specific T cells may express 
different IMRs [76, 77].  As tumor antigen-specific T cells are the critical mediators of 
T cell-mediated destruction of tumor cells, knowledge of the specific IMRs expressed 
by these T cells in response to MK-3475 will be critical for rational selection of 
additional IMR targets for therapy in combination with MK-3475.
 
 
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(2)
Objective: To use clinical response data from the study patients with metastatic disease 
that receive neoadjuvant MK-3475 to potentially identify the correlation between 
clinical response and tumor immune cell infiltration
Purpose:  The primary hypothesis that MK-3475 will stimulate a 2-fold or greater 
increase in tumor immune cell infiltrates in 30% of RCC patients treated with 
neoadjuvant MK-3475 is based on clinical study results, but whether the increase in 
immune cell infiltrates occurs in the 30% of patient with RCC who respond to PD-1 
blockade is unknown.  Clinical responses in the subset of patients with metastatic 
disease that receive neoadjuvant MK-3475 may allow tumor responses and immune 
responses to be correlated.  
(3)
Objective:  To evaluate baseline as well as changes in levels of serum/plasma 
biomarkers, including but not limited to sPD-L1, miRNAs, proteins, antibodies, nucleic 
acids and exosomes after neoadjuvant MK-3475 therapy as potential biomarkers of the 
immune response to treatment
Purpose: 
Blood-based biomarkers predictive of response to MK-3475 would be 
valuable for future patient selection, while those that provide an early readout of 
response would be valuable for modifying patient therapy.  This study will seek to 
identify potential blood-based biomarkers appropriate for subsequent validation in 
larger studies.   
(4)
Objective:  To evaluate differences in tumor tissue miRNA expression levels in 
response to treatment with MK-3475
Purpose: Changes in tumor miRNA expression profiles may help identify mechanisms 
of resistance to MK-3475 therapy.  
(5)
Objective: 
To isolate and transform B cells that secrete mAbs that specifically 
recognize RCC tumor antigens from the peripheral blood of RCC patients treated with 
MK-3475  
Purpose:  Relatively little is known about the role of B cells and antibody responses in 
tumor immunity. It is possible and likely that PD-1 blockade with MK-3475 will act to 
reverse anergy not only in tumor-specific CTL but also in tumor antigen-specific helper 
T cells that provide help to B cells producing tumor antigen-specific antibodies.  It is 
thus possible that in MK3475 treated patients both cellular and humoral responses 
contribute to efficacy and tumor-specific antibodies with therapeutic potential are 
present and can be characterized.
(6)
Objective:  To evaluate urine exosomes as a potential biomarker of immunologic 
response to neoadjuvant MK-3475 treatment
Purpose:
Exosomes in urine may offer a readily available source of biomarkers to 
predict response to MK-3475 in RCC.  
 
 
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(7)
(8)
(9)
Future Biomedical Research
4.3.1
The Sponsor will conduct Future Biomedical Research on specimens routinely and 
specifically collected during this clinical trial. This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysi s 
 
 
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and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.4
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male and female subjects with newly diagnosed RCC at least 18 years of age will be enrolled 
in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial. The subject
may also provide consent for Future Biomedical Research.  However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
2. Be ≥18 years of age on day of signing informed consent.
3. Have newly diagnosed RCC, with a primary tumor diameter of more than 4 cm (≥ T1b), 
not previously treated, and be a candidate for operative tumor resection.
4. Be willing and able to undergo pre-treatment baseline image-guided core biopsy of their 
primary RCC (unless a diagnostic biopsy has already been performed within 45 days 
prior to the first dose of MK-3475 and sufficient RCC tissue is available for study-related 
analyses). 
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
 
 
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6. Demonstrate adequate organ function as defined in Table 1, based on screening labs.
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥ 1,500 /mcL
Platelets
≥ 100,000 / mcL
Hemoglobin
≥ 9 g/dL or ≥ 5.6 mmol/L
Renal
Serum creatinine OR
Measured or calculateda  creatinine 
clearance
(GFR can also be used in place of creatinine 
or CrCl)
≤ 1.5 X upper limit of normal (ULN) OR
≥ 60 mL/min for subject with creatinine levels > 1.5 X
institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN  OR
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels >1.5 ULN
AST (SGOT) and ALT (SGPT)
≤  2.5 X ULN   OR
≤  5 X ULN for subjects with liver metastases
Coagulation
International  Normalized  Ratio  (INR)  or
Prothrombin Time (PT)
Activated Partial Thromboplastin Time
(aPTT)
≤ 1.5 X ULN 
≤ 1.5 X ULN 
a Creatinine clearance should be calculated per institutional standard.
7. Be a male, or a non-pregnant and non-breast feeding female; further:
a.
if female with reproductive potential: subject must demonstrate a serum β-human 
chorionic gonadotropin (β–hCG) level consistent with the nongravid state at the 
screening visit and agree to use (and/or have their partner use) two (2) acceptable 
methods of birth control beginning at the screening visit, throughout the trial and until 
120 days after the last dose of MK-3475 or until the last blood draw (for non-
treatment controls).  Acceptable methods of birth control are defined in Section 5.7.2.
b. if postmenopausal female:  subject is without menses for at least 1 year and have a 
documented follicle stimulating hormone (FSH) level in the postmenopausal range at 
screening,
c.
if a surgically sterile female:  subject is status post hysterectomy, oophorectomy, or 
tubal ligation. 
 
 
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NOTE: These procedures must be confirmed with medical records. In the absence of 
documentation, hysterectomy may be confirmed by pelvic exam or if necessary by 
ultrasound; oophorectomy may be confirmed by hormone levels, particularly FSH in 
the post-menopausal range, but tubal ligation subjects without records should be 
excluded, unless they demonstrate a serum β-human chorionic gonadotropin (β–hCG) 
level consistent with the nongravid state at the screening visit and agree to use (and/or 
have their partner use) two (2) acceptable methods of birth control beginning at the 
screening visit, throughout the trial and until 120 days after the last dose of MK-3475 
or until the last blood draw (for non-treatment controls).  Information must be 
captured appropriately within the site's source documents
8. Male subjects with a female partner of childbearing potential should agree to use an 
adequate method of contraception starting with the first dose of study therapy through 
120 days after the last dose of study therapy or until the last blood draw (for non-
treatment controls).  If their partner is pregnant, male subjects must agree to use a 
condom and no additional method of contraception is required for the pregnant partner. If 
their partner is of child-bearing potential, male subjects should use a condom with 
spermicide.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of screening.
2. Has a diagnosis of immunosuppression or has received systemic steroid therapy or any
other form of immunosuppressive therapy within 4 weeks prior to screening.
3. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy for the 
treatment of RCC.
4. Has a known additional malignancy (other than RCC) that is progressing or requires 
active treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, and in situ cervical cancer that has undergone potentially curative 
therapy.
5. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. The presence of RCC metastases to other sites is permitted.
6. Has an active autoimmune disease or a documented history of autoimmune disease. 
Subjects with vitiligo or resolved childhood asthma/atopy are an exception to this rule.
Subjects that require intermittent use of bronchodilators will not be excluded from the 
study. 
7. Has a history of (non-infectious) pneumonitis that required treatment with steroids or 
current pneumonitis.
8. Has an active infection requiring systemic therapy.
 
 
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9. Is receiving anticoagulant therapy or has received anticoagulant therapy within 10 days
prior to screening.  Certain platelet aggregation inhibitors are permitted (see Section 5.5.1 
below)
10. Has severe cardiovascular disease, i.e. arrhythmias, requiring chronic
treatment, 
congestive heart failure (NYHA Class III or IV) or symptomatic ischemic heart disease.
11. Has hepatic decompensation (Child-Pugh score > 6 [class B and C]).
12. Has uncontrolled thyroid dysfunction.  Subjects with hypothyroidism stable on thyroid 
hormone replacement will not be excluded from the study.
13. Has uncontrolled diabetes mellitus.
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected maximal duration of the trial, which would extend from the screening visit
through 120 days after the last dose of study drug of MK-3475 or until the last blood 
draw (for non-treatment controls).
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-CTLA-4 antibody (including ipilimumab) or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways.
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
20. Has received a live vaccine within 30 days prior to screening.
Trial Treatment(s)
5.2
The treatment to be used in this trial is outlined below in Table 2.
Table 2
Trial Treatment
Biologic
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen
Use
MK-3475
200 mg
Q3 weeks
IV
2 (or up to 3*) 
doses
Experimental, 
Neoadjuvant 
MK-3475
200 mg
Q3 weeks
IV
Up to 17 doses†
Experimental, 
Post-Resection 
*Potential increase in number of doses will be based on interim analysis (see Section 8.0).
†MK-3475 doses may be withheld due to toxicity, as described in Section 5.2.1.2.
 
 
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Trial Treatment should begin within 28 days of randomization or treatment assignment for 
those randomized to receive neoadjuvant MK-3475.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
For those subjects randomized to receive neoadjuvant treatment, MK-3475 (200 mg) will be 
administered intravenously Q3W for a total of two (or possibly three) doses.  Two to three 
weeks following the final dose, patients should undergo SOC surgical resection of their RCC 
tumors. 
Following recovery from surgical RCC resection, all subjects may receive MK-3475 (200 
mg) administered intravenously Q3W for up to 17 doses (1 year of treatment).
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
5.2.1.2
Dose Modification and Toxicity Management Guidelines for Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 6 for neoadjuvant dosing and Table 3 for post-resection dosing. 
Neoadjuvant MK-3475
5.2.1.2.1.1
Based on the first interim analysis of lymphocytic infiltrates in tumors resected from the first 
9 subjects, if an increase in tumor lymphocytic infiltration of 2-fold or greater is not observed 
in more than one of the 6 subjects in this group that received a 2 dose course of neoadjuvant 
 
 
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MK-3475, all subsequent subjects enrolled in this trial may be treated with 3 doses of MK-
3475.  Details are described in Section 8.0 – Statistical Analysis Plan.
Administration of neoadjuvant MK-3475 during this trial must be discontinued for drug-
related toxicities above Grade 1 in severity and for severe or life-threatening AEs as 
described in Section 5.6.1. Such subjects should proceed with SOC surgical RCC resection as 
soon as they have sufficiently recovered from the AE to undergo this procedure.  
For subjects without metastatic disease at the time of surgical RCC resection who experience 
drug-related toxicities above Grade 1 during neoadjuvant treatment, post-resection MK-3475
should also not be administered and the subject should be permanently discontinued.  
However, subjects with known metastatic disease at the time of surgical RCC resection who 
develop Grade 2 or greater drug-related AEs during neoadjuvant MK-3475 treatment may
still be eligible to receive post-resection MK-3475 if the drug-related AE severity as listed in 
Table 3 below does not prescribe permanent treatment discontinuation.    
Post-Resection MK-3475
5.2.1.2.1.2
Post-resection administration of MK-3475 must be withheld for drug-related toxicities and 
severe or life-threatening AEs as per Table 3 below. See Section 5.6.2 for supportive care 
guidelines, including use of corticosteroids
to be followed during post-resection 
administration of MK-3475 (only applicable in the Post-Resection Phase of the study).
 
 
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
(During Post-Resection Phase ONLY)
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab must be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of pneumonitis

Evaluate 
participants 
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus).

Participants 
with 
≥ 
Grade 
2 
diarrhea 
suspecting 
colitis 
should 
consider 
GI 
consultation and performing endoscopy to rule 
out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement therapy 
for participants with T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and 
initiate hormonal replacements as 
clinically indicated.  

Monitor 
for 
signs 
and 
symptoms 
of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat 
with 
non-selective 
beta-
blockers 
(eg, 
propranolol) 
or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate 
thyroid 
replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(prednisone 
1-2 
mg/kg 
or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE administer 
corticosteroids

Ensure 
adequate 
evaluation 
to 
confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other immune-
related AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure 
adequate 
evaluation 
to 
confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of event.  
Events that require 
discontinuation 
include and not 
limited to:  Guillain-
Barre Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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Timing of Dose Administration
5.2.2
MK-3475 solution for intravenous administration will be prepared and dosed per the 
instructions outlined in the Pharmacy Manual.
MK-3475 will be administered as a 30 minute IV infusion every 3 weeks (Q3W).  The study 
site(s) should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).  
Trial treatment should be administered following the schedule in Section 6.0 and after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Unless otherwise specified, trial treatment may be administered up to 3 days before or 
after the scheduled day of each cycle for administrative reasons.
All trial treatments will be administered on an outpatient basis.
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
Subjects will be assigned randomly according to a computer-generated allocation schedule.
The sample allocation schedule is shown in Table 4.
Table 4
Sample Allocation Schedule
Patientsa
Treatment Group
n=24
200 mg MK-3475 Q3 weeks, 2 or 3 dosesb
n=12
Control
a Patients will be randomized to receive neoadjuvant MK-3475 or control.  Allocation will be done in 
blocks of 3, ensuring 6 treated and 3 controls will be available for the first interim analysis.  
Depending on results of the first interim analysis, the control arm (and allocation numbers associated 
with the control arm) may be dropped from the allocation schedule, in which case patient numbers will 
be 33 and 3 for MK-3475 and controls, respectively.  
b Also depending on the results of the first interim analysis, the number of neoadjuvant doses of MK-
3475 may be increased from 2 to 3.
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
 
 
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Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
If a subject does not discontinue all prior medications within 14 days or 5 half-lives of 
receiving the first dose of MK-3475, he/she may be included in the study if the investigator 
can rationalize that the specific use of a prior medication is not clinically relevant within the 
context of the trial.
Concurrent use of any prescription or non-prescription medication, or concurrent vaccination,
during the course of the trial (i.e., after randomization or allocation) must first be discussed 
between the investigator and Sponsor Clinical Director prior to administration, unless 
appropriate medical care necessitates that therapy or vaccination should begin before the 
investigator and Sponsor Clinical Director can consult.  The subject will be allowed to 
continue in the trial if both the Sponsor Clinical Director and the investigator agree.
Acceptable Concomitant Medications 
5.5.1
All concomitant medication will be recorded on the case report form (CRF) including all
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids.  If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date may also be included on the CRF.
All concomitant medications received within 28 days before screening and 30 days after the 
last dose of trial treatment should be recorded.  Concomitant medications administered after 
30 days after the last dose of trial treatment should be recorded for SAEs and ECIs as defined 
in Section 7.2.
Paracetamol/acetaminophen may be used for minor ailments without prior consultation with 
the investigator or the Sponsor Clinical Director.
Subjects receiving therapy with NSAIDS are permitted to continue this medication 
throughout the study, as clinically indicated.  Subjects receiving other platelet aggregation 
inhibitors (e.g. Clopidogrel) may continue such medications, provided they are held for at 
least 5 days prior to pretreatment tumor biopsy and prior to surgical RCC resection, and are
not restarted until at least the day following the procedure.  
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination 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 subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
 
 
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Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phases of this trial:

Anti-cancer systemic chemotherapy or biological therapy, other than the study 
prescribed administration of MK-3475

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than MK-3475

Radiation therapy
Note: Radiation therapy to a symptomatic lesion or to the brain may be 
considered on a case-by-case basis after consultation with the Sponsor.  Such a 
radiated lesion should not be a RECIST 1.1 target lesion.

Live vaccines within 30 days prior to screening and while participating in the trial.  
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine.
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed.

Systemic glucocorticoids, for any purpose other than to modulate AEs of suspected 
immunologic etiology or on the day of surgical RCC resection to modulate 
perioperative nausea.  
Note: If systemic glucocorticoids are administered to a subject receiving MK-3475 
during the neoadjuvant phase of the trial to modulate an AE of suspected 
immunologic etiology, the guidance in Section 5.2.1.2.1.1 should be followed with 
regard to continued MK-3475 administration.   

Anticoagulants, other than those administered by subcutaneous injection for deep 
vein thrombosis (DVT) prophylaxis in the perioperative and postoperative period. 
Prohibited anticoagulants include, but are not limited to heparin (iv), enoxaparin, and 
warfarin.  Note: platelet aggregation inhibitors are permitted with certain restrictions 
(See Section 5.5.1).
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
Upon completion of the first visit in the follow-up phase of the trial (See Section 6- Trial 
Flow Chart), there are no prohibited therapies.
 
 
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Rescue Medications & Supportive Care
5.6
All AEs are to be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.0 (http://ctep.cancer.gov). 
NOTE: RESCUE MEDICATION AND SUPPORTIVE CARE GUIDELINES 
SIGNIFICANTLY DIFFER BETWEEN THE NEOADJUVANT AND POST-
RESECTION PHASES OF THIS TRIAL.
Supportive Care Guidelines During the Neoadjuvant Portion of this Trial
5.6.1
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below:

Diarrhea: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or 
without fever) and of bowel perforation (such as peritoneal signs and ileus).  In 
symptomatic subjects, infectious etiologies should be ruled out, and if symptoms are 
persistent and/or severe, endoscopic evaluation should be considered.
o
In subjects with severe enterocolitis (Grade 3-4), neoadjuvant MK-3475 
treatments will be discontinued and treatment with systemic corticosteroids 
should be initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  
When symptoms improve to Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month.
o
In subjects with moderate enterocolitis (Grade 2), neoajduvant MK-3475 will 
be discontinued and anti-diarrheal treatment should be started.  If symptoms 
are persistent for more than one week, systemic corticosteroids should be 
initiated (e.g., 0.5 mg/kg/day of prednisone or equivalent).  When symptoms 
improve to Grade 1 or less, corticosteroid taper should be started and 
continued over at least 1 month.  
o
All subjects who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.

Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Subjects 
should be strongly encouraged to maintain liberal oral fluid intake.

Anti-infectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice.

Immune-related adverse events: Please see Section 5.6.1.1 below and the separate 
guidance document in the Administrative
binder regarding diagnosis and 
management of adverse experiences of a potential immunologic etiology.  
 
 
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
Management of Infusion Reactions:  Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs.  Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness 
of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; 
Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation;
Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or 
exacerbation of tumor pain due to treatment); Urticaria (hives, welts, wheals); 
Vomiting.
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of MK-3475 during the neoadjuvant phase of this study.
Table 5
Infusion Reaction Treatment Guidelines-Neoadjuvant MK-3475 Only
NCI CTCAE Grade
Treatment
Premedication at
Subsequent Dosing
Grade 1
Mild reaction; infusion interruption 
not 
indicated; 
intervention 
not 
indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the 
opinion of the investigator.
None
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic medications indicated 
for ≤24 hrs.
Stop Infusion.
Additional 
appropriate 
medical 
therapy may include but is not limited 
to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the 
opinion of the investigator.
If symptoms resolve within one hour 
of stopping drug infusion, the infusion 
may be restarted at 50% of the 
original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 
toxicity should be permanently 
discontinued 
from 
further 
neoadjuvant
MK-3475
administration.
No subsequent neoadjuvant MK-
3475 dosing.  Subject should 
proceed to SOC RCC resection.  
Only for subjects with known 
metastatic disease at the time of 
RCC resection:
If post-resection MK-3475 is to 
be subsequently administered, 
subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of 
antipyretic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged 
(i.e., 
not 
rapidly 
responsive 
to 
symptomatic 
medication and/or brief interruption 
of infusion); recurrence of symptoms 
following 
initial 
improvement; 
hospitalization indicated for other 
clinical 
sequelae 
(e.g., 
renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor 
or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not limited 
to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the 
opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently 
discontinued from further MK-
33475 administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
5.6.1.1
Supportive Care Guidelines for Events of Clinical Interest (ECIs) and 
Immune-Related Adverse Events (irAEs) During Neoadjuvant MK-3475 Only
Events of clinical interest of a potential immunologic etiology may be defined as an adverse 
event of unknown etiology, associated with drug exposure and is consistent with an immune 
phenomenon.  irAEs may be predicted based on the nature of MK-3475, its mechanism of 
action, and reported experience with immunotherapies that have a similar mechanism of 
action.  Special attention should be paid to AEs that may be suggestive of potential irAEs.  
An irAE can occur shortly after the first dose or several months after the last dose of 
treatment.  
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE.  Subjects who 
develop a Grade 2 or higher irAEs should be discussed immediately with the Sponsor.  
Recommendations for managing irAEs during the neoadjuvant phase of the trial that are not 
detailed elsewhere in the protocol are detailed in Table 6.
 
 
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Table 6
General Approach to Handling irAEs- Neoadjuvant Phase Only
irAE
Discontinue study 
treatments?
Supportive Care
Grade 1
No action
Provide symptomatic treatment.
Grade 2
Discontinue neoadjuvant MK-
3475 treatment.
Consider systemic corticosteroids in addition 
to appropriate symptomatic treatment.
Grade 3 and Grade 4
Discontinue neoadjuvant MK-
3475 treatment.
Systemic corticosteroids are indicated in 
addition 
to 
appropriate 
symptomatic 
treatment.  May utilize 1 to 2 mg/kg 
prednisone or equivalent per day.
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks.
5.6.1.2
Supportive Care Guidelines for Pneumonitis- Neoadjuvant MK-3475 Only
Subjects with symptomatic pneumonitis should immediately stop receiving treatments and 
have an evaluation.  The evaluation may include bronchoscopy and pulmonary function tests 
to rule out other causes such as infection.  For subjects who are determined to have study 
drug associated pneumonitis, the suggested treatment plan is outlined in Table 7.
Table 7
Recommended Approach for Handling Pneumonitis- Neoadjuvant Phase Only
Study Drug Associated 
Pneumonitis
Discontinue study treatments?
Supportive Care
Grade 1 (asymptomatic)
No action
Intervention not indicated
Grade 2, 3 and 4
Discontinue neoadjuvant MK-3475
treatment.
Systemic corticosteroids are 
indicated.  
Supportive Care Guidelines During Post-Resection MK-3475 Treatment for this 
5.6.2
Trial
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.1.2, [Table 3].  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab. 
 
 
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Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to [Table 3] in Section 
5.2.1.2 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 8. 
Table 8
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines-Post-Resection Phase Only
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild 
reaction; 
infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires 
therapy 
or 
infusion interruption but 
responds 
promptly 
to 
symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDs, 
narcotics, 
IV 
fluids); 
prophylactic 
medications indicated for 
≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of _____ with:
Diphenhydramine 50 mg po 
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication 
and/or 
brief 
interruption of infusion); 
recurrence of symptoms 
following 
initial 
improvement; 
hospitalization 
indicated 
for other clinical sequelae 
(e.g., 
renal 
impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory 
support 
indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Contraception
5.7.2
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if MK-
3475 has transient adverse effects on the composition of sperm.  Non-pregnant, non-breast-
feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as (1) 
surgically sterilized, or (2) postmenopausal (a woman who has not had menses for greater 
than 1 year will be considered postmenopausal (and this will be confirmed by FSH testing)), 
 
 
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or (3) not heterosexually active for the duration of the trial.  The two birth control methods 
can consist of two barrier methods or a barrier method plus a hormonal method to prevent 
pregnancy. Subjects should start using birth control from the screening visit throughout the 
study period up to 120 days after the last dose of study drug or until the last blood draw (for 
non-treated controls).
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide, as per local regulations or 
guidelines.  Appropriate hormonal contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including oral, 
subcutaneous, intrauterine, or intramuscular agents).
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.2.  
If there is any question that a subject will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study.
Use in Pregnancy 
5.7.3
If a subject inadvertently becomes pregnant while on treatment with MK-3475, the subject 
will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor.   
If a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and followed as described 
above and in section 7.2.2.
Use in Nursing Women
5.7.4
It is unknown whether MK-3475 is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment.
 
 
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Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

For subjects who have declined a study-prescribed pre-treatment core needle biopsy 
but instead have undergone a diagnostic biopsy performed as per local SOC from 
which tissue will be submitted, this biopsy was not performed within 45 days prior to 
the first dose of MK-3475 or tissue submitted is not sufficient for the specified study-
related analyses.   

The subject, if randomized to receive neoadjuvant MK-3475, interrupts neoadjuvant 
trial medication administration for more than 7 consecutive days or 1 cumulative 
missed dose.

The subject has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol.

The subject has a confirmed positive serum pregnancy test.

In subjects assigned to receive neoadjuvant MK-3475, histologic analysis of the pre-
treatment core needle biopsy does not confirm the diagnosis of RCC with one or more 
clear cell components present.

In all subjects, histologic examination of the surgically excised tumor tissue does not 
confirm the diagnosis of RCC with clear cell elements.

In subjects assigned to receive neoadjuvant MK-3475, the patient does not undergo 
surgical RCC resection within 5 weeks of the final dose of MK-3475.
 
 
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
In subjects assigned to the control group (no neoadjuvant MK-3475), the patient fails 
to undergo surgical RCC resection within 6 weeks of randomization.

The subject has not recovered from surgical RCC resection and therefore does not 
begin post-resection MK-3475 within 60 days of surgery.
Note:  Exception if Sponsor approves a longer interval between surgery and the 
start of post-resection MK-3475

In subjects with metastatic disease at the time of RCC resection, radiologic disease 
progression is confirmed by local site assessment during post-resection MK-3475 
administration.
Note: Such subjects should be managed by irRECIST, with PD confirmed as 
outlined in Section 5.8.1. 
Note: Exception if Sponsor approves treatment continuation (Section 5.8.1)

In subjects without metastatic disease at the time of RCC resection, metastatic or 
locally recurrent disease is confirmed by local site assessment during post-resection 
MK-3475 administration.
Note:  Exception if Sponsor approves treatment continuation (Section 5.8.1)

Unacceptable adverse experiences as described in Section 5.2.1.2 Dose Modification.

Intercurrent illness that prevents further administration of treatment.

Investigator decides to withdraw the subject.

Noncompliance with trial treatment or procedure requirements.

The subject is lost to follow-up.

The subject has completed 17 administrations (approximately 1 year) of post-
resection MK-3475 treatment. 

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol 
Flow Chart) and Section 7.1.5 (Visit Requirements). For those subjects receiving MK-
3475, following the final dose of study drug, each subject will be followed for 30 days for 
adverse event monitoring (serious adverse events will be collected for 90 days after the 
end of MK-3475 treatment as described in Section 7.2.3.1).  
Subjects who discontinue for reasons other than disease progression will have post-
treatment follow-up for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent or becoming lost to follow-up.  After documented 
disease progression each subject will be followed by telephone for OS until death, 
withdrawal of consent, or the end of the trial, whichever occurs first.
 
 
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Treatment after Initial Radiologic Progression (irRECIST-based Management)
5.8.1
Note: irRECIST-based management is ONLY applicable in cases where metastatic RCC was 
identified pre-operatively and the subject is receiving post-resection MK-3475.
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with 
cytotoxic agents, and can manifest as a clinical response after an initial apparent increase in 
tumor burden (i.e., pseudoprogression) or even the appearance of new lesions.  Standard 
RECIST-based assessment of disease progression may, thus, not provide an accurate 
assessment of response to immunotherapeutic agents such as pembrolizumab.  For this 
reason, irRECIST has been developed to help guide treatment decisions during tumor 
immunotherapy.
For subjects who have initial radiological evidence of radiological PD by RECIST 1.1 as 
determined by the site, the investigator may elect to continue a subject on study treatment 
until repeat imaging is obtained (irRECIST-based management) (see Table 9).  This clinical 
judgment decision by the investigator should only be made if the subject is clinically stable, 
based on clinical factors including performance status, clinical symptoms, and laboratory 
data.  Such subjects may continue to receive study treatment and a imaging-based tumor 
assessment should be repeated ≥ 4 weeks later in order to reassess PD per investigator 
assessment.  
Clinical stability is defined by the following: 

Absence of signs and symptoms of clinically significant progression of disease, 
including worsening of laboratory values,

No decline in ECOG performance status,

Absence of rapid progression of disease, AND

Absence of tumor progression at critical anatomical sites that requires urgent 
alternative medical intervention (e.g., CNS metastasis with potential for cord 
compression) 
NOTE:  Subjects exhibiting toxicity from trial therapy as outlined in Section 5.2.1.2 and 
7.2 may NOT continue to receive trial therapy.
NOTE: Any subject deemed clinically unstable should be discontinued from trial 
treatment at investigator-assessed 1st radiologic evidence of PD and is not required to 
have repeat imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the investigator should consider all target and non-target lesions as well as any incremental 
new lesion(s).
 
 
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Upon repeat imaging, PD will be confirmed if ANY of the following occur by irRECIST:

Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir

Non-target disease resulting in initial diagnosis of PD is worse (qualitative 
assessment)

New lesion resulting in initial diagnosis of PD is worse (qualitative assessment)

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from trial therapy (exception noted below in this Section 5.8.1).
Upon repeat imaging, PD will have failed to be confirmed if ALL of the following occur by 
irRECIST: 

Tumor burden is < 20 % or < 5 mm absolute increase compared to nadir

Non-target disease resulting in initial diagnosis of PD is stable or improved 
(qualitative assessment)

New lesion resulting in initial diagnosis of PD is stable or improved (qualitative 
assessment)

No incremental new lesion(s) since last evaluation

No incremental new non-target progression since last evaluation
If repeat local site imaging fails to confirm PD by irRECIST and the subject continues to be 
clinically stable, treatment may continue and follow the regular imaging schedule. 
When feasible, subjects should not be discontinued until after PD is confirmed by the local 
site investigator radiology assessment.  This allowance to continue treatment despite initial 
radiologic PD takes into account the observation that some subjects can have a transient 
tumor flare in the first few months after the start of immunotherapy, and then experience 
subsequent disease response.  Subjects who are deemed clinically unstable are not required to 
have repeat tumor imaging for confirmation of PD.  Tumor flares include any of the 
following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
Additional details about irRECIST are referenced in the Merck TIP Sheet for RECIST 1.1 
and irRECIST.
 
 
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Table 9
Imaging and Treatment after First Radiologic Evidence of PD (irRESIST-
based Management) (Post-Resection MK-3475 Only)
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence 
of 
PD 
by 
RECIST 1.1 
Repeat 
imaging at > 4 
weeks at site 
to confirm PD
May continue study 
treatment at the local 
site 
investigator’s 
discretion 
while 
awaiting confirmatory 
tumor imaging by site 
by irRECIST.
Repeat imaging 
at > 4 weeks to 
confirm PD per 
physician 
discretion only
Discontinue treatment
Repeat tumor 
imaging 
confirms 
PD 
by 
irRECIST 
at the local site
No additional 
imaging 
required
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor)
No 
additional 
imaging 
required
N/A
Repeat tumor 
imaging shows 
SD, PR or CR 
by 
irRECIST 
at the local site
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue 
study 
treatment at the local 
site 
investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study treatment 
if condition has improved 
and/or clinically stable per 
investigator’s 
discretion. 
Next tumor image should 
occur 
according 
to 
the 
regular imaging schedule 
outlined in the protocol
Subject Replacement Strategy
5.9
If a subject discontinues from the trial, a replacement subject may be enrolled if deemed 
appropriate by the investigator and Sponsor.  The replacement subject will generally receive 
the same treatment or treatment sequence (as appropriate) as the subject being replaced.  The 
replacement subject will be assigned a unique randomization number.  The trial site should 
contact the Sponsor for the replacement subject’s randomization number.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
 
 
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A trial may be paused during review of newly available preclinical/clinical safety, 
pharmacokinetic, pharmacodynamic, efficacy or biologic data or other items of interest, prior 
to a final decision on continuation or termination of the trial.  It may be necessary to keep the 
trial open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the trial.  If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated.  The overall trial end will then not be 
identified until the Sponsor has made the decision to end the trial following this review 
period.  The Competent Authority(ies) and Institutional Review Board(s)/Independent Ethics
Committee(s) [IRB(s)/IEC(s)] will be appraised of the maximum duration of the trial beyond 
the last subject out and the justification for keeping the trial open.
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
Trial Flow Chart - Patients Randomized to Neoadjuvant MK-3475
6.1
Trial Period:
Screening
Randomizationa
Pretreatment 
Core Biopsy
MK-3475
SOC Tumor 
Resection
Post-operative 
Follow Up
Week:
-2
-2
-1
1
4
7
12b
Scheduling window (days)
±14
±14
±6
±3
±3
-7/+14
-5/+7
Administrative Procedures
Informed Consentc
X
Informed Consent for Future Biomedical Researchd
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Medical History
X
ECOG Performance Scale Assessment
X
Concomitant Medication Reviewe
X
X
X
X
X
X
Clinic Procedures/Assessments
Full Physical Examinationf
X
X
X
Directed Physical Examinationf
Xg
X
Vital Signs, Weight and Heighth
X
X
X
Xg
X
12-Lead Electrocardiogram (performed locally)
Xi
as clinically indicated
Tumor Core Needle Biopsyj
Xk
Xl
MK-3475 Administrationm
X
X
SOC Tumor Resection
X
Adverse Events Monitoringn
X
X
X
X
X
X
Assessment of Surgical Complications 
Xo
Laboratory Procedures/Assessments
Pregnancy Test- Urine or Serum -HCG or FSHp
Xi
X
PT/INR and aPTT
Xi
Xq,r
X
CBC with Differential
Xi
X
X
Xq
X
Chemistry
Xi
X
X
Xq
X
Urinalysis
Xi
T3, FT4, and TSH
Xi
X
X
Blood for HLA typing
Xs,t
HIV/Hepatitis Screen 
Xi
 
 
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Trial Period:
Screening
Randomizationa
Pretreatment 
Core Biopsy
MK-3475
SOC Tumor 
Resection
Post-operative 
Follow Up
Week:
-2
-2
-1
1
4
7
12b
Scheduling window (days)
±14
±14
±6
±3
±3
-7/+14
-5/+7
Protocol-Specific Specimen Collection
Tissue 
Collection
Fresh tumor tissue for shipping (TIL analysis, 
histoculture, tumor cell isolation and IMR 
expression analysis)
X
Tumor tissue for FFPE (IHC; DNA for 
mutational analysis, TCR utilization, promoter 
methylation analysis; RNA for gene expression 
and miRNA analysis)
Xu
Xv,w
Fresh tumor tissue for snap freezing (DNA 
isolation, metabolic profiling, laser capture 
microdissection)
X
Fresh non-malignant kidney tissue from resected 
tumor specimen for snap freezing (DNA 
isolation)
X
Fresh tumor tissue in RNAlater solution (RNA 
extraction, gene expression)
X
Fresh non-malignant kidney tissue in RNAlater 
solution (RNA extraction, gene expression)
X
Blood
PBMC Phenotypic Analysis
Xt
Xq
X
PBMC Isolation and Cryopreservation (Antigen-
specific T cell response evaluation)
Xt
Xq
X
Plasma (miRNA, and exosome evaluation)
Xt
Xq
X
Serum (biomarkers)
Xt
Xq
X
Serum (PK/PD)
Xx
Xy
Xq
X
RNA 
isolation 
(gene 
expression, 
miRNA 
expression)
Xt
Xq
X
DNA isolation (TCR utilization)z
Xt
Xq
X
B cell isolation and transformation
Urine for exosome isolation and analysis
Xt
Xaa
X
 
 
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a.
Randomization, initially 2:1 neoadjuvant MK-3475:controls.  Randomization will occur only after written consent is obtained and will occur after all screening assessments 
have been completed. Randomization can occur at any time point after screening and prior to core biopsy.
b. This follow up visit must occur no less than 30 days after the day of SOC tumor resection.
c.
Written consent must be obtained prior to performing any protocol-specific procedure.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within 28 days prior to screening.  
d. If the subject signs the FBR consent, leftover samples may be kept for Future Biomedical Research.
e.
Prior medications – Record all medications taken within 28 days of screening visit.  Concomitant medications – Enter new medications started during the trial through 30 
days after the last dose of trial treatment.  Record all medications taken for SAEs as defined in Section 7.2
f.
Full PE at screening and neoadjuvant MK-3475 treatment visits; Directed PE for all other visits.
g. These procedures may be performed up to 36 hours prior to the start of the SOC RCC tumor resection surgical procedure.  
h. Vital signs include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening visit only. Vital signs will be collected at screening, 
prior to the administration of each dose of trial treatment, at SOC tumor resection, and at post-operative follow-up.
i.
Laboratory tests for screening are to be performed within 28 days prior to the first dose of trial treatment. See section 7.1.3 for details regarding laboratory testing.
j.
If a diagnostic biopsy has already been performed per local SOC and sufficient tissue from that sample is available and will be submitted for all study-related analyses 
specified for the preoperative biopsy tissue, the study-specified pretreatment biopsy will not be required and these assessments should be performed on the day that 
pretreatment blood and urine samples (see footnote t below) are collected.
k. Percutaneous core needle biopsy of RCC performed under image guidance. This procedure may take place any time between randomization to the MK-3475 treatment group 
and the start of treatment with MK-3475. This study-prescribed pretreatment core needle biopsy is not required if a diagnostic biopsy has been performed per local SOC for 
diagnostic purposes, this biopsy will have been performed within 45 days prior to the first dose of MK-3475, and sufficient tissue is available from such a specimen for all 
study-related analyses specified for the pretreatment biopsy.
l.
During the surgical procedure and prior to cross-clamping of the renal artery, under direct vision a core needle biopsy of the RCC may be performed at the discretion of the 
operating surgeon and subject to local IRB approval.
m. The number of doses of MK-3475 may be increased to three doses, based on the results of the first interim analysis, as described in Section 8.0 (See Table 12 for the flow 
chart should this occur).
n. AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.
o. At this visit, the occurrence of any surgical complications within 30 days of the operative procedure will specifically be assessed.
p. For female subjects of reproductive potential, a urine pregnancy test should be performed within 72 hours of the first dose of trial treatment.  If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be 
repeated if required by local guidelines. For women thought to be post-menopausal, serum FSH will be measured to confirm post-menopausal status.
q. Blood for study related analyses may be collected at any time prior to surgery on the day of surgery.  Ideally these blood samples will be collected via the iv cannula placed 
in preparation for surgery, but these samples may also be collected via venipuncture earlier on the day of surgery, at the discretion of the clinical care team
r.
Blood for assessment of these coagulation parameters may be drawn up to 72 hours before the day of SOC tumor resection, at the discretion of the operative team.  If such a 
sample is collected, a sample for these tests will not need to be collected on the day of surgery.
s.
Low resolution HLA-A and B typing, to be performed by local HLA typing laboratory.
t.
Blood and urine samples should be collected on the day of the pretreatment core biopsy, However, if tissue from a biopsy previously performed per local SOC for diagnostic 
purposes will be submitted for all specified study-related analyses, these blood and urine samples should be collected as close to the time of this biopsy as possible and must 
be collected prior to the first dose of MK-3475.  
 
 
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u. A minimum of 3 18-gauge core biopsy tumor samples will be collected.  The harvested cores will be placed in single cassette for formalin fixation and paraffin embedding.  
The entire specimen will then be cut onto slides.  After the diagnosis of RCC is confirmed by the local site pathologist, the remaining tissue sections will be used for study 
related analyses.
v. A minimum of 3 18-gauge core biopsy tumor samples may be collected intraoperatively under direct vision by the surgeon prior to cross-clamping of the renal artery on the 
side of the RCC.  The harvested cores will be placed in single cassette for formalin fixation and paraffin embedding.  The FFPE block will then be shipped to Central 
Laboratory.
w. Following tumor resection, additional tumor tissue will be collected for formalin fixation and paraffin embedding.  These FFPE blocks will then be shipped to Central 
Laboratory.
x. Blood sample to be collected 30 minutes after the completion of MK-3475 dosing.
y. Blood samples to be collected immediately prior to and 30 minutes after the completion of MK-3475 dosing.
z.
Any leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent.
aa. Urine will be collected prior to surgery on the day of the surgical RCC resection.
 
 
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Trial Flow Chart - Patients Randomized to No Treatment Control Group
6.2
Trial Period:
Screening
Randomizationa
SOC Tumor 
Resection
Post-Operative 
Follow-up
Week 
-2
-2
1
6b
Scheduling window (days)
±14
±14
±14
-5/+7
Administrative Procedures
Informed Consentc
X
Informed Consent for Future Biomedical Researchd
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Medical History
X
ECOG Performance Scale Assessment
X
Concomitant Medication Reviewe
X
X
X
Clinic Procedures/Assessments
Full Physical Examinationf
X
Directed Physical Examinationf
Xg
X
Vital Signs, Weight and Heighth
X
Xg
X
12-Lead Electrocardiogram (performed locally)
Xi
As clinically indicated
SOC Tumor Resection
X
Tumor Core Needle Biopsyj
Xj
Adverse Events Monitoringk
X
X
X
Assessment of Surgical Complications
Xl
Laboratory Procedures/Assessments
Pregnancy Test- Urine or Serum -HCG or FSHm
Xi
X
PT/INR and aPTT
Xi
Xn,o
X
CBC with Differential
Xi
Xn
X
Chemistry
Xi
Xn
X
Urinalysis
Xi
T3, FT4, and TSH
Xi
Blood for HLA typing
Xn,p
HIV/Hepatitis Screen 
Xi
 
 
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Trial Period:
Screening
Randomizationa
SOC Tumor 
Resection
Post-Operative 
Follow-up
Week 
-2
-2
1
6b
Scheduling window (days)
±14
±14
±14
-5/+7
Protocol-Specific Specimen Collection
Tissue Collection
Fresh tumor tissue for shipping (TIL analysis, histoculture, tumor cell 
isolation and IMR expression analysis)
X
Tumor tissue for FFPE (IHC; DNA for mutational analysis, TCR 
utilization, promoter methylation analysis; RNA for gene expression 
and miRNA analysis)
Xq,r
Fresh tumor tissue for snap freezing (DNA isolation, metabolic 
profiling, laser capture microdissection)
X
Fresh non-malignant kidney tissue from resected tumor specimen for 
snap freezing (DNA isolation)
X
Fresh tumor tissue in RNAlater solution (RNA extraction, gene 
expression)
X
Fresh non-malignant kidney tissue in RNAlater solution (RNA 
extraction, gene expression)
X
Blood
PBMC Phenotypic Analysis
Xm
X
PBMC Isolation and Cryopreservation (Antigen-specific T cell 
response evaluation)
Xm
X
Plasma (miRNA, and exosome evaluation)
Xm
X
Serum (biomarkers)
Xm
X
Blood for RNA isolation (gene expression, miRNA expression)
Xm
X
Blood for DNA isolation (TCR utilization)s
Xm
X
Urine for exosome isolation and analysis
Xt
X
 
 
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a.
Randomization, initially 2:1 neoadjuvant MK-3475:controls.  Randomization will occur only after written consent is obtained and will occur after all screening 
assessments have been completed.
b.
This follow up visit must occur no less than 30 days after the day of SOC tumor resection.
c.
Written consent must be obtained prior to performing any protocol-specific procedure.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within 28 days prior to screening.
d.
If the subject signs the FBR consent, leftover samples may be kept for Future Biomedical Research.
e.
Prior medications – Record all medications taken within 28 days of screening visit.  Concomitant medications – Enter new medications started during the trial through 
the Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 7.2
f.
Full PE at screening visit; Directed PE for all other visits.
g.
These procedures may be performed up to 36 hours prior to the start of the SOC RCC tumor resection surgical procedure.
h.
Vital signs include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening visit only. Vital signs will be collected at 
screening, prior to the administration of each dose of trial treatment, at SOC tumor resection, and at post-operative follow-up.
i.
Laboratory tests for screening are to be performed prior to randomization. See section 7.1.3 for details regarding laboratory testing.
j.
During the surgical procedure and prior to cross-clamping of the renal artery, under direct vision a core needle biopsy of the RCC may be performed at the discretion of 
the operating surgeon and subject to local IRB approval.
k.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness.
l.
At this visit, the occurrence of any surgical complications within 30 days of the operative procedure will specifically be assessed.
m.
For female subjects of reproductive potential, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine 
tests) should be repeated if required by local guidelines. For women thought to be post-menopausal, serum FSH will be measured to confirm post-menopausal status.
n.
Blood for study related analyses may be collected at any time prior to surgery on the day of surgery.  Ideally these blood samples will be collected via the iv cannula 
placed in preparation for surgery, but these samples may also be collected via venipuncture earlier on the day of surgery, at the discretion of the clinical care team.
o.
Blood for assessment of these coagulation parameters may be drawn up to 72 hours before the day of SOC tumor resection, at the discretion of the operative team.  If 
such a sample is collected, a sample for these tests will not need to be collected on the day of surgery.
p.
Low resolution HLA-A and B typing, to be performed by local HLA typing laboratory.
q.
A minimum of 3 18-gauge core biopsy tumor samples may be collected intraoperatively under direct vision by the surgeon prior to cross-clamping of the renal artery on 
the side of the RCC (see footnote h). The harvested cores will be placed in single cassette for formalin fixation and paraffin embedding.  The FFPE block will then be 
shipped to Central Laboratory for further processing and analysis.
r.
Following tumor resection, additional tumor tissue will be collected for formalin fixation and paraffin embedding.  These FFPE blocks will then be shipped to Central 
Laboratory.
s.
Any leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent.
t.
Urine will be collected prior to surgery on the day of the surgical RCC resection.
 
 
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Trial Flow Chart - Patients Randomized to Neoadjuvant MK-3475 (3 DOSE REGIMEN)
6.3
Trial Period:
Screening
Randomizationa
Pretreatment 
Core Biopsy
MK-3475
SOC Tumor 
Resection
Post-Operative 
Follow-up
Week:
-2
-2
-1
1
4
7
10
15b
Scheduling window (days)
±14
±14
±6
±3
±3
±3
-7/+14
-5/+7
Administrative Procedures
Informed Consentc
X
Informed Consent for Future Biomedical Researchd
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Medical History
X
ECOG Performance Scale Assessment
X
Concomitant Medication Reviewe
X
X
X
X
X
X
X
Clinic Procedures/Assessments
Full Physical Examinationf
X
X
X
X
Directed Physical Examinationf
Xg
X
Vital Signs. Weight and Heighth
X
X
X
X
Xg
X
12-Lead Electrocardiogram (performed locally)
Xi
as clinically indicated
Tumor Core Needle Biopsyj
Xk
Xl
MK-3475 Administrationm
X
X
X
SOC Tumor Resection
X
Adverse Events Monitoringn
X
X
X
X
X
X
X
Assessment of Surgical Complications 
Xo
Laboratory Procedures/Assessments
Pregnancy Test- Urine or Serum -HCG or FSHp
Xi
X
PT/INR and aPTT
Xi
Xq,r
X
CBC with Differential
Xi
X
X
X
Xq
X
Chemistry
Xi
X
X
X
Xq
X
Urinalysis
Xi
T3, FT4, and TSH
Xi
X
X
Blood for HLA typing
Xs,t
HIV/Hepatitis Screen 
Xi
 
 
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Trial Period:
Screening
Randomizationa
Pretreatment 
Core Biopsy
MK-3475
SOC Tumor 
Resection
Post-Operative 
Follow-up
Week:
-2
-2
-1
1
4
7
10
15b
Scheduling window (days)
±14
±14
±6
±3
±3
±3
-7/+14
-5/+7
Protocol-Specific Specimen Collection
Tissue 
Collection
Fresh tumor tissue for shipping (TIL analysis, 
histoculture, tumor cell isolation and IMR 
expression analysis)
X
Tumor tissue for FFPE (IHC; DNA for 
mutational analysis, TCR utilization, promoter 
methylation analysis; RNA for gene expression 
and miRNA analysis)
Xu
Xv,w
Fresh tumor tissue for snap freezing (DNA 
isolation, metabolic profiling, laser capture 
microdissection)
X
Fresh non-malignant kidney tissue from 
resected tumor specimen for snap freezing 
(DNA isolation)
X
Fresh tumor tissue in RNAlater solution (RNA 
extraction, gene expression)
X
Fresh non-malignant kidney tissue in RNAlater 
solution (RNA extraction, gene expression)
X
Blood
PBMC Phenotypic Analysis
Xt
Xq
X
PBMC Isolation and Cryopreservation 
(Antigen-specific T cell response evaluation)
Xt
Xq
X
Plasma (miRNA, and exosome evaluation)
Xt
Xq
X
Serum (biomarkers)
Xt
Xq
X
Serum (PK/PD)
Xx
Xy
Xq
X
RNA isolation (gene expression, miRNA 
expression)
Xt
Xq
X
DNA isolation (TCR utilization)z
Xt
Xq
X
B cell isolation and transformation
Urine for exosome isolation and analysis
Xt
Xaa
X
 
 
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a.
Randomization, initially 2:1 neoadjuvant MK-3475:controls.  Randomization will occur only after written consent is obtained and will occur after all screening assessments 
have been completed. Randomization can occur at any time point after screening and prior to core biopsy.
b.
This follow up visit must occur no less than 30 days after the day of SOC tumor resection.
c.
Written consent must be obtained prior to performing any protocol-specific procedure.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within 28 days prior to screening.  
d.
If the subject signs the FBR consent, leftover samples may be kept for Future Biomedical Research.
e.
Prior medications – Record all medications taken within 28 days of screening visit.  Concomitant medications – Enter new medications started during the trial through 30 
days after the last dose of trial treatment.  Record all medications taken for SAEs as defined in Section 7.2
f.
Full PE at screening and neoadjuvant MK-3475 treatment visits; Direct PE for all other visits.
g.
These procedures may be performed up to 36 hours prior to the start of the SOC RCC tumor resection surgical procedure.
h.
Vital signs include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening visit only. Vital signs will be collected at screening, 
prior to the administration of each dose of trial treatment, at SOC tumor resection, and at post-operative follow-up.
i.
Laboratory tests for screening are to be performed within 28 days prior to the first dose of trial treatment. See section 7.1.3 for details regarding laboratory testing.
j.
If a diagnostic biopsy has already been performed per local SOC and sufficient tissue from that sample is available and will be submitted for all study-related analyses 
specified for the preoperative biopsy tissue, the study-specified pretreatment biopsy will not be required, and these assessments should be performed on the day that 
pretreatment blood and urine samples (see footnote w below) are collected.   
k.
Percutaneous core needle biopsy of RCC performed under image guidance. This procedure may take place any time between randomization to the MK-3475 treatment 
group and the start of treatment with MK-3475.  This study-prescribed pretreatment core needle biopsy is not required if a diagnostic biopsy has been performed per local 
SOC for diagnostic purposes, this biopsy will have been performed within 45 days prior to the first dose of MK-3475, and sufficient tissue is available from such a specimen 
for all study-related analyses specified for the pretreatment biopsy.
l.
During the surgical procedure and prior to cross-clamping of the renal artery, under direct vision a core needle biopsy of the RCC may be performed at the discretion of the 
operating surgeon and subject to local IRB approval.
m.
The number of doses of MK-3475 may be increased to three doses, based on the results of the first interim analysis, as described in Section 8.0 (See Table 9 for the flow 
chart should this occur).
n.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.
o.
At this visit, the occurrence of any surgical complications within 30 days of the operative procedure will specifically be assessed.
p.
For female subjects of reproductive potential, a urine pregnancy test should be performed within 72 hours of the first dose of trial treatment.  If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be 
repeated if required by local guidelines. For women thought to be post-menopausal, serum FSH will be measured to confirm post-menopausal status.
q.
Blood for study related analyses may be collected at any time prior to surgery on the day of surgery.  Ideally these blood samples will be collected via the iv cannula placed 
in preparation for surgery, but these samples may also be collected via venipuncture earlier on the day of surgery, at the discretion of the clinical care team.
r.
Blood for assessment of these coagulation parameters may be drawn up to 72 hours before the day of SOC tumor resection, at the discretion of the operative team.  If such a 
sample is collected, a sample for these tests will not need to be collected on the day of surgery.
s.
Low resolution HLA-A and B typing, to be performed by local HLA typing laboratory.
t.
Blood and urine samples should be collected on the day of the pretreatment core biopsy, However, if tissue from a biopsy previously performed per local SOC for diagnostic 
purposes will be submitted for all specified study-related analyses, these blood and urine samples should be collected as close to the time of this biopsy as possible and must 
be collected prior to the first dose of MK-3475.  
 
 
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u.
A minimum of 3 18-gauge core biopsy tumor samples will be collected.  The harvested cores will be placed in single cassette for formalin fixation and paraffin embedding.  
The entire specimen will then be cut onto slides.  After the diagnosis of RCC is confirmed by the local site pathologist, the remaining tissue sections will be used for study 
related analyses.
v.
A minimum of 3 18-gauge core biopsy tumor samples may be collected intraoperatively under direct vision by the surgeon prior to cross-clamping of the renal artery on the 
side of the RCC.  The harvested cores will be placed in single cassette for formalin fixation and paraffin embedding.  The FFPE block will then be shipped to Central 
Laboratory.
w.
Following tumor resection, additional tumor tissue will be collected for formalin fixation and paraffin embedding.  These FFPE blocks will then be shipped to Central 
Laboratory.
x.
Blood sample to be collected 30 minutes after the completion of MK-3475 dosing.
y.
Blood samples to be collected immediately prior to and 30 minutes after the completion of MK-3475 dosing.
z.
Any leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent.
aa.
Urine will be collected prior to surgery on the day of the surgical RCC resection.
 
 
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Trial Flow Chart – Post-Resection MK-3475 Treatment (All Subjects)
6.4
Treatment Period:
Post-Resection MK-3475 (3-Week Cycles)
End of Treatment or 
Discontinuation Visitc
Post-Treatment
30 Day Follow-up
90 Day Phone Call
Treatment Week:
1a
4
7
Q3Wb
52
30 days after last dose of
treatmentc
90 days after last dose of 
treatment
Scheduling Window (days):
+3
± 3
± 3
± 3
± 3
(±3)
(+7)
Clinical Procedures/Assessments
MK-3475 Administration
X
X
X
X
Adverse Events Monitoringd
X
X
X
X
X
X
Concomitant Medication Review
X
X
X
X
X
X
Laboratory Procedures/Assessments
Pregnancy Test-Urine -HCG
Xe
X
T3, FT4, and TSH 
X
X
Xf
X
Laboratory Studies
Laboratory studies should be performed at the discretion of the treating physician.
PBMC Isolation and Cryopreservation 
(Antigen-specific T cell response evaluation)
X
Efficacy Measurements
Tumor imaging 
Xg
Additional tumor imaging at the discretion of the treating physicianh
a.
Post-resection MK-3475 administration should begin within 45 days (±15 days) following surgical RCC resection, but only after the Post-operative Follow-Up visit in Table 6.1, 6.2, or 6.3, and 
the subject has fully recovered from the surgical procedure.
b.
MK-3475 200 mg IV Q3W can be continued for up to 17 treatment cycles (1 year of treatment).
c.
If the Discontinuation visit occurs approximately 30 days from last dose of treatment, the same procedures do not need to be repeated for the 30 Day Follow-up visit.
d.
Record all AEs occurring within 30 days after the last dose of MK-3475. Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days after the last dose of MK-
3475 or the start of new anti-cancer treatment, whichever comes first.   
e.
For female subjects of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to the first dose of trial treatment.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines. 
f.
Thyroid function testing (T3, FT4, and TSH) should be repeated every 6 weeks/every other cycle during post-resection treatment with MK-3475.
g.
Optional tumor imaging should ideally be performed prior to the start of post-resection MK-3475.  For patients with known metastatic disease at the time of RCC resection, this imaging should be 
performed at least 30 days following surgery but before the first dose of post-resection MK-3475.
h.
The treating physician should obtain additional SOC tumor imaging studies as clinically indicated.  For subjects with known metastatic disease at the time of RCC resection, local assessment of 
response should be assessed by the investigator using either RECIST v1.1 or irRECIST.  
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  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 subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial (See Sections 5.1.2 and 5.1.3).
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. See Section 5.5 for a description of allowed and prohibited medications.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
 
 
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7.1.1.7
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
7.1.1.8
Trial Compliance (Medication)
Interruptions from the protocol specified neoadjuvant MK-3475 treatment
require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.7).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment. 
All AEs of unknown etiology associated with MK-3475 exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 5.6.1.1 and the separate guidance document in the
Administrative Binder regarding the identification, evaluation and management of AEs of a 
potential immunological etiology.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
7.1.2.2
Physical Exam
7.1.2.2.1
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during 
screening, at Day 1 of each cycle, as specified in Section 6.0 – Trial Flow Charts.  Clinically 
significant abnormal findings should be recorded as medical history. After the ICF is signed, 
new clinically significant abnormal physical examination findings should be recorded as 
AEs.
 
 
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7.1.2.2.2
Directed Physical Exam
The investigator or qualified designee will perform a directed physical exam as per Section 
6.0 – Trial Flow Charts and as clinically indicated.  New clinically significant abnormal 
findings should be recorded as AEs. 
7.1.2.3
Vital Signs
The investigator or qualified designee will take vital signs as specified in the Trial Flow 
Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory rate, and blood 
pressure.  Weight will be recorded as specified in the Trial Flow Chart.  Height will be 
measured at screening only.
7.1.2.4
Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures at Screening.  
Clinically significant abnormal findings should be recorded as medical history.  Additional 
time points for standard 12-lead ECGs will be performed as per Section 6.0 – Trial Flow 
Charts.  Clinically significant abnormal findings seen on the follow-up ECGs should be 
recorded as adverse events.
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 12.7) at 
screening.   
7.1.2.6
Tumor Imaging and Assessment of Disease
The report from the clinical imaging study used to establish the diagnosis of RCC will be 
collected and reviewed at Screening.  The images from these studies may be requested and 
collected and stored for possible further analysis.  For any subsequent clinical imaging 
studies performed as part of SOC therapy through the study period, reports will be collected 
and reviewed, and images may be requested and stored for possible further analysis.  No 
study-specified tumor imaging studies will be performed.   
7.1.2.7
Assessment of Disease
RECIST 1.1 will be applied by the site as the primary measure for assessment of tumor 
response in those subjects with metastatic RCC at the time of surgical resection who then 
receive post-resection MK-3475 in this trial.   
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in Section 12.4.
 
 
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7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 10.
Table 10
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum/urine β-human 
chorionic gonadotropin 
(β-hCG)
Hemoglobin
Alkaline phosphatase
Glucose
Hepatitis
Platelet count
Alanine aminotransferase 
(ALT)
Protein
HIV
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
HLA-typing
Bicarbonate
Microscopic exam, 
if abnormal results 
are noted
T3, FT4, TSH
Calcium
PT/INR, aPTT
Chloride
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
Blood Urea Nitrogen/ 
Blood Urea
 
 
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7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
The decision as to which plasma and/or urine samples collected, if any, will be assayed for 
evaluation of PK/PD
will be collaboratively determined by the Departments of 
Pharmacokinetics, Pharmacodynamics & Drug Metabolism and the appropriate department 
within Early-Stage Development.  If indicated, these samples may also be assayed and/or 
pooled for assay in an exploratory manner for metabolites and/or additional PD markers.
7.1.3.2.1 Protocol Specific Specimen Collection
Tumor Tissue Collection
7.1.3.2.1.1
Pretreatment image-guided percutaneous core needle tumor biopsy (patient randomized to 
receive neoadjuvant MK-3475) for FFPE (RCC diagnosis confirmation, TIL analysis by 
IHC, DNA for TIL analysis, RNA for gene profiling).  A study-prescribed pretreatment core 
needle biopsy is not required if a diagnostic biopsy has already been performed per local 
SOC, this biopsy has been performed within 45 days prior to the first dose of MK-3475, and 
sufficient tissue is available from such a biopsy for the study-related analyses specified for 
the pretreatment biopsy.
Intraoperative core needle tumor biopsy under direct vision (all patients) for FFPE (TIL 
analysis by IHC, DNA for TIL analysis, RNA for gene profiling), prior to renal artery cross-
clamping, at the discretion of the operating surgeon, and subject to approval by the site IRB
Fresh resected tumor tissue (TIL analysis, histoculture, tumor cell isolation and IMR 
expression analysis): 10 cm3 consisting of non-necrotic tumor tissue in approximately 1 cm3
pieces, shipped fresh to Merck Research Laboratories.  These tumor tissue pieces do not need 
to be contiguous within the tumor.
 
 
 
 
Resected non-malignant kidney tissue for DNA isolation (mutational analysis-negative 
control): one piece of tissue, approximately 0.5 cm x 0.5 cm x 0.5 cm in size, snap frozen; 
and one piece of tissue, approximately 0.5 cm x 0.5 cm x 0.5 cm in size, in RNAlater 
solution  
Resected tumor tissue for storage in RNAlater solution (RNA for gene expression analysis, 
miRNA analysis): one non-necrotic piece of tumor tissue, approximately 0.5 cm x 0.5 cm x 
0.5 cm in size
 
 
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Resected non-malignant kidney tissue for DNA isolation (mutational analysis-negative 
control): one piece of tissue, approximately 0.5 cm x 0.5 cm x 0.5 cm in size, snap frozen
Blood Collection
7.1.3.2.1.2
Whole blood (PBMC phenotypic analysis)
Whole blood for PBMC isolation and cryopreservation (Antigen-specific T cell response 
evaluation)
Plasma (miRNA, exosome evaluation, other biomarkers)
Serum (protein evaluation, PK/PD measurements, other biomarkers)
Blood for RNA isolation (gene expression, miRNA expression)
Blood for DNA isolation (TCR utilization, promoter methylation)
Blood for B cell isolation and transformation
Urine Collection
7.1.3.2.1.3
Urine for exosome isolation and analysis
7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Any leftover samples collected as part of the main study, including leftover DNA
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
The investigator or trial coordinator must notify the Sponsor when a subject has been 
discontinued/withdrawn from the trial.  If a subject discontinues for any reason at any time 
during the course of the trial, at the time of discontinuation or as soon as possible after 
discontinuation depending upon the phase the subject is in, the subject may be asked to return 
to the clinic (or be contacted) for a discontinuation visit as outlined for Post-operative Follow 
Up visit or Discontinuation visit/30 Day Follow-up in Section 6.0 – Trial Flow Charts to 
have the applicable procedures conducted.  The investigator should perform a follow-up 
phone call 90 days after the last dose of trial drug to determine if any SAEs/ECIs have 
occurred since the discontinuation visit. Any AEs which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 7.2 - Assessing and Recording Adverse Events.
 
 
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7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Domiciling
Subjects will report to the clinical research unit (CRU) on the scheduled day of trial drug 
administration and remain in the unit until 2 hours post-dose on that day in each treatment 
period.  At the discretion of the investigator, subjects may be requested to remain in the CRU 
longer.
7.1.4.4
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
ECG equipment
Equipment to measure vital signs
Infusion pumps
 
 
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Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
Up to 2 weeks prior to randomization, potential subjects will be evaluated to determine that 
they fulfill the entry requirements as set forth in Section 5.1.  Screening procedures may be 
repeated after consultation with the Sponsor.  Any rescreening will be based on the medical 
judgment of the investigator, depending on patient status and risk-benefit assessment of 
delayed surgery versus administration of neoadjuvant MK-3475 therapy, in consultation with 
the Sponsor.
Written consent must be obtained prior to performing any protocol specific procedure.  
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within 28 days prior to 
screening, except for the following:
• For women of reproductive potential, a repeat pregnancy test utilizing urine will 
be performed within 72 hours prior to first dose of trial treatment, if randomized 
to receive neoadjuvant MK-3475.
• For women of reproductive potential, a repeat pregnancy test utilizing urine will 
be performed within 72 hours prior to first dose of post-resection MK-3475.
7.1.5.2
Image-guided Percutaneous Tumor Core Needle Biopsy
Patients randomized to receive neoadjuvant MK-3475 will undergo image-guided 
percutaneous core needle biopsy of their RCC tumor prior to the first dose of MK-3475.  The 
selection of the image modality for guiding the biopsy will be at the discretion of the study 
site investigator, based on local SOC, and will be performed in an outpatient setting.  A 
minimum of 3 18-gauge biopsy cores of tissue will be collected.  A study-prescribed 
pretreatment core needle biopsy is not required if a diagnostic biopsy has already been 
performed per local SOC, this biopsy will have been performed within 45 days prior to the 
first dose of MK-3475, and sufficient tissue is available from such a specimen for the study-
related analyses specified for the pretreatment biopsy.
All of the collected cores from the study-prescribed biopsy will be paraffin embedded in a 
single cassette.  The site pathologist and/or his/her designee will then section the entire tissue 
block (See Study Operations Manual).  After the local pathologist confirms the diagnosis of 
RCC, all of the cut tissue sections not used to confirm the diagnosis of RCC will be shipped 
to the Sponsor’s laboratory for further study-related analyses.  
If tissue from a diagnostic biopsy performed per local SOC is to be submitted, slides cut from 
the single FFPE block containing a minimum of three 18-gauge biopsy cores (or an 
 
 
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equivalent volume of tumor tissue) will be shipped to the Sponsor’s laboratory for further 
study-related analyses. Ideally, the entire FFPE block is sectioned and all slides submitted.
7.1.5.3
Neoadjuvant MK-3475 Treatment
Approximately one week following percutaneous tumor biopsy, patients randomized to 
receive neoadjuvant MK-3475 will begin receiving this agent.  MK-3475 will be given every 
3 weeks, for a total of 2 doses (which may be increased to 3 doses, as discussed in Section 
8.0).  Patients randomized to the control group will not receive any study drug or placebo and 
will bypass this neoadjuvant treatment period.
7.1.5.4
SOC Surgical RCC Resection
All patients enrolled in this trial will undergo SOC surgical excision of their RCC.  For those 
patients randomized to receive neoadjuvant MK-3475, surgery should be performed 
approximately 2-3 weeks following the final dose of MK-3475.  For patients randomized to 
the control group, surgery should be performed within 6 weeks of randomization.  The 
decision to perform partial or complete nephrectomy and the surgical approach (open vs 
laparoscopic) will be left to the discretion of the operating surgeon.
In the operating room during the surgical procedure, an intraoperative core needle biopsy of 
the tumor may be performed under direct vision by the operating surgeon prior to cross-
clamping of the renal artery. A minimum of three 18-gauge core biopsy tumor samples will 
be collected, fixed in formalin, and then placed in a single cassette for paraffin embedding.  
As discussed in Section 4.2.1.4 (subsection “Rationale for Intraoperative Core Needle 
Biopsies in this Trial”), the performance of this intraoperative RCC biopsy, which is critical 
for minimizing warm ischemia-induced potentially confounding changes in RCC gene 
expression, will be at the discretion of the operating surgeon and subject to approval by the 
study site IRB.
In the operating room, upon removal of the tumor from the patient, the surgeon or his/her 
designee will harvest and appropriately process the fresh tumor on the “back table.”  If the 
operating surgeon has not collected the intraoperative core needle tumor biopsy samples prior 
to renal artery crossclamping, core needle samples should be collected from the excised RCC 
tumor specimen on the back table in the operating room after the specimen has been removed 
from the patient and prior to further tumor specimen processing.  Details regarding the tumor 
sample processing are included in the Study Operations Manual.  
7.1.5.5
Follow-up After Surgical RCC Resection
All subjects will return to clinic approximately 5 weeks (30-42 days) following SOC surgical 
RCC resection for a routine postoperative visit, which will include assessment for AE
occurrences and collection of blood and urine samples for study-related analyses. Assessment 
for surgical complications within the 30 day postoperative period will also be performed at 
this visit for all subjects. 
 
 
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7.1.5.6
Post-Resection MK-3475 Treatment
Following recovery from surgery, all subjects may receive post-resection MK-3475, 200 mg 
IV Q3W for up to 1 year.  
Subjects with known metastatic RCC at the time of surgical resection ideally should undergo 
SOC radiologic tumor imaging prior to the start of post-resection MK-3475 administration.  
After the start of post-resection MK-3475, all subjects should be followed by SOC radiologic 
imaging to assess response to treatment at intervals to be selected by their treating physician. 
This physician should utilize RECIST 1.1 and/or irRECIST to assess response to MK-3475
and for making treatment decisions.  
For all subjects, AEs should be monitored throughout the post-resection phase and graded in 
severity according to the guidelines outlined in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0.
Treatment with post-resection MK-3475 may continue until documented disease progression
or recurrence, unacceptable AE(s), intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw the subject, consent withdrawn by subject, 
start of new anti-cancer treatment, subject lost to follow up, subject pregnancy, 
noncompliance with trial treatment or procedure requirements, completion of 17 cycles of 
post-resection MK-3475 (approximately 1 year of treatment), or discontinuation for 
administrative reasons.
7.1.5.7
Follow-up After Post-resection MK-3475 Treatment
For subjects who complete or discontinue early from post-resection MK-3475 treatment, 
safety follow up visit should be conducted approximately 30 days (± 3 days) after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. SAEs and ECIs that occur within 90 days of the end of treatment or before 
initiation of a new anti-cancer treatment should also be followed and recorded. Pregnancy
status should be queried approximately 120 days after the end of treatment, and survival 
status 1 and 2 years following surgical tumor resection.
7.1.5.8
Critical Procedures Based on Trial Objectives: Timing of Procedure 
For this trial, the pretreatment percutaneous tumor biopsy in patients randomized to receive 
neoadjuvant MK-3475 is the critical procedure. This procedure must be performed at a 
minimum of one day before the first dose of MK-3475.
All other procedures should be completed as close to the prescribed/scheduled time as 
possible. Trial procedures can be performed prior or after the prescribed/scheduled time.  
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.  
 
 
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7.1.5.9
Trial Design/Dosing/Procedures Modifications Permitted within Protocol 
Parameters
This is a Phase I assessment of MK-3475 in humans, and the PK, PD and safety profiles of 
the compound are still being elucidated.  This protocol is written with some flexibility to 
accommodate the inherent dynamic nature of Phase I clinical trials.  Modifications to the 
dose, dosing regimen and/or clinical or laboratory procedures currently outlined below may
be required to achieve the scientific goals of the trial objectives and/or to ensure appropriate 
safety monitoring of the trial subjects.  As such, some alterations from the currently outlined 
dose and/or dosing regimen may be permitted based on newly available data; and can include
the following:

Repeat of or decrease in the dose of the trial drug administered in any given 
period/panel

Decrease in the duration of trial drug administration (e.g., number of days) 

Adjustment of the dosing interval (e.g., divided doses [BID to QD, QD to BID, TID 
or vice versa])
The PK/PD sampling scheme currently outlined in the protocol may be modified during the 
trial based on newly available PK or PD data (e.g., to obtain data closer to the time of peak 
plasma concentrations).  If indicated, these collected samples may also be assayed in an 
exploratory manner for metabolites and/or additional PD markers.
Up to an additional 50 mL sample of blood may be drawn for safety, PK, and/or PD analyses.  
The total blood volume withdrawn from any single subject will not exceed the maximum 
allowable volume during his/her participation in the entire trial (Section 12.4). 
The timing of procedures for assessment of safety procedures (e.g., vital signs, ECG, safety 
laboratory tests, etc.) currently outlined in the protocol may be modified during the trial 
based on newly available safety, tolerability, PK or PD data (e.g., to obtain data closer to the 
time of peak plasma concentrations).  Additional laboratory safety tests may be added to 
blood samples previously drawn to obtain additional safety information (e.g., adding 
creatinine kinase to serum chemistry panel that was already drawn). These changes will not 
increase the number of trial procedures for a given subject during his/her participation in the 
entire trial. 
It is understood that the current trial may employ some or none of the alterations described 
above.  Any alteration made to this protocol to meet the trial objectives must be detailed by 
the Sponsor in a letter to the Trial File and forwarded to the investigator for retention.  The 
letter may be forwarded to the IRB/ERC at the discretion of the investigator.
 
 
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Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during the course of the use of the Sponsor's product in clinical 
trials or within the follow-up period specified by the protocol, or prescribed in clinical 
practice, from overdose (whether accidental or intentional), from abuse and from withdrawal.
For randomized subjects only, AEs that occur from the time the consent is signed through the 
time of randomization will only be reported as AEs if they are the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. All AEs will be recorded from the time of 
randomization through 30 days following cessation of treatment (for MK-3475 treated 
patients), or 14 days following the last blood draw (for non-treated controls), and at each 
examination, on the AE case report forms/worksheets. The reporting timeframe for adverse 
events meeting any serious criteria is described in section 7.2.3.1. The investigator will make 
every attempt to follow all subjects with non-serious adverse events for outcome. 
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5x the indicated dose).  No specific information is available on the treatment 
of overdose of pembrolizumab.  In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial or within 120 days of 
completing the trial (Last dose of study drug for MK-3475 treated patients, or last blood draw 
for non-treated controls) or 30 days following cessation of treatment if the subject initiates 
new anticancer therapy, whichever is earlier.  All subjects who become pregnant 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.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper.  Sponsor Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
 
 
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Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose;
●
Is an other important medical event 
Refer to Table 11 for additional details regarding each of the above criteria.
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause that occurs to any subject from the time the consent is signed through 90 days 
following cessation of treatment (for MK-3475 treated patients), or 14 days following the last 
blood draw (for non-treated controls), or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, whether or not related to the 
Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper.  Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
Additionally, any serious adverse event, 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 in the previous paragraph also 
must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor either by electronic media or paper.  Sponsor Contact 
information can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
7.2.3.3
Surgical complications 
All subjects enrolled in this clinical trial will undergo SOC surgical RCC tumor resection.  
Control subjects will proceed to surgery without study-related treatment, while patients 
randomized to receive neoadjuvant MK-3475 will proceed to surgery 2-3 weeks following 
the final MK-3475 dose.  As such, any surgical complications in the intra- and postoperative 
period (30 days from the time of surgery) will be recorded, and will include but will not be 
limited to the following:
1. the need for and the volume of blood transfusions in the perioperative period
2. hospital readmission following discharge
3. thromboembolic events
4. cardiovascular events
5. pulmonary complications
6. gastrointestinal complications
7. postoperative infection
8. incision-related complications
 
 
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Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
 
 
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Table 11
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid 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 or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
test drug 
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event 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 drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
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
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Primary Safety
Incidence of adverse experiences will be descriptively summarized for all adverse 
experiences and Grade 3 or 4 adverse experiences separately. Summary statistics and plots 
will be generated for the change from baseline values in the vital signs, ECG 
parameters,
and
selected
laboratory
safety
parameters
for
subjects,
as
deemed
clinically appropriate. Depending on the safety parameter, the difference from baseline
will either be computed on the original scale (raw change from baseline) or on the log
scale and back- transformed for reporting (percent change from baseline). 
Summary
statistics for the raw laboratory safety tests, ECGs, and/or vital signs may also be
computed, as deemed clinically appropriate.
Primary PD Hypothesis
To assess the primary PD hypothesis, the posterior probability that the true response rate is at 
least 30% will be calculated based on a beta-binomial Bayesian model.  A beta prior with 
parameters =0.1 and =0.1 will be assumed.  The primary PD hypothesis will be met with 
at least 80% posterior probability at interim analysis 1, at least 70% posterior probability at 
interim analysis 2, or at least 60% posterior probability at interim analysis 3.
Interim Analysis:  There will be up to 3 interim analyses done for this study.  Details of the 
interim analysis strategy are provided in Section 8.2.6.
Power
Safety
If no AE of a given type is observed in any subject receiving neoadjuvant MK-3475, then the 
true incidence of the adverse experience at that dose is at most 13%, 10%, 9%, 6%, or 5% 
with 80% confidence when the sample size among those receiving neoadjuvant MK-3475 is 
12, 15, 18, 24 or 33, respectively.
 
 
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Pharmacodynamics
If the true immune infiltration response rate is 40%, there is ~85% power to meet the primary 
hypothesis at either the second or third interim analysis, or at the end of the study.  If the true 
response rate is 45%, there is ~85% to meet the primary hypothesis at either the second or 
third interim analysis.  To have high power (>80%) to meet the primary hypothesis after the 
second interim analysis, the true response rate must be greater than or equal to 55%.
Statistical Analysis Plan
8.2
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Discovery Medicine Department of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Results Memo for this study.
Hypotheses
8.2.1
Primary (Safety)
Neoadjuvant MK-3475 treatment will be well tolerated in patients undergoing subsequent 
surgical RCC tumor resection.  
Primary (PD)
Neoadjuvant MK-3475 therapy will stimulate a 2-fold or greater increase in intratumoral 
lymphocytic infiltration in at least 30% of patients with RCC.
Secondary (PD)
1.
 
 
 
 
 
 
 
 
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Tertiary (PD)
Analysis Endpoints
8.2.2
Primary Safety
The primary safety endpoints in this study include all types of adverse experiences, in 
addition to laboratory safety assessments, ECGs, and vital signs.
Primary PD
The primary PD endpoint in this study is the intratumoral lymphocytic infiltration in patients 
with RCC.  Patients with at least a 2-fold increase in intratumoral lymphocytes will be 
considered immune cell infiltration responders.
Secondary PD
 
 
. 
 
 
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Tertiary PD
 
 
 
 
Exploratory PD
There are several exploratory endpoints in this study that include the following:
Approaches to Analyses
8.2.3
The following populations are defined for the analysis and reporting of data. All subjects 
will be reported, and their data analyzed, according to the treatment(s) they actually received.
All Subjects as Treated (AST) - All subjects who received at least one dose of the 
investigational drug. This population will be used for assessments of safety and tolerability.
Per-Protocol (PP) – The set of data generated by the subset of subjects who comply with the 
protocol sufficiently to ensure that these data will be likely to exhibit the effects of treatment, 
according to the underlying scientific model. Compliance covers such considerations as 
exposure to
treatment,
availability of measurements and absence of major protocol 
violations. Major protocol violators will be identified to the extent possible by individuals
responsible for data collection/compliance, and its analysis and interpretation. 
Any
subjects or data values excluded from analysis will be identified, along with their reason
for exclusion, in the Results Memo for this study. At the end of the study, all subjects
who are compliant with the study procedure as aforementioned and have available data
 
 
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from at least one treatment will be included in the primary analysis dataset. This population
will be used for the all PD analyses.
Statistical Methods
8.2.4
Primary Safety
Incidence of adverse experiences will be descriptively summarized for all adverse 
experiences and Grade 3 or 4 adverse experiences separately. Summary statistics and plots 
will be generated for the change from baseline values in the vital signs, ECG parameters,
and
selected
laboratory
safety
parameters
for
subjects,
as
deemed
clinically 
appropriate. Depending on the safety parameter, the difference from baseline will either
be computed on the original scale (raw change from baseline) or on the log scale and
back- transformed for reporting (percent change from baseline). Summary statistics for
the raw laboratory safety tests, ECGs, and/or vital signs may also be computed, as deemed
clinically appropriate.
The incidence of intra- and postoperative complications will also be determined. Intra- and 
postoperative complications are not uncommon in patients undergoing surgical RCC 
resection, even in those proceeding directly to surgery without any neoadjuvant therapy.  In 
a report of 58 such patients, the transfusion rate was 62.1% (median of 3.5 ± 6.6 units of 
blood products), and the complication rate was 27.6%, consisting of the need for surgical 
reexploration (5.2%), hospital readmission (8.6%), thromboembolic complications (1.7%), 
cardiovascular complications (3.4%), pulmonary complications (6.9%), gastrointestinal 
complications (10.3%), infectious complications (3.4%) and incision-related complications 
(6.9%) [79].  The incidence of surgical complications for patients receiving neoadjuvant 
MK-3475 will be summarized and contrasted with these published complication rates, as 
the total number subjects in this trial as well as the limited number of untreated controls will 
be of insufficient power to make accurate within study comparisons.  
Primary PD
To assess the primary PD hypothesis, the posterior probability that the true response rate is at 
least 30% will be calculated based on a beta-binomial Bayesian model.  A beta prior with 
parameters =0.1 and =0.1 will be assumed.  The primary PD hypothesis will be met with 
at least 80% posterior probability at interim analysis 1, at least 70% posterior probability at 
interim analysis 2, or at least 60% posterior probability at interim analysis 3.  Additional 
sensitivity analyses may be performed where the definition of a responder is varied from 2-
fold or greater increase in intratumoral lymphocytic infiltration to increases less than 2-fold.
 
 
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Secondary PD
 
 
 
A two-sample t-test will be used to assess the difference in the expression of pretreatment 
tumor PD-1 ligands between immune cell infiltration responders and non-responders among 
patients receiving neoadjuvant MK-3475.  If normality is not deemed tenable, data 
transformations will be considered, or a Wilcoxon rank sum test will be used.  If enrollment 
of controls continues after the first interim analysis, similar analyses may also be done to 
compare patients receiving MK-3475 relative to controls.
Tertiary PD
 
  
 
 
 
 
 
 
 
 
 will be compared using a Bayesian model fit that has a fixed effect for 
method, and a random effect for patient to account for the within-patient correlation of 
measurements obtained from the same patient, using flat priors and an assumption of 
normality.  If normality is not tenable, other distributions for the number of TILs may be 
considered.  The posterior probability that the methylation approaches are within +/-10% of 
the ICH approach will be quantified.  A posterior probability of 50% will satisfy this tertiary 
hypothesis.
 
 
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Exploratory PD Objectives
Many of the exploratory PD objectives will be addressed using descriptive statistics, 
including:

Differences in the IMR expression profiles between RCC tumor antigen-specific CD8+ T 
cells and unselected TILs in patients that are HLA-A2+

Stimulation of antigen-specific anti-tumor immune responses in patients with RCC
Other exploratory objectives will be assessed using simple measures of association of 
potential biomarkers with immune infiltration (i.e., Pearson’s or Spearman’s correlation):

Evaluate baseline as well as changes in serum/plasma levels of proteins, miRNAs, 
exosomes, nucleic acids, circulating antibodies, and other biomarkers after neoadjuvant 
MK-3475 therapy as potential biomarkers of the immune response to therapy

Evaluate differences in tumor tissue miRNA expression levels in response to treatment 
with MK-3475

Evaluate urine exosomes as a potential biomarker of immunologic response to 
neoadjuvant MK-3475 treatment

Assess changes in RCC tumor tryptophan and arginine metabolism in response to MK-
3475 treatment
The above objectives may also be assessed using a two-sample t-test to look at differences 
between immune infiltrate responders and non-responders.  If normality is not deemed 
tenable, data transformations will be considered, or a Wilcoxon rank sum test may be used.
Two-sample t-tests will also be used to identify a possible correlation between clinical 
response and tumor immune cell infiltration by testing if the magnitude of immune cell 
infiltration differs between patients who have evidence of a clinical response versus those 
who do not among patients with metastatic disease.  If normality is not deemed tenable, data 
transformations will be considered, or a Wilcoxon rank sum test may be used.
A paired t-test will be used to assess whether IMR ligand expression changes after treatment 
with MK-3475 in pre-treatment tumor biopsy tissue and resected tumor.  If normality is not 
deemed tenable, data transformations will be considered, or a Wilcoxon signed rank test will 
be used. 
Multiplicity
8.2.5
Since there is only one primary PD hypothesis, no multiplicity adjustment will be made when 
testing the primary hypothesis.  The secondary and tertiary PD hypotheses will only be tested 
if the primary PD hypothesis is met.  There are six separate secondary hypotheses and more 
than 8 tertiary hypotheses.  Benjamini and Hochberg’s false discovery rate multiplicity 
 
 
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adjustment will be applied at a rate of 10% when testing the secondary and tertiary 
hypotheses. 
Interim Analysis
8.2.6
There will be up to 3 interim analyses done for this study.  The first interim analysis will be 
performed after the initial 9 RCC patients, randomized 2:1 to either receive neoadjuvant MK-
3475 vs. control (proceed to SOC RCC resection), have all undergone tumor resection and 
the assessment of tumor immune cell infiltrates has been completed.  At the first interim 
analysis, the number of patients with an immune cell infiltration “response”, defined as a 2-
fold or greater increase in the immune cell infiltrate in RCC tumor specimens compared with 
that in the pretreatment tumor biopsy specimens from the same patient, will be examined in
the 6 patients receiving neoadjuvant MK-3475.  If 4 or more of the first 6 patients receiving 
neoadjuvant MK-3475 respond, randomization will continue 2:1 to receive either 
neoadjuvant MK-3475 or control (proceed to SOC RCC resection), respectively, for the 
remainder of the study.  If less than 4 of the first 6 patients receiving neoadjuvant MK-3475 
respond, all subsequently enrolled patients may receive neoadjuvant MK-3475 with no 
further patients being randomized to the control group.  Further, if there are 0 or 1 responders
in the first 6 patients receiving neoadjuvant MK-3475, then the number of doses of MK-3475 
that will be administered in patients subsequently enrolled may be increased from two to 
three (with the 200 mg dose and the Q3W dosing interval remaining the same).   The 
probabilities of various outcomes after the first interim analysis are provided in Table 12
below, assuming a true immune cell infiltration response rate of 5%, 30%, or 70%.
Table 12
First Interim Analysis Outcome Scenarios
Various outcomes after the first interim analysis assuming a true immune cell infiltration 
response rate of 5%, 30%, or 70%
Outcome of first
Probability if true response rate = 
interim analysis
Action
5%
30%
70%
0-1 responders
Enroll all subsequent 
patient to MK-3475, 
increase from 2 to 3 doses
97%
42%
1%
2-3 responders
Enroll all subsequent 
patient to MK-3475, 
continue with 2 doses
3%
51%
24%
4-6 responders
Continue 2:1 
randomization 
(MK-3475:Control)
< 1%
7%
74%
The second interim analysis will occur after a total of 18 RCC patients have undergone tumor 
resection, with either 15 receiving neoadjuvant MK-3475 with 3 controls or 12 receiving 
neoadjuvant MK-3475 with 6 controls. The primary PD hypothesis will be assessed, and 
success will be declared and enrollment may stop if there is at least 80% posterior probability 
that the true response rate is at least 30%.  If success cannot be declared after the initial 18 
 
 
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patients, an additional 9 patients may be enrolled and randomized as determined by the 
results of the first interim analysis, and a third interim analysis will occur after 27 RCC 
patients have undergone tumor resection, with either 24 receiving neoadjuvant MK-3475 
with 3 controls or 18 receiving neoadjuvant MK-3475 with 9 controls.  The primary 
hypothesis will be assessed, and success will be declared and enrollment may stop if there is
at least 70% posterior probability that the true response rate is at least 30%.  If success cannot 
be declared after the initial 27 patients, an additional 9 patients may be enrolled and 
randomized as determined by the results of the first interim analysis.  The final analysis will 
be performed after 36 RCC patients have undergone tumor resection.  At the final analysis, 
success will be declared if there is at least 60% posterior probability that the true response 
rate is at least 30%.
After each interim analysis, decisions related to enrolling additional patients may deviate 
from the rules defined above based on the accumulating data, at the discretion of the 
Sponsor.
In addition, decisions related to stopping the study for futility may also be considered at each 
interim analysis.  At the second interim analysis, if there are only 0 or 1 responders the study 
may be stopped for futility.  The probability of this happening when the true response rate is 
30% is 8.5% (3.5%) with a sample size of 12 (15).  At the third interim analysis, if there are 2 
or less responders the study may be stopped for futility.  The probability of this happening 
when the true response rate is 30% is 6.0% (1.2%) with a sample size of 18 (24).
Power
8.2.7
Primary Safety:  If a serious (Grade 3 or Grade 4) adverse experience occurs at a rate of 1%, 
5% or 10% then the chance of observing such an adverse event among the various possible 
sample sizes are provided in Table 13.
Table 13
Probability of Observing Serious Grade 3 or Grade 4 Adverse Experience for 
Various AE Rates
Serious AE
Probability (%) of observing serious AE among MK-3475 treated patients
Rate
nMK = 12
nMK = 15
nMK = 18
nMK = 24
nMK = 33
1%
11
14
17
21
28
5%
46
54
60
71
82
10%
72
79
85
92
97
nMK = final number of patients receiving neoadjuvant MK-3475
If no AE of a given type is observed in any subject receiving neoadjuvant MK-3475, then the 
true incidence of the adverse experience at that dose is at most 13%, 10%, 9%, 6%, or 5%
with 80% confidence when the sample size among those receiving neoadjuvant MK-3475 is 
12, 15, 18, 24 or 33, respectively.
 
 
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Primary PD:  
Table 14 shows the cumulative probabilities of stopping and declaring success on the 
primary PD hypothesis after each interim analysis assuming various true immune cell 
infiltration response rates and implementing the interim analysis strategy as described in 
Section 8.2.6.  If the true immune infiltration response rate is 40%, there is ~85% power to 
meet the primary hypothesis at either the second or third interim analysis, or at the end of the 
study.  If the true response rate is 45%, there is ~85% to meet the primary hypothesis at 
either the second or third interim analysis.  To have high power (>80%) to meet the primary
hypothesis after the second interim analysis, the true response rate must be greater than or 
equal to 55%.
Table 14
Cumulative Probabilities of Stopping and Declaring Success After Each 
Interim Analysis Assuming Various True Immune Cell Infiltration Response Rates
True immune 
cell infiltration 
Probability (%) of stopping and declaring success 
(obtaining stated level of posterior probability that the true immune 
cell infiltration response rate of MK-3475 at least 30%)
response rate
After IA 2
After IA 3
At end of study
5%
<0.1
<0.1
<0.1
10%
<0.1
<0.1
0.1
15%
0.3
0.7
1.0
20%
1.7
4.3
6.6
25%
6.3
14.4
22.0
30%
13.0
29.4
44.0
35%
25.5
50.1
67.5
40%
39.2
69.3
84.8
45%
53.6
83.7
94.6
50%
68.7
92.8
98.5
55%
82.0
97.5
99.8
60%
90.1
99.2
>99.9
65%
95.3
99.8
>99.9
70%
98.3
>99.9
>99.9
IA = interim analysis
If the second interim analysis sample size is 12 (15) receiving neoadjuvant MK-3475, at least 
80% posterior probability that the true immune cell infiltration response rate is 30% will be 
obtained if at least 6 (7) patients respond.  If the third interim analysis sample size is 18 (24) 
receiving neoadjuvant MK-3475, at least 70% posterior probability that the true immune cell 
infiltration response rate is 30% will be obtained if at least 7 (9) patients respond.  If the final 
analysis sample size is 24 (33) receiving neoadjuvant MK-3475, at least 60% posterior 
probability that the true immune cell infiltration response rate is 30% will be obtained if at 
least 6 (11) patients respond.  Therefore, the analyses supporting the secondary and tertiary 
hypotheses will have as few as 6 responders.
 
 
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9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 15.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 15
Product Description
Product Name & Potency
Dosage Form
MK-3475
Lyophilized 50mg/vial
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
 
 
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Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
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 institutional review board, ethics review committee (IRB/ERC) 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 trial 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.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifyin g 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
 
 
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3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  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.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
 
 
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Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial 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 as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
 
 
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period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
 
 
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disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
 
 
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When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases,
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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29. Choueiri TK.  Clinical Treatment Decisions for Advanced Renal Cell Cancer.  J Natl 
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interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, 
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60. Heng D, Xie W, Regan M, Warren M, Golshayan A, Sahi C, et al. Prognostic Factors for 
overall survival in patients with metastatic renal cell carcinoma treated with vascular 
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62. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy Followed by Interferon 
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England Journal of Medicine 2001;345(23):1655-9.
63. Mickisch GHJ, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy 
plus interferon-alfa-based immunotherapy compared with interferon alfa alone in 
metastatic renal-cell carcinoma: a randomised trial. The Lancet 2001;358(9286):966-70.
64. Gedye C, Kurban G, Gallie BL, et al.  Surgical ischemia and detection of clear cell renal 
cell carcinoma biomarkers. Journal of Clinical Oncology, 2014 ASCO Annual Meeting 
Abstracts 2014;32(15_suppl (May 20 Supplement)): e15571.
 
 
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65. Giorgadze T, Qureshi F, Aulicino M, Jacques SM. Retroperitoneal recurrence of a stage 1 
renal cell carcinoma four years following core biopsy and fine needle aspiration: Possible 
needle tract seeding. Diagnostic Cytopathology 2012;41(5):470-2.
66. Mullins JK, Rodriquez R. Renal cell carcinoma seeding of a percutaneous biopsy tract. 
Can Urol Assoc J 2013;7(3-4):E176-E9.
67. Song J, Kim E, Mobley J, et al. Port Site Metastasis after Surgery for Renal Cell 
Carcinoma: Harbinger of Future Metastasis. The Journal of Urology 2014(0).
68. Castillo OA, Vitagliano G. Port Site Metastasis and Tumor Seeding in Oncologic 
Laparoscopic Urology. Urology 2008;71(3):372-8.
69. Minervini A, Ficarra V, Rocco F, et al. Simple Enucleation is Equivalent to Traditional 
Partial Nephrectomy for Renal Cell Carcinoma: Results of a Nonrandomized, 
Retrospective, Comparative Study. The Journal of Urology 2011;185(5):1604-10.
70. Robert C, Schachter J, Long GV, et al.  Pembrolizumab versus Ipilimumab in Advanced 
Melanoma.  The New England Journal of Medicine 2015;372:2521-2532.
71. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by 
inhibiting adaptive immune resistance.  Nature 2014;515:568–571.
72. Nguyen MM, Gill IS, Ellison LM. The Evolving Presentation of Renal Carcinoma in the 
United States: Trends From the Surveillance, Epidemiology, and End Results Program. 
The Journal of Urology 2006;176(6):2397-400.
73. Oda T, Miyao N, Takahashi A, et al. Growth rates of primary and metastatic lesions of 
renal cell carcinoma. International Journal of Urology 2001;8(9):473-7.
74. Wieczorek G, Asemissen A, Model F, et al. Quantitative DNA Methylation Analysis of 
FOXP3 as a New Method for Counting Regulatory T Cells in Peripheral Blood and Solid 
Tissue. Cancer Research 2009;69(2):599-608.
75. Walter S, Weinschenk T, Stenzl A, et al. Multipeptide immune response to cancer 
vaccine IMA901 after single-dose cyclophosphamide associates with longer patient 
survival. Nat Med 2012;18(8):1254-61.
76. Baitsch L, Baumgaertner P, Dev, et al. Exhaustion of tumor-specific CD8+ T cells in 
metastases 
from 
melanoma 
patients. 
The 
Journal 
of 
Clinical 
Investigation 
2011;121(6):2350-60.
77. Baitsch L, Legat A, Barba L, et al. Extended Co-Expression of Inhibitory Receptors by 
Human CD8 T-Cells Depending on Differentiation, Antigen-Specificity and Anatomical 
Localization. PLoS ONE 2012;7(2):e30852.
 
 
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78. Chen JL, Rathmell K, McDermott DF, Stadler WM. Circulatiing mir-21 and mir-378 are 
predictive of progression-free survival (PFS) in patients treated with everolimus in 
metastatic renal cell cancer (mRCC). Journal of Clinical Oncology 2012;30(15_suppl 
(May 20)):4617.
79. Margulis V, Matin SF, Tannir N, et al. Surgical Morbidity Associated With 
Administration of Targeted Molecular Therapies Before Cytoreductive Nephrectomy or 
Resection of Locally Recurrent Renal Cell Carcinoma. The Journal of Urology 
2008;180(1):94-8.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck 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
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The leftover specimen(s) collected in the current trial will be used to study various causes 
for how subjects may respond to a drug/vaccine.  The leftover specimen(s) will be stored 
to provide a resource for future trials conducted by Merck focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects 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 Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
 
 
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To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
 
 
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Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  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 trial site will be shipped to a central laboratory and then shipped to 
the Merck 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 Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
 
 
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administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research. When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial.
Merck has developed strict security, policies and procedures to address subject 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.
 
 
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It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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Approximate Blood/Tissue/Urine Volumes Drawn/Collected by Trial Visit and by 
12.4
Sample Types
Approximate blood sample volumes that will be collected are listed in Table 16 and Table 17
for patients randomized to receive neoadjuvant MK-3475 or to proceed directly to SOC 
surgical RCC tumor resection, respectively.
Table 16
Estimated Blood Sample Volumes - Patients Randomized to Neoadjuvant 
MK-3475
Trial Period: Screening Pretreatment 
Core Biopsy
MK-3475
SOC 
Tumor 
Resection
Post-op 
Follow-up
Post 
Resection
MK-3475
Week:
-2
-1
1
4
7
12
+7a
Scheduling window (days)
±14
±6
±3
±3
-7/+14
-5/+7
±7
Thyroid tests and Pregnancy Test-
Serum-HCG/FSHb (at screening)
3.5
3.5
3.5
3.5
3.5
PT/INR and aPTT
3
3
CBC with Differential
4
4
4
4
4
Chemistry (includes LFTs)
6
6
6
6
6
Blood for HLA typing
4
HIV/Hepatitis Screen (per site SOP) 
3.5
Blood for PBMC Phenotypic Analysis
15
15
15
Blood 
for 
PBMC 
Isolation 
and 
Cryopreservation
64
64
64
64
Blood for plasma collection
20
20
20
Blood for serum collection (biomarkers)
4
4
4
Blood for serum collection (PK/PD)
3.5
7
3.5
3.5
Blood for RNA isolation (PAXgene 
tube)
2.5
2.5
2.5
Blood for DNA isolation (PAXgene 
tube)c
8.5
8.5
8.5
Blood 
for 
B 
cell 
isolation 
and 
transformation
48
Total Volume of Blood Collectedd
20
118
17
21.5
134
179
64
Subtotals=
Neoadjuvant Phase = 488.6
64
Study Total= 552.6  ml
a.
7 weeks after the first dose of post-resection MK-3475
b. Women of child bearing potential will undergo serum -HCG testing or women’s post-menopausal status will be 
confirmed by measuring FSH levels.
c.
Any leftover DNA may be kept for Future Biomedical Research if the subject signs the FBR consent.
d. If additional pharmacokinetic/pharmacodynamics and/or safety analysis is necessary, additional blood (up to 50 ml)
may be obtained. Note: never to exceed 50 ml.
 
 
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Table 17
Estimated Blood Sample Volumes - Patients Randomized to No Treatment 
Control Group
Trial Period:
Screening
SOC Tumor 
Resection
Post-op 
Follow-up
Post Resection 
MK-3475
Week 
-2
1
6
+7a
Scheduling window (days)
±14
±14
-5/+7
±7
Thyroid tests and Pregnancy Test- Serum 
-HCG/FSHb (at screening) 
3.5
3.5
3.5
PT/INR and aPTT
3
3
CBC with Differential
4
4
4
Chemistry (includes LFTs)
6
6
6
Blood for HLA typing
4
HIV/Hepatitis Screen (per site SOP) 
3.5
Blood for PBMC Phenotypic Analysis
15
15
Blood 
for 
PBMC 
Isolation 
and 
Cryopreservation
64
64
64
Blood for plasma collection
20
20
Blood for serum collection
4
4
Blood for RNA isolation (PAXgene tube)
2.5
2.5
Blood for DNA isolation (PAXgene tube)c
8.5
8.5
Total Volume of Blood Collectedd
20
134.5
127.5
64
Study Total= 346 ml
a. 7 weeks after the first dose of post-resection MK-3475
b. Women of child bearing potential will undergo serum -HCG testing or women’s post-menopausal status will be 
confirmed by measuring FSH levels.
c. Any leftover DNA may be kept for Future Biomedical Research if the subject signs the FBR consent.
d. If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 ml) 
may be obtained. Note: never to exceed 50 ml.
Approximate tissue sample volumes (tumor and adjacent non-malignant kidney tissue) that 
will be collected are listed in Table 18 and Table 19 for patients randomized to receive 
neoadjuvant MK-3475 or to proceed directly to SOC surgical RCC tumor resection, 
respectively.  
 
 
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Table 18
Estimated Tissue Sample Volumes - Patients Randomized to Neoadjuvant 
MK-3475
Trial Period:
Pretreatment 
Core Biopsy
MK-3475
SOC Tumor Resection
Week:
-1
1
4
7
Scheduling window (days)
±6
±3
±3
-7/+14
Tumor Core Needle Biopsy- Pretreatment
Approximately 
0.06 cm3
Fresh tumor tissue for shipping (TIL analysis, 
histoculture, tumor cell isolation and IMR 
expression analysis)
10 cm3
Intraoperative Tumor Core Needle Biopsy
Approximately 0.06 cm3
Tumor tissue for FFPE (IHC; DNA for mutational 
analysis, TCR utilization, promoter methylation 
analysis; RNA for gene expression and miRNA 
analysis)
Three pieces, each 0.5 cm x 0.5 
cm x 0.3 cm
Total Volume = 0.225 cm3
Fresh tumor tissue for storage in RNA later 
solution (RNA extraction-gene expression, miRNA 
analysis)
One piece, 0.5 cm x 0.5 cm x 0.5 
cm
Total Volume = 0.125 cm3
Fresh tumor tissue for snap freezing (DNA 
isolation, metabolic profiling, laser capture 
microdissection)
Three pieces, each 0.5 cm x 0.5 
cm x 0.5 cm
Total Volume = 0.375 cm3
Fresh non-malignant kidney tissue from resected 
tumor specimen for snap freezing (DNA isolation)
One piece, 0.5 cm x 0.5 cm x 0.5 
cm
Total Volume = 0.125 cm3
Fresh non-malignant kidney tissue in RNAlater 
solution (RNA extraction, gene expression)
One piece, 0.5 cm x 0.5 cm x 0.5 
cm
Total Volume = 0.125 cm3
Volumes =
0.06 cm3
10.98 cm3
Approximate Total Volume of Tissue Samples = 11.0 cm3
 
 
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Table 19
Estimated Tissue Sample Volumes - Patients Randomized to No Treatment 
Control Group
Trial Period:
Screening
SOC Tumor Resection
Week 
-2
-2
Scheduling window (days)
±14
±14
Fresh tumor tissue for shipping (TIL analysis, histoculture, 
tumor cell isolation and IMR expression analysis)
10 cm3
Intraoperative Tumor Core Needle Biopsy
Approximately 0.06 cm3
Tumor tissue for FFPE (IHC; DNA for mutational analysis, 
TCR utilization, promoter methylation analysis; RNA for gene 
expression and miRNA analysis)
Three pieces, each 0.5 cm x 0.5 
cm x 0.3 cm
Total Volume = 0.225 cm3
Fresh tumor tissue for storage in RNA later solution (RNA 
extraction-gene expression, miRNA analysis)
One piece, 0.5 cm x 0.5 cm x 0.5 
cm
Total Volume = 0.125 cm3
Fresh tumor tissue for snap freezing (DNA isolation, metabolic 
profiling, laser capture microdissection)
Three pieces, each 0.5 cm x 0.5 
cm x 0.5 cm
Total Volume = 0.375 cm3
Fresh non-malignant kidney tissue from resected tumor 
specimen for snap freezing (DNA isolation)
One piece, 0.5 cm x 0.5 cm x 0.5 
cm
Total Volume = 0.125 cm3
Fresh non-malignant kidney tissue in RNAlater solution (RNA 
extraction, gene expression)
One piece, 0.5 cm x 0.5 cm x 0.5 
cm
Total Volume = 0.125 cm3
Approximate Total Volume of Tissue Samples = 11.0 cm3
Approximate urine volumes that will be collected for research analysis are listed in Table 20
and Table 21 for patients randomized to receive neoadjuvant MK-3475 or to proceed directly 
to SOC surgical RCC tumor resection, respectively.  
Table 20
Estimated Urine Sample Volumes - Patients Randomized to Patients 
Randomized to Neoadjuvant MK-3475
Trial Period:
Pretreatment 
Core Biopsy
SOC Tumor 
Resection
Follow-up
Week:
-1
7
12
Scheduling window (days)
±6
-7/+14
-5/+7
Urine for exosome isolation and analysis
100 ml
100 ml
100 ml
Total volume of urine collected=
300 ml
 
 
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Table 21
Estimated Urine Sample Volumes – Patients Randomized to No Treatment 
Control Group
Trial Period:
SOC Tumor Resection
Follow-up
Week:
2
6
Scheduling window (days)
±14
-5/+7
Urine for exosome isolation and analysis
100 ml
100 ml
Total volume of urine collected=
200 ml
 
 
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List of Abbreviations and Definitions
12.5
Abbreviation/Term
Definition
AE
Adverse Event
ASCO
American Society of Clinical Oncology
AST
All  Subjects  as  Treated  
ARG1
Arginase 1
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte Antigen 4
DVT
Deep Vein Thrombosis
ECG
Electrocardiogram
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
FDAAA
Food and Drug Administration Amendments Act 
FDAMA
Food and Drug Administration Modernization Act 
FFPE
formalin-fixed paraffin-embedded
HIV
Human Immunodeficiency Virus
IA
Interim Analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
IHC
immunohistochemical
IDO
indoleamine 2,3-dioxygenase
IMR
immune modulatory receptor
iNOS
inducible nitric oxide synthase
irAEs
Immune-Related Adverse Events
ITIM
Immunoreceptor tyrosine-based inhibition motif
ITSM
Immunoreceptor tyrosine-based switch motif
IV
Intravenous
LAG-3
lymphocyte activation gene 3
MEL
Melanoma
MDSC
myeloid derived suppressor cell
NCI 
National Cancer Institute 
NCS
not clinically significant
NHANES
National Health and Nutrition Examination Survey
NSCLC
Non-Small Cell Lung Cancer
NYHA
New York Heart Association
PGT
Pharmocogenetic
PD
Pharmacodynamic
PD-1
programmed cell death-1
PD-L1
programmed cell death 1 ligand 1
PD-L2
programmed cell death 1 ligand 2
PP
Per-Protocol
Q2W
every 2 weeks
Q3W
every 3 weeks
 
 
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Abbreviation/Term
Definition
RCC
renal cell cancer
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOC
standard of care
SOP
standard operating procedure
TCR
T cell receptor
Tigit
T cell immunoreceptor with Ig and ITIM domains
TILs
tumor infiltrating lymphocytes
V-type
Variable-type
 
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
12.6
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting
(http://ctep.cancer.gov/reporting/ctc.html).
 
 
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Eastern Cooperative Oncology Group (ECOG) Performance Scale
12.7
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
5
Dead
*As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., 
Group Chair.
 
 
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Algorithm for Assessing Out-of-Range Laboratory Values
12.8
For all laboratory values obtained at pre-study (screening) visit and/or pre-dose evaluation:
A. If all protocol-specified laboratory values are normal, the subject may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the subject will be excluded 
from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1. The subject may be excluded from the study.
2. The subject may be included in the study if the abnormal value(s) is not clinically 
significant (NCS) (the investigator must annotate the laboratory value “NCS” on the 
laboratory safety test source document).
3. The subject may be included in the study if the abnormality is consistent with a pre-
existing medical condition which is not excluded per protocol (e.g., elevated 
eosinophil count in a subject with asthma or seasonal allergies) the medical condition 
should be annotated on the laboratory report or
4. The abnormal test may be repeated (refer to items a. and b. below for continuation of 
algorithm for repeated values).  Unless a spurious result is suspected, repeat testing 
for any given abnormal laboratory screening test result will only be performed once. 
a.
If the repeat test value is within the normal range, the subject may enter the study.
b. If the repeat test value is still abnormal, the study investigator will evaluate the 
potential subject with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question.  If such diseases can be ruled out, and if the abnormal laboratory value 
is not clinically relevant, then the subject may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
subject will be excluded from the study.
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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