Clinical trial NCT02853305
Conditions: Urothelial Carcinoma Associated 1 RNA, Human
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-09-15; Completion date: 2022-09-15
Enrollment: 1010 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the efficacy and safety of pembrolizumab (pembro, MK-3475) with or without chemotherapy versus chemotherapy alone in participants with advanced or metastatic urothelial carcinoma (bladder cancer).

The primary hypotheses are that pembrolizumab plus chemotherapy is superior to chemotherapy alone with respect to Progression-free Survival (PFS) and Overall Survival (OS) in all participants, and that pembrolizumab alone is superior to chemotherapy alone with respect to OS in all participants and in participants with programmed cell death ligand 1 (PD-L1) positive tumors (Combined Positive Score \[CPS\] ≥10%).

Detailed description:
As specified by the protocol, the study hypotheses will be evaluated by comparing the pembro combo arm or pembro arm separately to the chemo arm.

Arms: arm 1: Participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m\^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m\^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m\^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion. arm 2: Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses. Eligible participants who stop pembrolizumab with SD or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion. arm 3: Participants receive ST chemotherapy with EITHER cisplatin 70 mg/m\^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m\^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m\^2 IV on Day 1 and Day 8 of each 3-week cycle.
Interventions: intervention 1: Pembrolizumab intervention 2: Cisplatin intervention 3: Carboplatin intervention 4: Gemcitabine
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: IV infusion intervention 4: IV infusion

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase III Randomized, Controlled Clinical 
Trial of Pembrolizumab with or without 
Platinum-Based Combination Chemotherapy 
versus Chemotherapy in Subjects with 
Advanced or Metastatic Urothelial Carcinoma
NCT02853305
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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, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase III Randomized, Controlled Clinical Trial of Pembrolizumab with or without 
Platinum-Based Combination Chemotherapy versus Chemotherapy in Subjects with 
Advanced or Metastatic Urothelial Carcinoma
IND NUMBER:  122,753
EudraCT NUMBER:  2015-005731-41
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
Trial Diagram........................................................................................................ 18
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 18
Primary Objective(s) & Hypothesis(es).............................................................. 18
Secondary Objective(s) & Hypothesis(es)........................................................... 19
Exploratory Objectives......................................................................................... 21
4.0
BACKGROUND & RATIONALE.......................................................................... 21
Background ........................................................................................................... 21
Pharmaceutical and Therapeutic Background .................................................... 21
Preclinical and Clinical Trials............................................................................. 22
Ongoing Clinical Trials....................................................................................... 22
Rationale................................................................................................................ 27
Rationale for the Trial and Selected Subject Population .................................... 27
Rationale for Dose Selection/Regimen/Modification......................................... 29
Rationale for the Use of Comparators ......................................................... 30
Rationale for Endpoints ...................................................................................... 31
Efficacy Endpoints....................................................................................... 31
4.2.3.1.1
Primary Endpoints ................................................................................ 31
4.2.3.1.2
Secondary Endpoints ............................................................................ 32
Exploratory Endpoints ................................................................................. 32
4.2.3.2.1
Patient-reported Outcomes ................................................................... 32
Safety Endpoints.......................................................................................... 32
Planned Exploratory Biomarker Research................................................... 33
Future Biomedical Research........................................................................ 34
Benefit/Risk ........................................................................................................... 35
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5.0
METHODOLOGY ................................................................................................... 35
Entry Criteria........................................................................................................ 35
Diagnosis/Condition for Entry into the Trial...................................................... 35
Subject Inclusion Criteria.................................................................................... 35
Subject Exclusion Criteria .................................................................................. 38
Trial Treatment..................................................................................................... 40
Dose Selection/Modification .............................................................................. 42
Dose Selection (Preparation) ....................................................................... 42
Dose Modification (Escalation/Titration/Other).......................................... 42
5.2.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................... 42
5.2.1.2.2
Dose Modifications for Cisplatin or Carboplatin ................................. 48
5.2.1.2.3
Dose Modifications for Gemcitabine.................................................... 48
5.2.1.2.4
Dose Modifications for Combination Therapy or Chemotherapy........ 48
Timing of Dose Administration.......................................................................... 49
Pembrolizumab ............................................................................................ 49
Cisplatin/Gemcitabine.................................................................................. 49
Carboplatin/Gemcitabine............................................................................. 49
Trial Blinding...................................................................................................... 49
Randomization ...................................................................................................... 50
Stratification.......................................................................................................... 50
Concomitant Medications/Vaccinations (Allowed and Prohibited)................. 50
Acceptable Concomitant Medications ................................................................ 51
Prohibited Concomitant Medications.................................................................. 51
Rescue Medications & Supportive Care............................................................. 52
Supportive Care Guidelines for Subjects Receiving Pembrolizumab ................ 52
Supportive Care Guidelines for Chemotherapy-related Adverse Events ........... 52
Diet/Activity/Other Considerations..................................................................... 52
Diet...................................................................................................................... 52
Contraception...................................................................................................... 52
Use in Pregnancy ................................................................................................ 54
Use in Nursing Women....................................................................................... 54
Subject Withdrawal/Discontinuation Criteria................................................... 55
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Discontinuation of Treatment ............................................................................. 55
Withdrawal from the Trial .................................................................................. 56
Treatment After Initial Radiologic Progression.................................................. 56
Discontinuation of Trial Therapy After Complete Response ............................. 57
Subject Replacement Strategy............................................................................. 57
Beginning and End of the Trial ........................................................................... 57
Clinical Criteria for Early Trial Termination ................................................... 58
6.0
TRIAL FLOW CHART ........................................................................................... 59
Initial Treatment Phase – Pembrolizumab Only (Pembro Only) .................... 59
Pembrolizumab + Chemotherapy (Combo) ....................................................... 63
Chemotherapy Only (Chemo Only).................................................................... 68
Second Course Phase (Re-treatment for Pembrolizumab [Pembro Only 
and Combo] Arms ONLY)................................................................................... 73
7.0
TRIAL PROCEDURES ........................................................................................... 75
Trial Procedures ................................................................................................... 75
Administrative Procedures.................................................................................. 75
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
Inclusion/Exclusion Criteria ........................................................................ 76
Subject Identification Card .......................................................................... 76
Medical History ........................................................................................... 76
Prior and Concomitant Medications Review............................................... 76
7.1.1.5.1
Prior Medications.................................................................................. 76
7.1.1.5.2
Concomitant Medications..................................................................... 76
Assignment of Screening Number............................................................... 77
Assignment of Treatment/Randomization Number..................................... 77
Trial Compliance (Medication/Diet/Activity/Other)................................... 77
Clinical Procedures/Assessments........................................................................ 77
Tumor Tissue Collection and Correlative Blood Sampling......................... 77
Adverse Event Monitoring........................................................................... 78
Physical Examination................................................................................... 78
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7.1.2.3.1
Full Physical Examination.................................................................... 78
7.1.2.3.2
Directed Physical Examination............................................................. 78
Vital Signs.................................................................................................... 78
12-Lead Electrocardiogram ......................................................................... 78
Eastern Cooperative Oncology Group Performance Scale.......................... 78
Patient-reported Outcomes........................................................................... 79
Tumor Imaging and Assessment of Disease................................................ 79
7.1.2.8.1
Initial Tumor Imaging........................................................................... 79
7.1.2.8.2
Tumor Imaging During the Trial .......................................................... 80
7.1.2.8.3
End of Treatment and Follow-up of Tumor Imaging ........................... 81
7.1.2.8.4
Second Course (Re-treatment) Tumor Imaging.................................... 81
RECIST 1.1 Assessment of Disease............................................................ 82
irRECIST Assessment of Disease................................................................ 82
Tumor Tissue Collection and Correlative Blood Sampling......................... 87
Tumor Tissue Collection: PD-L1 Status...................................................... 87
Laboratory Procedures/Assessments .................................................................. 87
Serum/Urine Pregnancy Test....................................................................... 87
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry, 
and 
Urinalysis).................................................................................................... 88
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 89
7.1.3.3.1
Exploratory Drug-drug Interaction Analysis ........................................ 89
Blood for RNA Analyses, Plasma Biomarker Analyses, and Serum 
Biomarker Analyses..................................................................................... 90
Planned Genetic Analysis Sample Collection.............................................. 90
Future Biomedical Research Sample Collection ......................................... 90
Other Procedures................................................................................................. 90
Withdrawal/Discontinuation........................................................................ 90
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 90
Blinding/Unblinding .................................................................................... 91
Calibration of Critical Equipment................................................................ 91
Visit Requirements.............................................................................................. 91
Screening...................................................................................................... 92
Treatment Period.......................................................................................... 92
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7.1.5.2.1
Second Course Phase (Re-treatment Period)........................................ 92
Posttreatment Visits ..................................................................................... 94
7.1.5.3.1
Discontinuation Visit............................................................................ 94
7.1.5.3.2
Safety Follow-up Visit.......................................................................... 94
7.1.5.3.3
Efficacy Follow-up ............................................................................... 94
7.1.5.3.4
Survival Follow-up Assessments.......................................................... 95
Survival Status ............................................................................................. 95
Assessing and Recording Adverse Events .......................................................... 95
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 96
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 97
Immediate Reporting of Adverse Events to the Sponsor.................................... 97
Serious Adverse Events ............................................................................... 97
Events of Clinical Interest............................................................................ 98
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 99
Evaluating Adverse Events................................................................................. 99
Sponsor Responsibility for Reporting Adverse Events .................................... 102
TRIAL GOVERNANCE AND OVERSIGHT................................................. 102
Scientific Advisory Committee......................................................................... 102
Trial Steering Committee.................................................................................. 102
Executive Oversight Committee....................................................................... 102
Data Monitoring Committee............................................................................. 102
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 103
Statistical Analysis Plan Summary ................................................................... 103
Responsibility for Analyses/In-House Blinding ............................................... 105
Hypotheses/Estimation....................................................................................... 106
Analysis Endpoints ............................................................................................. 106
Efficacy Endpoints............................................................................................ 106
Safety Endpoints ............................................................................................... 106
Analysis Populations........................................................................................... 106
Efficacy Analysis Populations .......................................................................... 106
Safety Analysis Populations ............................................................................. 107
Statistical Methods.............................................................................................. 107
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Statistical Methods for Efficacy Analyses........................................................ 107
Progression-free Survival (PFS) ................................................................ 107
Overall Survival (OS) ................................................................................ 109
Objective Response Rate ........................................................................... 110
Statistical Methods for Safety Analyses ........................................................... 110
Demographic and Baseline Characteristics ...................................................... 112
Interim Analyses ................................................................................................. 112
Safety Interim Analysis..................................................................................... 112
Efficacy Interim Analysis ................................................................................. 112
Multiplicity .......................................................................................................... 115
Sample Size and Power Calculations ................................................................ 117
Subgroup Analyses and Effect of Baseline Factors ......................................... 118
Compliance (Medication Adherence)................................................................ 119
Extent of Exposure.............................................................................................. 119
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 119
Investigational Product ...................................................................................... 119
Packaging and Labeling Information ............................................................... 120
Clinical Supplies Disclosure............................................................................... 120
Storage and Handling Requirements................................................................ 120
Discard/Destruction/Returns and Reconciliation ............................................ 121
Standard Policies................................................................................................. 121
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 121
Confidentiality..................................................................................................... 121
Confidentiality of Data ..................................................................................... 121
Confidentiality of Subject Records................................................................... 121
Confidentiality of Investigator Information...................................................... 122
Confidentiality of IRB/IEC Information........................................................... 122
Compliance with Financial Disclosure Requirements..................................... 122
Compliance with Law, Audit and Debarment ................................................. 123
Compliance with Trial Registration and Results Posting Requirements...... 125
Quality Management System............................................................................. 125
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Data Management............................................................................................... 125
Publications ......................................................................................................... 125
11.0
LIST OF REFERENCES....................................................................................... 127
12.0
APPENDICES......................................................................................................... 133
Merck Code of Conduct for Clinical Trials...................................................... 133
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 135
ECOG Performance Status Categories............................................................. 139
Common Terminology for Adverse Events V4.0 (CTCAE) ........................... 140
Country-specific Requirements......................................................................... 141
France-specific Requirements........................................................................... 141
List of Abbreviations .......................................................................................... 143
13.0
SIGNATURES......................................................................................................... 146
Sponsor's Representative ................................................................................... 146
Investigator.......................................................................................................... 146
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LIST OF TABLES
Table 1
Primary Hypotheses ............................................................................................... 19
Table 2
Key Features of Ongoing KEYNOTE Bladder Trials............................................ 26
Table 3
Adequate Organ Function ...................................................................................... 37
Table 4
Trial Treatments ..................................................................................................... 41
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab 
Monotherapy, 
Coformulations or IO Combinations...................................................................... 44
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................... 47
Table 7
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease.................................................................................................................... 85
Table 8
Laboratory Tests..................................................................................................... 88
Table 9
Evaluating Adverse Events .................................................................................. 100
Table 10 Censoring Rules for Primary and Sensitivity Analysis of PFS............................ 109
Table 11 Analysis Strategy for Primary and Key Secondary Efficacy Objectives ............. 110
Table 12 Analysis Strategy for Safety Endpoints................................................................ 111
Table 13 Decision Guidance (Boundary Z Statistic, P-Value, and Approximate Hazard 
Ratio) for the Interim and Final Analysis of PFS and OS.................................... 114
Table 14 Assumptions of Hazard Ratios for Superiority between Different Conditions.... 117
Table 15 Power of Primary Hypotheses Tests .................................................................... 118
Table 16 Product Descriptions ............................................................................................ 120
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LIST OF FIGURES
Figure 1 Trial Diagram ......................................................................................................... 18
Figure 2 Flow Chart for Imaging After First Site-Identified Progression of Disease .......... 86
Figure 3 Multiplicity Strategy............................................................................................. 116
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-361-10
10-JUN-2021
Global: To update the dose modification and toxicity management guidelines 
for immune-related adverse events (irAEs).
3475-361-09
10-APR-2020
France: Due to a significant drop off in the accrual of progression-free survival 
(PFS) events, the requirement for the final analysis of approximately 532 PFS 
events in the combo and chemo arms in all subjects has been removed.  The 
other requirements for the final analysis remain in place.
3475-361-08
10-APR-2020
Global: Due to a significant drop off in the accrual of PFS events, the 
requirement for the final analysis of approximately 532 PFS events in the 
combo and chemo arms in all subjects has been removed. 
The other 
requirements for the final analysis remain in place.
3475-361-07
24-OCT-2019
France: In order to account for a potential delayed treatment effect, which was 
observed with immunotherapy study data external to this study, the Statistical 
Analysis Plan was revised.
3475-361-06
23-OCT-2019
Global: In order to account for a potential delayed treatment effect, which was 
observed with immunotherapy study data external to this study, the Statistical 
Analysis Plan was revised.
3475-361-05
8-MAR-2018
France: Based on their review of preliminary data from KEYNOTE-361, the 
external 
Data 
Monitoring 
Committee 
recommended 
accrual 
to 
the 
pembrolizumab monotherapy arm for subjects whose tumors are PD-L1 
CPS<10% be stopped.
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Document
Date of Issue
Overall Rationale
3475-361-04
8-MAR-2018
Global: Based on their review of preliminary data from KEYNOTE-361, the 
external 
Data 
Monitoring 
Committee 
recommended 
accrual 
to 
the 
pembrolizumab monotherapy arm for subjects whose tumors are PD-L1 
CPS<10% be stopped.
3475-361-03
14-NOV-2017
France: Based on recent results from KEYNOTE-045 (KN045) and 
KEYNOTE-052 (KN052), the Statistical Analysis Plan was revised and 
simplified.
3475-361-02
14-SEP-2017
Global: Based on recent results from KEYNOTE-045 (KN045) and 
KEYNOTE-052 (KN052), the Statistical Analysis Plan was revised and 
simplified.
3475-361-01
12-OCT-2016
To update entrance criteria, particularly in regard to estimated creatinine 
clearance as an assessment of renal function and to require audiograms since 
subjects with Grade ≥2 audiometric hearing loss are not eligible for cisplatin.
3475-361-00
20-JUN-2016
Original
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.2.1
Immune-Related 
Events and Dose 
Modification 
(Withhold, Treat, 
Discontinue)
The dose modification and 
toxicity management 
guidelines for irAEs and 
table were updated.
The dose modification and toxicity management 
guidelines for irAEs and table were updated as requested 
by the US Food and Drug Administration (FDA) in an 
effort to harmonize the presentation of safety 
information across all FDA-approved programmed cell 
death 1/ ligand 1 (PD-1/L1) antibody prescribing 
information.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Appendix 12.5
Appendix 12.5.1
Country-specific Requirements
France-specific Requirements
Country-specific requirements 
for France were added to a 
country-specific appendix.
A country-specific amendment 
is being rolled into the global 
amendment and placed within a 
country-specific appendix.
Whole document
Correction 
of 
minor 
administrative 
and 
typographical errors.
Corrections.
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase III Randomized Controlled Trial of Pembrolizumab With or 
Without Chemo vs Chemo in Advanced Urothelial Carcinoma
Sponsor Product Identifiers
Pembrolizumab
Trial Phase
Phase III
Clinical Indication
Treatment of subjects with advanced or metastatic urothelial 
carcinoma
Trial Type
Interventional
Type of control
Active control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
1.
Pembrolizumab (MK-3475)
2.
Pembrolizumab with chemotherapy (cisplatin or carboplatin 
with gemcitabine)
3.
Chemotherapy (cisplatin or carboplatin with gemcitabine).
Number of trial subjects
Approximately 990 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
3 years from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject 
signs the Informed Consent Form (ICF) through the final protocol-
specific contact.
After a screening period of 42 days, subjects will be randomized to 
one of the 3 treatment arms: pembrolizumab monotherapy (pembro 
only), pembrolizumab+chemotherapy+standard of care (SOC) 
(combo), and chemotherapy+SOC (chemo only).  The safety and 
feasibility of combo therapy will be assessed by means of a safety 
interim analysis after the last of the first 10 subjects enrolled in the 
combo treatment arm completes 2 cycles of treatment. Treatment on 
trial will continue until verification of disease progression is 
confirmed by blinded independent central review
(BICR), 
unacceptable adverse event(s)
(AEs), intercurrent illness that 
prevents further administration of treatment, investigator’s decision 
to withdraw the subject, subject withdrawal of consent, pregnancy of 
the subject, noncompliance with trial treatment or procedures 
requirements,
or 
subject 
receives 
35 administrations 
of 
pembrolizumab (approximately 2 years) (pembro only and combo 
treatment arms only).
Investigators may consider stopping trial 
treatment (pembrolizumab) for subjects on the pembrolizumab arms
(pembro only and combo) who attain a complete response (CR) if 
they meet criteria for holding therapy. Subjects who stop treatment 
and subsequently have progressive disease may be eligible for up to 
17 administrations (1 year) of pembrolizumab re-treatment if they 
1) have received 35 doses of pembrolizumab and stop trial treatment 
for reasons other than disease progression or intolerability or 
2) attained a confirmed CR after being treated with pembrolizumab 
for at least 8 administrations, and had at least 2 treatments with 
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pembrolizumab after CR was declared (Section 7.1.5.2.1).
The 
decision to re-treat will be at the discretion of the investigator; 
re-treatment will occur only if the subject meets the criteria for 
re-treatment and the trial is ongoing.
After the last dose of trial treatment, each subject will be followed for 
30 days for AE monitoring. Serious AEs (SAEs) will be collected 
for 90 days after the last dose of trial treatment or 30 days after the 
end of treatment if the subject initiates new anti-cancer therapy, 
whichever is earlier. All drug-related SAEs and events of clinical 
interest (ECIs) will be reported regardless of time frame. Subjects 
who discontinue trial treatment without disease progression will have 
post-treatment follow-up for disease status, including radiographic 
imaging, until disease progression initiating a nontrial cancer 
treatment, withdrawing consent, or becoming lost to follow-up.  
Subjects who discontinue treatment due to disease progression will 
also continue to be followed for survival status. All subjects will be 
followed for overall survival approximately every 12 weeks until 
death, withdrawal of consent, or the end of the trial.  To ensure 
current and complete survival data is available at the time of database 
locks, updated survival status may be requested during the course of 
the study by the Sponsor.
Once the participant has achieved the study objective or the study has 
ended, the participant is discontinued from this study and will be 
enrolled in an
extension study to continue protocol-defined 
assessments.
A list of abbreviations used in this document can be found in Appendix 12.6.
2.0 TRIAL DESIGN
Trial Design
This is a Phase III randomized, active-controlled, parallel-group, multisite, open-label trial to 
determine the efficacy and safety of pembrolizumab with or without chemotherapy versus 
chemotherapy alone in subjects with advanced or metastatic urothelial carcinoma (bladder 
cancer). Subjects will be enrolled regardless of programmed death-ligand 1 (PD-L1) status
(Combined Positive Score [CPS] ≥10% or CPS <10%). Approximately 1,300 subjects will be 
screened. Approximately 990 subjects will be randomized. The population will comprise of 
subjects with advanced or metastatic urothelial carcinoma whose disease is not subject to 
curative surgery. Subjects must have measurable disease based on Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 as determined by investigator/site radiologist. During 
the 42-day screening period, each subject must provide a newly obtained or archival 
formalin-fixed paraffin-embedded (FFPE) tumor biopsy for PD-L1 determination by 
immunohistochemistry (IHC) by a central laboratory.
The biopsy should be from a 
muscle-invasive urothelial carcinoma or a metastatic biopsy, originating from the original
tumor.
Randomization Ratio
1:1:1 (all arms) for all subjects from trial initiation until 21-FEB-2018.
After 21-FEB-2018, 1:1:1 (all arms) for subjects whose tumors are
PD-L1 CPS ≥10% and 1:1 (combo arm and chemo only arm) for
subjects whose tumors are PD-L1 CPS <10%.
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Note:  PD-L1 CPS ≥10% and CPS <10% are replacing the designation of PD-L1 positive and 
negative, respectively, that were referenced in the overall trial design used in the base 
protocol (KN361-00).
Subjects will be stratified based on PD-L1 results, and therefore adequacy of tissue specimen
for PD-L1 determination is required.
In the pembro only arm and combo arm, each subject will receive the following dose of 
pembrolizumab:

Pembrolizumab 200 mg every 3 weeks (Q3W) (Day 1 of each 3-week cycle) for a 
maximum of 35 doses.
In the combo and chemo only arms, each subject will receive 6 cycles of platinum-based 
combination chemotherapy as per investigator’s choice (based on clinical factors; refer to 
Section 4.2.1 for cisplatin ineligibility guidelines) of either:

Cisplatin intravenous (IV) infusion 70 mg/m2 on Day 1 (or Day 2 if required per 
local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m2 Day 1 
and Day 8 of each 3-week cycle 
OR (only if ineligible for cisplatin; refer to Section 4.2.1 for cisplatin ineligibility 
guidelines)

Carboplatin IV infusion area under the curve 5 (AUC 5) (or AUC 4.5 if required per 
local guidelines) Day 1 (or Day 2 if required per local guidelines) of each 3-week 
cycle + gemcitabine IV infusion 1,000 mg/m2 Day 1 and Day 8 of each 3-week 
cycle.
To ensure that random distribution is maintained across all 3 arms, including the pembro
only arm, trial randomization will be stratified by the investigator’s choice of chemotherapy 
regimen, which must be specified prior to randomization. Cisplatin eligibility will have no 
impact on randomization into treatment arms.
Prior to 21-FEB-2018, subjects were equally randomized to one of the 3 treatment arms. As 
of 21-FEB-2018, subjects with tumors that are PD-L1 CPS≥10% will be equally randomized 
to one of the 3 treatment arms. Subjects with tumors that are PD-L1 CPS<10% will no longer 
be randomized to the pembro only arm; they will be equally randomized to either the combo 
arm or the chemo only arm. No change in study treatment is required for subjects randomized 
prior to 21-FEB-2018.
The primary efficacy endpoints will be the progression-free survival (PFS) for combo vs
chemo only in the all-subject population using BICR and RECIST 1.1 to determine disease 
progression, and overall survival (OS) for combo vs chemo only in the all-subject population 
and OS for pembro only vs chemo only in the PD-L1 CPS ≥10% and all-subject population.  
Secondary endpoints will include objective response rates (ORR), disease control rate 
(DCR), and duration of response (DOR) using BICR and RECIST 1.1 to determine disease 
progression, for both the PD-L1 CPS ≥10% population and the all-subject population. The 
proportion of subjects who are progression-free at specific time points will also be assessed. 
Exploratory endpoints include health-related quality of life as assessed by the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC 
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QLQ-C30) and European Quality of Life (EuroQol) EQ-5D™, as well as the relationship 
between genetic variations and response to treatment.
This trial will use an independent, external Data Monitoring Committee (DMC) to monitor 
safety and efficacy. The safety and feasibility of combination therapy will be assessed by 
means of a safety interim analysis. The interim safety analysis will be conducted when 
10 subjects in the combo arm have completed 2 cycles of treatment. Refer to Section 8.7.1 –
Safety Interim Analysis for details and criteria of the combination safety interim analyses. 
The interim PFS/OS analysis is event driven.
More details are given in Section 8.7.2 –
Efficacy Interim Analysis.
Subjects will be evaluated for safety at every visit and by radiographic imaging every
9 weeks (63 days ±7) after randomization, or more frequently if clinically indicated, to assess 
response to treatment. 
Subjects who remain on treatment beyond 54 weeks will have 
imaging performed every 12 weeks (84 days ±7) thereafter. All imaging obtained on trial
will be submitted to a BICR that will assess the images using RECIST 1.1 for determination 
of ORR, DOR, DCR, and PFS.
Subjects in either pembrolizumab arm (pembro only or combo) who stop trial treatment after 
receiving 35 administrations for reasons other than disease progression or intolerability, or 
who attain a confirmed CR and stop trial treatment after 2 additional doses beyond the initial 
determination of CR, may be eligible for up to 17 administrations of re-treatment upon 
experiencing disease progression. The decision to re-treat will be at the discretion of the 
investigator only if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject still meets the safety parameters listed in the inclusion/exclusion 
criteria, and the trial remains open (refer to Section 7.1.5.2.1 – Second Course Phase for 
details).
The protocol does not allow subjects to cross over to pembrolizumab if they have progression 
on chemotherapy.
After the end of trial treatment, subjects will be followed for 30 days for AE monitoring and 
events of clinical interest (ECI), or until the subject initiates new anticancer therapy, 
whichever comes first.  Serious AEs (SAEs) will be collected for 90 days after the trial 
treatment or 30 days after the end of treatment, if the subject initiates new anti-cancer 
therapy, whichever is earlier.
Subjects who discontinue or complete the entire regimen of trial therapy for reasons other 
than documented confirmed disease progression must have posttreatment follow-up for 
disease status every 9 weeks (63 days ±7) during the first year of the trial until Week 54 and,
then every 12 weeks (84 days ±7) until one of the following occurs: verification of disease 
progression by BICR, a new nontrial cancer treatment is initiated, consent is withdrawn, 
death, becoming lost to follow-up, or the end of the trial, whichever comes first. All subjects 
will be followed up for OS every 12 weeks (84 days ±7) until death, withdrawal of consent, 
or the end of the trial. This can be performed in a variety of manners including phone, e-mail, 
chart review, or review of public records.
This study will be conducted in compliance with the Merck Code of Conduct for Clinical 
Trials (refer to Appendix 12.1), Good Clinical Practices, and the ethical principles that have 
their origin in the Declaration of Helsinki.
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Refer to Appendix 12.6 for a list of abbreviations used in the text of this protocol.
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.
Trial Diagram
The design of the trial is shown in Figure 1, below.
Figure 1
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In male and female subjects with advanced/unresectable (inoperable) or metastatic urothelial 
carcinoma of the renal pelvis, ureter [upper urinary tract], bladder, or urethra at least 18 years 
of age:
Primary Objective(s) & Hypothesis(es)
Objectives: To compare PFS using RECIST 1.1 as assessed by BICR in the all-subject 
population for combo vs chemo only, and to compare OS for combo vs chemo only in the 
all-subject population and for pembro only vs chemo only in the PD-L1 CPS ≥10% and 
all-subject population.
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Hypothesis (H1): Combo is superior to chemo only with respect to PFS using RECIST 1.1 
as assessed by BICR in all subjects (both PD-L1 CPS ≥10% and CPS <10%).
Hypothesis (H2): Combo is superior to chemo only with respect to OS in all subjects (both 
PD-L1 CPS ≥10% and CPS <10%).
Hypothesis (H3a): Pembro only is noninferior to chemo only with respect to OS in PD-L1
CPS ≥10% subjects.
Hypothesis (H3b): Pembro only is superior to chemo only with respect to OS in PD-L1 
CPS ≥10% subjects.
Hypothesis (H4a): Pembro only is noninferior to chemo only with respect to OS in all 
subjects (both PD-L1 CPS ≥10% and CPS <10%).
Hypothesis (H4b): Pembro only is superior to chemo only with respect to OS in all subjects 
(both PD-L1 CPS ≥10% and CPS <10%).
Refer to Table 1 for a list of the primary hypotheses and their abbreviations in this protocol.
Table 1
Primary Hypotheses
Hypothesis Number 
Hypothesis
H1
PFS, all subjects, superiority, combo vs chemo only
H2
OS, all subjects, superiority, combo vs chemo only
H3a
OS, PD-L1 CPS ≥10%, noninferiority, pembro only vs
chemo only
H3b
OS, PD-L1 CPS ≥10%, superiority, pembro only vs chemo
only
H4a
OS, all subjects, noninferiority, pembro only vs chemo only
H4b
OS, all subjects, superiority, pembro only vs chemo only
Note: The success of the trial will ultimately depend on the demonstration of superiority related to H1 (PFS) 
or H2 (OS) due to the multiplicity strategy detailed in Section 8.8.
Abbreviations/Terms: all subjects=PD-L1 CPS ≥10% and CPS <10%; chemo only=chemotherapy (cisplatin 
or carboplatin+gemcitabine)+SOC; combo=pembrolizumab+chemotherapy (cisplatin or 
carboplatin+gemcitabine)+SOC; CPS=combined positive score for PD-L1 positivity; H=hypothesis; 
OS=overall survival; PD-L1=programmed cell death-ligand 1; pembro=pembrolizumab; PFS=progression-
free survival; SOC=standard of care.
Secondary Objective(s) & Hypothesis(es)
1. Objective:  To evaluate the safety and tolerability profile in all subjects (PD-L1 
CPS ≥10% and CPS <10%) in the following treatment groups:
a) Pembro only
b) Combo
c) Chemo only
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2. Objective:  To compare the ORR using RECIST 1.1 as assessed by BICR between 
the following treatment comparisons:
a) Combo versus chemo only
b) Pembro only versus chemo only
Hypothesis (H5a): Combo is superior to chemo only with regard to ORR in all 
subjects (PD-L1 CPS ≥10% and CPS <10%).
Hypothesis (H5b): Pembro only is superior to chemo only with regard to ORR in all 
subjects (PD-L1 CPS ≥10% and CPS <10%).
3. Objective:  To evaluate the DOR in all subjects (PD-L1 CPS ≥10% and CPS <10%) 
using RECIST 1.1 as assessed by BICR in the following treatment groups:
a) Pembro only
b) Combo
c) Chemo only
4. Objective: To evaluate the disease control rate (DCR=combined complete response, 
partial response, and stable disease rates) in all subjects (PD-L1 CPS ≥10% and 
CPS <10%) using RECIST 1.1 as assessed by BICR in the following treatment 
groups:
a) Pembro only
b) Combo
c) Chemo only
5. Objective:  To estimate PFS at milestone time points (6 months, 12 months, 
18 months, 24 months) in all subjects (PD-L1 CPS ≥10% and CPS <10%) using
RECIST 1.1 as assessed by BICR in the following treatment groups:
a) Pembro only
b) Combo
c) Chemo only
6. Objective:  To evaluate time to deterioration (TTD), defined as the time from 
baseline to first onset of patient-reported outcome (PRO) deterioration, and score 
change from baseline in health-related quality of life scores assessed using the 
EORTC QLQ-C30 among all subjects (both PD-L1 CPS ≥10% and CPS <10%) in the 
following treatment groups:
a) Pembro only
b) Combo
c) Chemo only
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Exploratory Objectives
1. Objective: To evaluate changes in health-related quality of life and characterize 
health utilities in all treatment groups, including change from baseline in 
health-related quality of life using the multi-item and single-item scales of the 
EORTC QLQ-C30 and health state and utility scores using EuroQol EQ-5D among 
all subjects.
2. Objective: To characterize utilities using EuroQol EQ-5D among all subjects (both 
PD-L1 CPS ≥10% and CPS <10%).
3. Objective: To compare PFS as assessed by BICR using immune-related RECIST 
(irRECIST) in PD-L1 CPS ≥10% subjects and in all subjects (both PD-L1 CPS ≥10% 
and CPS <10%) between the following treatment comparisons:
a) Combo versus chemo only
b) Pembro only versus chemo only
4. Objective: To compare the ORR as assessed by BICR using irRECIST in all subjects 
(PD-L1 CPS ≥10% and CPS <10%) between the following treatment comparisons:
a) Combo versus chemo only
b) Pembro only versus chemo only
5. Objective: To characterize the pharmacokinetic (PK) and pharmacodynamic profiles
of treatment with pembrolizumab in the pembro only and combo treatment groups.
6. Objective: 
To identify molecular
(genomic, metabolic, and/or proteomic) 
biomarkers
that may be indicative of clinical response/resistance, safety, 
pharmacodynamic activity, and/or the mechanism of action of pembrolizumab and 
other treatments.
4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with PD-L1 and programmed cell death-ligand 2 (PD-L2).  Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
KEYTRUDA™ (pembrolizumab) is indicated for the treatment of patients across a number 
of indications because of its mechanism of action to bind the PD-1 receptor on the T-cell.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab (MK-3475).
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1]. Accumulating evidence shows a correlation 
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between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in solid malignances such as ovarian, colorectal, and pancreatic cancer.  Tumor-
infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable objective 
tumor responses in cancers such as melanoma [2] [3].
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
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4), which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2) [4] [5].
The structure of murine PD-1 has been resolved [6]. PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (IgV-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 [4] [7] [8] [9].  The mechanism by which PD-1 
down-modulates T-cell responses is similar to, but distinct from that of CTLA-4, as both 
molecules regulate an overlapping set of signaling proteins [10] [11].  As a consequence, the 
PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in advanced 
urothelial carcinoma.
Preclinical and Clinical Trials
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other 
treatments. 
Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have shown antitumor
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma,
melanoma, and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted 
CD8+ T-cell infiltration into the tumor and the presence of IFN-, granzyme B and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell function in vivo [2] [3] [12] [13] [14].  Experiments have confirmed the in vivo 
efficacy of PD-1 blockade as a monotherapy as well as in combination with chemotherapy in 
syngeneic mouse tumor models. (For more information, refer to the IB.)
Ongoing Clinical Trials
The safety, tolerability, and antitumor activity of pembrolizumab were assessed in subjects 
with recurrent or metastatic urothelial cancer in the Phase 1b KN012 (NCT01848834), an 
open-label nonrandomized trial of pembrolizumab 10 mg/kg, IV once every 2 weeks (Q2W) 
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in advanced solid tumors.  Archival or newly obtained tumor samples from subjects with 
advanced carcinoma of the renal pelvis, ureter, bladder, or urethra were screened for PD-L1 
expression using a prototype IHC assay.  PD-L1 expression in stroma or ≥1% of tumor cells 
was required for trial entry. Subjects received pembrolizumab 10 mg/kg Q2W until CR, 
progression, or unacceptable toxicity.
Subjects
deriving benefit could remain on 
pembrolizumab beyond initial progression. 
Response was assessed every 8 weeks per 
RECIST 1.1 by independent central review (primary efficacy end point).
In the KN012 trial, a total of 33 subjects with bladder cancer were enrolled and received 
pembrolizumab 10 mg/kg Q2W.  Median age was 70 years (range 44 to 85); 72.7% of 
subjects had an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 1, 
51.6% had received ≥2 prior therapies for advanced disease, and 30.3% had liver metastases.
As of the data cutoff date, the ORR (CR+PR) in 33 urinary tract cancer subjects was 21.2%
(7/33) as measured by RECIST 1.1 by BICR.  Similarly, the ORR was 21.2% by site 
assessment and when measured by irRECIST.  The ORR was 25.9% (7/27) in the primary 
endpoint FAS population both by BICR and site assessment.  Notably, 48% (16/33) of 
urinary tract cancer subjects showed tumor reduction, and this shows benefit in a larger pool 
of subjects beyond those who experienced a confirmed response from pembrolizumab as 
measured by RECIST 1.1.
A response of at least 6 months in duration based on 
Kaplan-Meier estimate was seen in 4 subjects (67% based on Kaplan-Meier estimation) who 
had a response as measured by RECIST 1.1.  The predefined efficacy objective (a 95% lower 
confidence limit of the observed ORR greater than 10%) was not met in the ASaT 
population, but was met in the FAS population. The median follow-up duration (defined as 
the time from randomization to the date of death, or database cutoff date if the subject was 
still alive) was 11.4 months.  The PFS rate in the ASaT population of urinary tract cancer 
subjects was 22.6% at 6 months and 12.9% at 12 months, and was similar to the FAS 
population. The median OS was 9.3 months.  The OS rate was 56.1% at 6 months and 42.1% 
at 12 months.
Overall, the number, type, and frequency of AEs and SAEs reported in this study, noting the 
limitation of the small sample size, were not indicative of any new safety concerns for 
pembrolizumab.  A total of 60.6% (20/33) of subjects experienced a drug-related AE and 
those most frequently reported (in greater than 10% of subjects) were fatigue (18.2%) and 
edema peripheral (12.1%). A total of 9 immune-mediated AEs of special interest (AEOSI)
were reported in 7 (21.2%) subjects.  Each AEOSI was reported in only one subject, except 
for myositis which was reported in 2 subjects.  Grade 3 AEOSI included myositis, colitis, 
rhabdomyolysis, rash pruritic, rash maculopapular, and stasis dermatitis.  Grade 2 AEOSI 
included myositis and uveitis.  The median time to onset for the first AEOSI was 44 days.  
The median episode duration was 27 days.  These findings did not result in any changes to 
the previously established safety profile of pembrolizumab.
KN045 (NCT02256436) is an ongoing randomized Phase 3 trial of pembrolizumab versus 
investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine in 
542 subjects with metastatic or locally advanced/unresectable urothelial cancer that has
recurred or progressed following platinum-based chemotherapy [15].
The primary trial
hypothesis is that pembrolizumab will prolong OS and PFS compared with paclitaxel,
docetaxel, or vinflunine.
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As of the data cutoff for the interim analysis, enrollment was complete with a total of 
542 subjects randomized and included in the ITT population by BICR (control: 272; 
pembrolizumab: 270). Subjects were treated with 200 mg of pembrolizumab every 3 weeks
(Q3W).  Overall, the 2 groups were well matched: histology was reported as pure transitional 
for 383 subjects (control: 197; pembrolizumab: 186) predominantly transitional for 
155 subjects (control: 73; pembrolizumab: 82), and “other” for 2 subjects in the 
pembrolizumab group.  The median age was 66 years (range 26 to 88); 55.5% of subjects had 
an ECOG PS of 1, 10% had received prior BCG therapy, and 87% had visceral disease at 
baseline.
The primary efficacy endpoints were OS and PFS. For the primary analysis of OS, all
subjects in the ITT population showed a statistically significant and clinically meaningful 
difference between the pembrolizumab and control treatment arms (the investigator’s choice 
of paclitaxel, docetaxel, or vinflunine), favoring pembrolizumab.  The HR for OS was 0.73
(95% CI: 0.59, 0.91), with a one-sided p-value of 0.0022, favoring pembrolizumab over the 
control. The median OS was 10.3 months in the pembrolizumab arm versus 7.4 months in 
the control arm.  The treatment effect was similar for each chemotherapy comparator.  The 
primary analysis of PFS among all subjects in the ITT population showed no statistically 
significant difference between the pembrolizumab and control treatment arms.  Median PFS 
was 2.1 months (95% CI: 2.0, 2.2) in the pembrolizumab arm versus 3.3 months (95% CI: 
2.3, 3.5) in the control arm (HR 95 [95% CI] = 0.98 [0.81, 1.19]; p = 0.416).  Consistent 
findings were shown in the CPS ≥10% and CPS ≥1% subpopulations for both OS and PFS.  
Overall, the efficacy data from KN045 demonstrate substantial benefit of pembrolizumab in 
subjects with urothelial carcinoma who have received platinum-containing chemotherapy, in 
the overall population, regardless of PD-L1 status.
Overall, pembrolizumab demonstrated a more favorable tolerability in comparison to control 
in the target population.  This was shown by a lower frequency of AEs, drug-related AEs, 
Grade 3 to 5 AEs, drug-related Grade 3 to 5 AEs, drug-related SAEs, and drug-related AEs 
leading to treatment discontinuation in the pembrolizumab arm in comparison to the control 
arm.  The most common drug-related adverse events (DRAEs) reported (>10% incidence) in 
the pembrolizumab compared with the control arm included fatigue (13.9% vs 27.8%), 
nausea (10.9% vs 24.3%), and pruritus (19.5% vs 2.7%).  Among the drug-related AEs 
observed in ≥10% of the subjects on pembrolizumab, with the exception of pruritus, all were 
reported in a lower or similar frequency among the subjects receiving pembrolizumab versus 
control.  Pruritus has been previously identified as an adverse drug reaction for 
pembrolizumab.  Adverse events of special interest (AEOSI) for this study were 
immune-mediated events and infusion-related reactions considered to be risks for 
pembrolizumab.  There were 45 (16.9%) subjects in the pembrolizumab arm with 1 or more 
AEOSIs.  In general, the frequency and severity of each AEOSI observed during the trial was 
similar to the previously described characterization of the safety profile of pembrolizumab.  
No indication-specific AEOSI was identified (new immune-mediated event causally 
associated with pembrolizumab).  In summary, the safety data from KN045 showed that 
pembrolizumab is well tolerated in the target population: pembrolizumab showed a more 
favorable tolerability in comparison to control, and no new safety risk was observed in 
association with pembrolizumab.
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KN052 (NCT02335424) is an ongoing open-label, Phase 2 trial of pembrolizumab for first-
line treatment in 374 subjects with advanced/unresectable (inoperable) or metastatic 
urothelial cancer who are not fit for cisplatin-based therapy. 
Subjects in KN052 are 
considered unfit for cisplatin if they meet at least 1 of the following criteria: a. ECOG PS of 
2 (the proportion of ECOG 2 subjects will be limited to approximately 50% of the total 
population); b. Creatinine clearance (CrCl) (calculated or measured) <60 mL/min, but 
≥30 mL/min (Note: Subjects with a CrCl [calculated or measured] <30 mL/min, or on 
dialysis are excluded from the trial); c. Common Terminology for Adverse Events
(CTCAE) v.4.0, Grade ≥2 audiometric hearing loss (25 decibels in 2 consecutive wave 
ranges); d. CTCAE v.4.0, Grade ≥2 peripheral neuropathy; or e. New York Heart 
Association Class III heart failure. The primary trial hypothesis was that pembrolizumab 
treatment would result in a clinically meaningful ORR in all participants and in participants 
with high CPS biomarker determination.  As of the data cutoff date, a total of 370 subjects 
with advanced/unresectable (inoperable) or metastatic urothelial cancer were enrolled and
treated with 200 mg of pembrolizumab every 3 weeks (Q3W). Median age was 74 years; 
32.4% of subjects had an ECOG PS of 2, 49.2% had renal dysfunction, 85.1% had visceral 
disease, 21.1% had liver metastasis, 81.9% were chemotherapy naïve, 90.3% had not 
received prior adjuvant or neoadjuvant platinum-based chemotherapy, and 85.4% had not 
received prior BCG therapy.
At the time of data cutoff, treatment with pembrolizumab resulted in a clinically meaningful 
ORR of 24.1% (95% CI: 19.8, 28.7) in all subjects and 27.0% (95% CI: 22.1, 32.4) among 
subjects who had the opportunity for at least 2 postbaseline imaging assessments. The CPS 
of ≥10% was found to be the optimal PD-L1 strongly positive or high cut point.  The ORR 
for subjects with CPS ≥10% in the discovery set (first 100 subjects) was 36.7% (95% CI: 
19.9, 56.1).  This was confirmed in the validation set where ORR for CPS ≥10% was 38.8% 
(95% CI: 28.1, 50.3).  Pembrolizumab treatment effect was observed in all subgroups 
including the elderly, those with poor ECOG PS, and those with CPS <1% tumors.  
Radiographic responses typically occurred within 2 months and were durable.  Most 
responses were ongoing at the time of data cutoff.  The median DOR had not been reached at 
the time of data cutoff, but the lower bound of the 95% confidence interval was found to be 
8.7 months.  For the longest responder, DOR was 13.6 months and ongoing.  The estimated 
DOR rate at 6 months was 78% (Kaplan-Meier estimate).  The DOR with pembrolizumab 
compares favorably to conventional chemotherapy where responses are typically short-lived.
Overall the frequency of AEs, SAEs, drug-related AEs, and fatal AEs were either consistent 
with previous experience with pembrolizumab or considered related to the underlying 
medical condition (advanced/unresectable or metastatic urothelial carcinoma) of the all 
patients as treated population.  The most common DRAEs reported (>10% incidence) were 
fatigue (16.8%) and pruritus (14.1%).  In general, the frequencies and severity of each of the 
AEOSIs observed during the trial were similar to the previously described characterization of 
the safety profile of pembrolizumab.  No indication specific AEOSI was identified (new 
immune-mediated event causally associated with pembrolizumab).  One subject had an 
AEOSI of severe myositis with a fatal outcome.  Pembrolizumab was well tolerated in the 
target population as shown by the low frequency of drug-related AEs leading to treatment 
discontinuation (5.1%), and no new safety risk was observed in association with 
pembrolizumab.
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KN057 (NCT02625961) is an ongoing open-label, Phase 2 trial of pembrolizumab for the
treatment of approximately 260 subjects with high-risk nonmuscle invasive bladder cancer 
(NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) vaccine. 
The primary 
hypotheses of this trial are that treatment with pembrolizumab will result in CR for subjects 
with carcinoma in situ (Cis) at baseline - NMIBC (Cohort A) - and will result in disease-free 
survival for 12 months in subjects with focal tumors that are resected, but are at high risk for 
recurrence without adjunctive therapy (Cohort B).
Refer to Table 2 for a list of the Sponsor’s ongoing trials in bladder cancer.
Table 2
Key Features of Ongoing KEYNOTE Bladder Trials
Trial Identifier
Type of Trial
Design Features
Trial Population
Dosage,
Regimen
Primary Efficacy 
Endpoint(s)
KN012
Ongoing
Multi-cohort, 
open-label,
Phase 1b 
basket 
trial
33 subjects enrolled in 
Cohort C (enrollment 
complete); all subjects 
with 
PD-L1 
positive 
tumors and recurrent or 
metastatic urinary tract 
cancer.
Pembrolizumab 
10 mg/kg Q2W
Safety; 
ORR 
(RECIST 1.1)
KN045 
Ongoing
Randomized,
controlled, open-
label Phase 3 trial
542 subjects randomized 
(enrollment 
complete); 
all subjects
with 2L+ 
urothelial cancer; control 
is 
physician’s 
choice 
chemotherapy 
(docetaxel, 
paclitaxel, 
vinflunine).
Pembrolizumab 
200 mg Q3W
OS; PFS 
KN052 
Ongoing
Single arm, open-
label Phase 2 trial
370
subjects enrolled;
subjects 
are 
first-line
advanced / unresectable 
(inoperable) 
or 
metastatic
urothelial 
bladder 
subjects, 
cisplatin -ineligible; up 
to 150 subjects will 
constitute a training set 
for 
CPS 
strongly 
positive
cutpoint 
determination.
Pembrolizumab 
200 mg Q3W
ORR
KN057 
Ongoing
Single arm, two-
cohort Phase 2
trial
Up to 260 subjects with 
NMIBC unresponsive to 
BCG will be treated in 2 
cohorts: Cohort A: Cis ± 
Ta/T1; Cohort B: HG Ta
and/or T1.
Pembrolizumab 
200 mg Q3W
CR rate in high-
risk 
nonmuscle 
invasive 
bladder 
cancer (Cohort A);
DFS (Cohort B)
Abbreviations: 2L=second-line; BCG=Bacillus Calmette-Guerin  tuberculosis vaccine; Cis=carcinoma in situ;  
CPS=combined positive score; CR=complete response; DFS=disease-free survival; HG=High Grade; KN=Keynote; 
NMIBC=nonmuscle invasive bladder cancer;  ORR=objective response rate; PD-L1=programmed death-ligand; 
Q2W=every 2 weeks; Q3W=every 3 weeks; RECIST=Response Evaluation Criteria in Solid Tumors; Ta and T1=WHO 
2004 pathologic classifications of NMIBC;  WHO=World Health Organization.
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Rationale
Rationale for the Trial and Selected Subject Population
Urothelial (transitional cell) carcinoma describes a range of tumors that arise from the 
urothelial endothelium, which lines the bladder, renal pelvis, ureter, and urethra.
The 
worldwide incidence of bladder cancer exceeds 300,000 cases annually, ranking it as the 
seventh most common cancer worldwide [16].
Urothelial carcinoma (as distinct from 
squamous cell or adenocarcinoma) is the predominant histologic type of bladder cancer in the 
United States (US) and Western Europe, where it accounts for approximately 90% of bladder 
cancers [17]. In other areas of the world, nonurothelial histologies are more frequent.
Bladder cancer is more common in men than women; the global incidence of bladder cancer 
among men and women is 37 and 9 per 100,000 person-years, respectively.  Incidence in 
white, black, Hispanic, and Asian men is 40, 21, 20, and 16 per 100,000 person-years,
respectively. Bladder cancer becomes more common with age, with the highest incidence 
rates reported in people aged 75 to 84 years [17].
Along with age, smoking, and occupational exposure to carcinogens, certain medical 
treatments (including pelvic radiation and cyclophosphamide), and genetic predisposition are 
risk factors for bladder cancer [18] [19] [20] [21].
Notably, bladder cancer is associated with the highest cost per patient from diagnosis to 
death of all malignancies, largely because of the frequent procedures required for disease 
monitoring and treatment [22].
Bladder cancer can be categorized as NMIBC, which represents approximately 75% of 
primary diagnoses and is characterized by frequent recurrence and high morbidity, but a low 
risk of mortality, or muscle-invasive bladder cancer, which represents the other 25% of 
primary diagnoses and is potentially lethal in approximately 50% of individuals [17] and 
includes anatomically the bladder vesicle itself as well as the upper urinary tract and the 
accompanying lymph node compartments.
Patients with advanced or metastatic urothelial carcinoma present unique challenges. These 
are clinical scenarios in which patients present with locally advanced disease that cannot be 
treated with definitive intent or as metastatic disease from the beginning, or with recurrent 
disease that is inoperable or with metastatic disease that has progressed following initial 
treatment with definitive intent. Although a variety of chemotherapeutic agents are used in 
this setting and initially are associated with response, the prognosis for patients is poor –
median survival from studies in these setting ranges from 8 to 15 months, and the majority of 
patients die from complications related to disease [23] [24]. The advanced/metastatic setting 
represents a clinical area in need of novel therapeutic approaches such as with checkpoint 
inhibitor therapy with or without chemotherapy [17].
Cisplatin-based combination chemotherapy is standard first-line treatment for patients with 
advanced bladder cancer based on randomized trials [23] [25] [26] [27] [28]. The median 
survival with these regimens is 13 to 15 months, and 5% to 15% of patients attain long-term 
survival. However, cisplatin ineligibility is common [29] [30].
Carboplatin is often substituted for cisplatin in such patients, but it is associated with inferior 
outcomes, as shown in a meta-analysis of randomized Phase 2 trials [31]. Galsky et al 
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conducted a meta-analysis of published trials in patients with metastatic urothelial carcinoma 
to assess clinical outcomes with cisplatin- versus carboplatin-based regimens. 
The 
meta-analysis evaluated 4 trials (one Phase 3 and three Phase 2 trials) with a total of 
286 patients; results showed that there was a significantly higher likelihood of achieving an 
objective response, and in particular, a complete response, with cisplatin-based therapy.  
These results supported the notion that cisplatin-based regimens “are favored for the first-line 
treatment of metastatic urothelial carcinoma (UC)” [29].
Established guidelines (i.e., National Comprehensive Cancer Network [NCCN] and 
European Society of Medical Oncology [ESMO]) include the following considerations in 
determining if a subject is clinically ineligible for cisplatin: CTCAE v.4.0, Grade ≥2 
peripheral neuropathy; CTCAE v.4.0, Grade ≥2 audiometric hearing loss (25 decibels in 
2 consecutive wave ranges); CrCl (calculated or measured) <60 mL/min, but ≥30 mL/min 
(note: Subjects with a CrCl [calculated or measured] <30 mL/min are excluded from this
trial); New York Heart Association Class III heart failure; and ECOG PS of 2.
A 
Phase 3
trial 
comparing 
gemcitabine/carboplatin 
(GC) 
with 
methotrexate/
carboplatin/vinblastine (MCAVI) in cisplatin-ineligible patients showed a median survival of 
only 8 to 9 months with both regimens [24].  Notably, those with both poor renal function 
and poor PS fared especially poorly with combination chemotherapy in this trial.  Thus, there 
remains a significant unmet medical need for well tolerated active therapies in this 
population.  According to the NCCN Guidelines, clinical trials of potentially less toxic 
therapies are recommended for this population of patients.
A Phase 1 combination of 
nivolumab plus platinum doublets (including pembrolizumab-cisplatin) showed tolerability 
in non–small cell lung cancer (NSCLC) [32] [33].  However, small numbers limit the 
efficacy evaluation.
Papadimitrakopoulou, et al reported data on the combination of 
pembrolizumab 
and 
chemotherapy 
(carboplatin/paclitaxel 
[Cohort 
A] 
or 
carboplatin/pemetrexed [Cohort C]) at the American Society of Clinical Oncology [34], with 
results from 49 subjects. The treatment-related Grade 3 to 4 AE rate was 32% to 38%. 
Potentially immune-related AEs were reported in 2 patients (8%) in Cohort A (Grade 3 rash 
and Grade 2 colitis), and 4 subjects
(17%) in Cohort C (Grade 3 colitis, Grade 2 
hypothyroidism, and Grade 1 colitis and hyperthyroidism).
The preliminary response rate 
was 28% for the combination with carboplatin/paclitaxel and 58% for the combination with 
carboplatin/pemetrexed. Thus, preliminary evidence suggests that the combination of an 
immune-checkpoint inhibitor with chemotherapy would be expected to be safe and tolerable 
and to have the potential for enhanced efficacy.
A Phase 2 combination of ipilimumab with platinum doublet (carboplatin-paclitaxel) showed 
tolerability in NSCLC and improved immune-related PFS when given in a phased approach 
[35]. A Phase 2 combination of ipilimumab with gemcitabine-cisplatin in bladder cancer has 
shown in pharmacodynamic (PD)
data that the addition of ipilimumab leads to 
immunostimulatory effects in circulating cells, suggesting that chemotherapy may not 
necessarily abrogate immune effects of checkpoint blockade [31].
Numerous ongoing
investigator-sponsored studies are investigating the safety and efficacy signal of 
pembrolizumab with chemotherapy in a variety of malignancies.
Pembrolizumab monotherapy was associated with an ORR of 27% in patients with 
chemotherapy-refractory metastatic PD-L1 positive urothelial carcinoma [36].
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Sixty-four percent of subjects in this cohort experienced reductions in the size of their 
tumors, and responses were durable. Other compounds have shown similar activity [37].  
PD-L1 expression in the tumor microenvironment was associated with higher response rates.
For this reason, the primary hypotheses have been designed to investigate efficacy both for 
“all comers” and for subjects with tumors with CPS ≥10% PD-L1 expression.
The prediction of response to anti-PD-1 therapy is based on the results from a trial by 
Topalian et al [38] who examined PD-LI expression in the archival specimens of 42 of the 
296 subjects treated with the PD-1 inhibitor nivolumab. Of those 17 subjects whose tumor 
cells did not stain positive for PD-L1 using a 5% threshold of tumor cell surface expression, 
no objective response by RECIST 1.1 was observed.  But among the 25 subjects whose 
tumor cells were considered positive for PD-L1, 9 responded (36%).  Therefore, it is 
hypothesized that PD-L1 expression may be a predictive biomarker of anti-PD-1 activity and 
subjects will be allocated by PD-L1 expression in this trial.
The present trial has been designed to confirm and elaborate on findings from prior and 
ongoing pembrolizumab trials in advanced urothelial carcinoma (KN012, KN045, and 
KN052) by investigating the use of pembrolizumab in an earlier disease setting as well as the 
potential for additive or synergistic therapeutic advantage associated with combining 
pembrolizumab with chemotherapy.  The primary trial hypothesis is that combo is superior to 
chemo only with respect to PFS using RECIST 1.1 as assessed by BICR in all subjects (both 
PD-L1 CPS ≥10% and CPS <10%).”
Rationale for Dose Selection/Regimen/Modification
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of 
data generated in the KEYTRUDA development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab across all indications and regardless of tumor type. As outlined 
below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W.

Clinical data showing meaningful improvement in benefit-risk including OS at 
200 mg Q3W across multiple indications.

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched and all comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W vs 10 mg/kg Q2W 
(KN001 B2, KN001 D, KN002, KN010 and KN021), and 3 studies compared 10 mg/kg 
Q3W vs 10 mg/kg Q2W (KN001 B3, KN001 F2, and KN006). All of these studies showed
flat dose- and exposure-response relationships across the doses studied representing an 
approximate 5 to 7.5 fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W 
provided similar responses to the highest doses studied. 
Subsequently, flat 
dose-/exposure-response relationships were also observed in other tumor types including 
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head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These 
findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively showed
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. 
Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. 
This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed-dosing
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed-dose and 2 mg/kg Q3W dose.
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across pembrolizumab protocols.
Rationale for the Use of Comparators
Cisplatin-based combination chemotherapy with gemcitabine is standard first-line treatment 
in the US (NCCN Guidelines) and Europe (ESMO guidelines for patients with advanced 
bladder cancer based on randomized trials) [17] [39] [40] [41] [23] [25] [26] [27] [28]. The 
median survival with these regimens is 13 to 15 months, but only 5% to 15% of patients 
attain long-term survival [29] [42] [30].
A Phase 3 trial comparing carboplatin plus gemcitabine with MCAVI in cisplatin-ineligible 
patients showed a median survival of only 8 to 9 months with both regimens. [24]. 
Gemcitabine
with 
cisplatin 
provides 
a 
similar 
long-term 
PFS
advantage 
to 
methotrexate/vinblastine/doxorubicin/cisplatin with a better safety profile and tolerability 
[23] [28].
Approximately 40% of patients with urothelial carcinoma who are usually elderly and 
suffering from serious comorbid medical conditions are not fit to be treated with 
cisplatin-based regimens [43] [30] [42].  Multiple trials have been performed in the “unfit” 
population, albeit using heterogeneous eligibility criteria to define cisplatin-ineligible.  While 
several regimens have been explored in this population (e.g., gemcitabine/oxaliplatin,
gemcitabine/paclitaxel, 
gemcitabine/vinorelbine, 
gemcitabine
/epirubicin), 
the 
most 
commonly explored has been the doublet of carboplatin plus gemcitabine, evaluated in at 
least 3 Phase 2 trials and one Phase 2/3 trial and recommended in the NCCN Guidelines [17] 
[24] [44] [40] [45]. Thus, for this clinical trial, subjects treated with SOC chemotherapy will 
be treated either with cisplatin and gemcitabine or carboplatin and gemcitabine.
A number of lines of evidence support the rationale to add pembrolizumab therapy to these 
chemotherapies.  First, gemcitabine has been shown to lead to immunogenic cell death. In an 
MC38 model, gemcitabine may have additive/synergistic effects with muDX400 (murine 
anti-PD-1) [39].
There is no antagonistic effect of GC in combination with concurrent 
pembrolizumab.
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Phase 1 combinations of an immune-checkpoint inhibitor therapy with platinum-containing 
doublet chemotherapy have been reported to show tolerability in NSCLC [34]. However, 
small numbers limit the efficacy evaluation. 
A Phase 2 checkpoint inhibitor-platinum 
combination has been reported to have shown tolerability and improved immune-related PFS
in NSCLC [35].  Because of these encouraging early findings and because not all patients 
derive clinical benefit with checkpoint inhibitor monotherapy or with chemotherapy alone, 
KN361 has been designed to include a combination arm, pembrolizumab with chemotherapy.
Additionally, 
KN021 
(NCT02039674), 
KN048 
(NCT02358031), 
and 
KN059 
(NCT02335411) have been investigating the addition of pembrolizumab to chemotherapy in 
lung cancer, head and neck cancer, and gastric cancer, respectively, since February 2014.  In 
KN021, these combinations included cisplatin, carboplatin, and gemcitabine, each combined 
with pembrolizumab. KN048 and KN059 have been designed to investigate pembrolizumab 
therapy with or without cisplatin/carboplatin and 5-flourouracil (5-FU), and pembrolizumab 
with or without cisplatin and 5-FU.
The doses and schedules of chemotherapy treatment, with and without pembrolizumab, have 
been based on these trials and will be as follows: cisplatin 70 mg/m2 or carboplatin AUC 5 
on Day 1; gemcitabine on Days 1 and 8 of a 3-week cycle.
Rationale for Endpoints
Efficacy Endpoints
4.2.3.1.1 Primary Endpoints
Progression-free Survival
Given the current paradigm changes, in the treatment continuum of metastatic bladder cancer 
an appropriate primary endpoint for this Phase III pivotal study in the form of PFS was 
chosen.
RECIST 1.1, as assessed by BICR, will be used to determine the dates of progression, as this 
methodology is accepted by regulatory authorities. 
The BICR will be blinded to the 
treatment assignment of the subjects to minimize bias in the response assessments.
Progression-free survival is an acceptable measure of clinical benefit for a late stage trial that 
demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of the 
effect is large and the therapy has an acceptable risk/benefit profile.  The use of BICR and 
RECIST 1.1 to assess PFS is typically considered acceptable by regulatory authorities.  
Images will be read by a central imaging vendor blinded to treatment assignment to minimize 
bias in the response assessments.  In addition, the final determination of radiologic 
progression will be based on the central assessment of progression, rather than a local site 
investigator/radiology assessment.  Real time determination of radiologic progression as 
determined by central review will be communicated to the site.
In addition, final determination of radiologic progressive disease (PD) will be based on the 
BICR assessment of progression, rather than local site investigator/radiology assessment.  
Expedited assessment by BICR in instances of suspected radiologic progression identified at 
the site (verification of PD) will be communicated to the site trial team.
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Overall Survival
Overall survival is defined as the time from randomization until death from any cause. 
Survival is considered the most reliable cancer endpoint, and when studies can be conducted 
to adequately assess survival, it is usually the preferred endpoint [46].
(Food and Drug 
Administration [FDA] Guidance for Industry: Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics, 2007, page 5.)
4.2.3.1.2 Secondary Endpoints
The secondary efficacy endpoints of this trial are to evaluate DOR, DCR, and ORR per 
RECIST 1.1 assessed by BICR.
Exploratory Endpoints
4.2.3.2.1 Patient-reported Outcomes
The EORTC QLQ-C30 and EuroQoL-5D (EQ-5D) PROs are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability.
EORTC QLQ-C30
The EORTC QLQ-C30 is the most widely used cancer-specific health-related quality of life
(QoL) instrument, which contains 30 items and measures 5 functional dimensions (physical, 
role, emotional, cognitive and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 
6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and QoL scale [47].  The EORTC QLQ-C30 is a 
psychometrically and clinically validated instrument appropriate for assessing QoL in 
oncology trials [47].
eEuroQoL EQ-5D
The eEuroQol-5D (eEQ-5D) is a standardized instrument for use as a measure of health 
outcome and will provide data to develop health utilities for use in economic analyses [48]. 
The 5 health state dimensions in the EQ-5D include the following:  mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression [49].  Each dimension has 3 levels:  no 
problems, some problems, extreme problems. The eEQ-5D also includes a graded (0 to 100) 
vertical visual analog scale on which the patient rates his or her general state of health at the 
time of the assessment.  This instrument has been used extensively in cancer studies and 
published results from these studies support its validity and reliability [50].
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with recurrent/progressive urothelial cancer.  The primary safety 
analysis will be based on subjects who experienced toxicities as defined by CTCAE Version 
4.0 criteria.  Safety will be assessed by quantifying the toxicities and grades experienced by 
subjects who have received pembrolizumab, including SAEs and ECIs.  The attribution to 
drug, time of onset, duration of the event, its resolution, and any concomitant medications 
administered will be recorded.  Adverse events will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes.  The mandatory Safety Follow-up Visit 
will be conducted approximately 30 days after the last dose of trial treatment or before the 
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initiation of a new antineoplastic treatment, whichever comes first.  All AEs that occur prior 
to the Safety Follow-up Visit should be recorded.  Subjects with an AE of Grade >1 will be 
followed until the resolution of the AE to Grade 0 to 1 or until the beginning of a new 
anti-neoplastic therapy, whichever occurs first.  Serious AEs will be collected for 90 days 
after the trial treatment or 30 days after the end of treatment, if the subject initiates new 
anticancer therapy, whichever is earlier.
Planned Exploratory Biomarker Research
Introduction
Cancer immunotherapies represent an important and novel class of antitumor agents.  
However, the mechanism of action of these exciting new therapies is not completely 
understood, and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. 
Thus, to aid future patients, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy as well as determinants of 
AEs in the course of our clinical trials.
These efforts will identify novel predictive/
pharmacodynamic biomarkers and generate information that will better guide single agent 
and combination therapy with immuno-oncology drugs. To identify novel biomarkers, we 
will collect biospecimens (blood components, tumor material, etc.) to support analyses of 
cellular components (e.g., protein, deoxyribonucleic acid [DNA], ribonucleic acid [RNA], 
metabolites) and other circulating molecules. Investigations may include, but are not limited 
to:
Germline (Blood) Genetic Analyses (e.g., single-nucleotide polymorphism [SNP] Analyses, 
Whole Exome Sequencing, and Whole Genome Sequencing)
This research will evaluate whether genetic variation within a clinical trial population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome to interpret tumor-specific DNA mutations. Finally, microsatellite instability (MSI) 
may be evaluated, as this is an important biomarker for some cancers (e.g., colorectal 
cancer).
Genetic (DNA) Analyses from Tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (i.e., mutations, 
methylation status, MSI etc.).  Key molecular changes of interest to immune-oncology drug 
development include (for example) the mutational burden of tumors and the clonality of 
T-cells in the tumor microenvironment.  Increased mutational burden (sometimes referred to 
as a “hyper-mutated”
state) may generate neo-antigen presentation in the tumor 
microenvironment. To conduct this type of research, it is important to identify tumor-
specific mutations that occur across all genes in the tumor genome. Thus, genome-wide 
approaches may be used for this effort. Note that to understand tumor-specific mutations; it 
is necessary to compare the tumor genome with the germline genome. 
Microsatellite 
instability may also be evaluated, as this is an important biomarker for some cancers (e.g., 
colorectal cancer).
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Tumor and Blood RNA Analyses
Both genome-wide and targeted messenger RNA expression profiling and sequencing in 
tumor tissue and in blood may be performed to define gene signatures that correlate to 
clinical 
response 
to 
treatment 
with 
pembrolizumab 
or 
other 
immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype.
Specific immune-related gene sets (such as those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system may also be evaluated (e.g., interleukin-10 [IL-10]).  
MicroRNA profiling may also be pursued.
Proteomics and Immunohistochemistry Using Blood or Tumor 
Tumor and blood samples from this trial may undergo proteomic analyses (e.g., PD-L1 IHC).  
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicate that 
this association may also be true in additional cancer types (i.e., triple-negative breast, head 
and neck, and gastric). Additional tumor or blood-derived proteins may also correlate with 
response to pembrolizumab. Therefore, tumor tissue may be subjected to proteomic analyses 
using a variety of platforms that could include, but are not limited to, immunoassays and
liquid chromatography/mass spectrometry. 
This approach could identify novel protein 
biomarkers that could aid in patient selection for pembrolizumab therapy.
Other Blood-derived Biomarkers: 
In addition to expression on the tumor tissue, PD-L1 and other tumor-derived proteins can be 
shed from tumors and released into the blood.  Assays such as enzyme-linked 
immunosorbent assay measure such proteins in serum. Correlation of expression with 
response to pembrolizumab therapy may identify new approaches for predictive biomarkers 
in blood, representing a major advance from today’s reliance on assessing tumor biomarkers.  
This research would serve to develop such assays for future clinical use.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research 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. 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 Future Biomedical Research are presented in Section 12.2 - Collection and Management 
of Specimens for Future Biomedical Research.
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Benefit/Risk
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Several lines of evidence suggest that immune-checkpoint inhibitor therapy can be highly 
active as monotherapy in advanced urothelial cancer. 
For example, pembrolizumab 
monotherapy was associated with an ORR of 27% in patients with chemotherapy-refractory 
metastatic PD-L1 positive urothelial carcinoma [36]. Sixty-four percent of patients in this 
cohort experienced reductions in the size of their tumors. Responses were durable (range 8 
to 64 weeks), and 19% of patients remained on pembrolizumab treatment after 1 year of 
initiating treatment [36]. Recently published data from atezolizumab, a PD-L1 antagonist, 
has shown similar activity [51].
Importantly, PD-L1 expression in the tumor microenvironment was associated with higher 
response rates. For this reason, this study will also investigate efficacy for both, all comers 
as well as for subjects with PD-L1 positive tumors.
In KN361, the Sponsor considers that superior efficacy associated with one or both 
experimental treatment arms, pembrolizumab and/or pembrolizumab with chemotherapy, in 
terms of either a PFS or OS advantage, would constitute a seminal improvement of treatment 
options for subjects with advanced or metastatic urothelial cancer.
The chemotherapy arm is the current SOC, with well-characterized risks listed in the 
labeling.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB, approved labeling, and informed consent 
documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects with advanced/unresectable (inoperable) or metastatic urothelial 
carcinoma of the renal pelvis, ureter [upper urinary tract], bladder, or urethra at least 18 years
old on the day of signing the informed consent will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have a histologically or cytologically confirmed diagnosis of advanced/unresectable 
(inoperable) or metastatic urothelial carcinoma of the renal pelvis, ureter [upper 
urinary tract], bladder, or urethra. 
Both transitional cell and mixed 
transitional/non-transitional cell histologies are allowed, but transitional cell 
carcinoma must be the predominant histology.
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2. Have measurable disease based on RECIST 1.1 as determined by the local site 
investigator/radiology assessment. Target lesions situated in a previously irradiated 
area are considered measurable if progression has been demonstrated in such lesions.
3. Voluntarily agree to participate by providing 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.
4. Be ≥18 years of age on the day of signing informed consent.
5. Have received no prior systemic chemotherapy for advanced or metastatic urothelial 
carcinoma, with the following exceptions:
a.
Neoadjuvant platinum-based chemotherapy with recurrence >12 months from 
completion of therapy is permitted.
b. Adjuvant platinum-based chemotherapy following radical cystectomy with 
recurrence >12 months from completion of therapy is permitted.
Note: Low-dose chemotherapy (e.g., low-dose cisplatin, cisplatin plus 5-FU, 
mitomycin plus 5-FU, or cisplatin plus paclitaxel) given concurrently with radiation 
to the primary tumor site is not considered systemic therapy. In the clinical setting, 
chemotherapy is given with the sole purpose of sensitizing the tumor to local 
radiation. It is not administered at doses with any systemic efficacy. Surgery is not 
considered first-line therapy following diagnosis of advanced/metastatic disease.
6. Have provided tissue for biomarker analysis from an archival tissue sample or newly 
obtained core or excisional biopsy of a tumor lesion not previously irradiated from a 
muscle-invasive urothelial carcinoma or a metastatic biopsy, originating from the 
original tumor.  A newly obtained biopsy is strongly preferred, but not required if 
archival tissue is evaluable.  If submitting unstained cut slides, freshly cut slides 
should be submitted to the testing laboratory within 14 days from when the slides are 
cut.  Refer to Section 7.1.2.12 in the protocol for an explanation.  PD-L1 status 
(CPS ≥10% or CPS <10%) must be determined by the central laboratory during the 
screening period prior to enrollment.
7. Have an ECOG PS of 0, 1, or 2.
8. Demonstrate adequate organ function as defined in Table 3.
(All screening labs
should be performed within 2 weeks prior to treatment initiation.) 
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Table 3
Adequate Organ Function
System
Laboratory Value
Hematological
ANC
≥1,500/mcL
Platelets
≥100,000/mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without a red blood cell 
transfusion within 2 weeks of the screening test
Renal – refer to Appendix 12.5 for country-specific requirements
Serum creatinine
OR calculated creatinine clearance a
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 × ULN OR
≥30 mL/min for subjects with creatinine levels 
>1.5 × institutional ULN
Hepatic
Serum total bilirubin
≤1.5 × ULN OR
Direct bilirubin ≤ULN for subjects with total bilirubin 
levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN OR
≤5 × ULN for subjects with active liver metastases
Alkaline Phosphatase
If >2.5 × ULN, then liver fraction should be 
≤2.5 × ULN 
Coagulation
INR PT
aPTT
≤1.5 × ULN 
This can vary if subject is receiving anticoagulant 
therapy, as long as PT or aPTT remains within 
therapeutic range of the anticoagulant’s intended use
Abbreviations: ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial 
thromboplastin time; AST=aspartate aminotransferase; CrCl=creatinine clearance; GFR=glomerular filtration 
rate; INR=International Normalized Ratio; mcL=microliters; PT=prothrombin time; SGOT=serum glutamic 
oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of normal.
a Creatinine clearance should be calculated per institutional standard.
9. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of trial medication.  If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
10. Female subjects of childbearing potential must be willing to use an adequate method 
of contraception as outlined in Section 5.7.2 – Contraception, for the course of the 
trial through 120 days after the last dose of pembrolizumab or 180 days after 
chemotherapy treatment.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
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11. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.7.2 – Contraception, starting with the first dose 
of trial therapy through 120 days after the last dose of pembrolizumab or 180 days 
after chemotherapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has disease that is suitable for local therapy administered with curative intent. An 
example of local therapy with curative intent is treatment with chemotherapy and 
radiation for Stage 3 disease. A subject with nonurothelial carcinoma of the urinary 
tract is also ineligible.
2. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigation device 
within 4 weeks of the first dose of treatment.
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to randomization.
4. Has an active autoimmune disease that has required systemic treatment in the past 
2 years 
(i.e., 
with 
use 
of 
disease-modifying 
agents, 
corticosteroids,
or 
immunosuppressive drugs).  Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.
a) Brief (<7 days) use of systemic corticosteroids is allowed when use is considered 
SOC.
b) Subjects with vitiligo, type I diabetes mellitus, hypothyroidism, or resolved 
childhood asthma/atopy would be an exception to this rule.
c) Subjects who require intermittent use of bronchodilators, inhaled steroids, or local 
steroid injections would not be excluded from the trial.
d) Subjects with hypothyroidism stable on hormone replacement or Sjøgren’s 
syndrome will not be excluded from the trial.
e) If a subject is on a stable dose of steroids for central nervous system (CNS)
metastases at screening, the subject will need to stop steroids 7 days prior to first 
dose in order to qualify for the trial.
5. Has had a prior anticancer mAb for direct antineoplastic treatment within 4 weeks 
prior to the first dose of trial treatment (6 weeks for nitrosoureas or mitomycin C) or 
who has not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to mAbs 
administered more than 4 weeks earlier. Subjects previously treated with a mAb will 
be eligible to participate after a 28-day washout period.
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6. Has not recovered (i.e., AE ≤Grade 1 or at baseline) from AEs due to a previously 
administered agent.
a) Subjects with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this
criterion and may qualify for the trial.
b) If subjects received major surgery they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting trial therapy.
7. Has a known additional malignancy that is progressing or requires active treatment
within the past 5 years.
a) Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer.
b) A history of prostate cancer that was identified incidentally following 
cystoprostatectomy for bladder cancer is acceptable, provided that the following 
criteria are met: Stage T2N0M0 or lower; Gleason score ≤6; prostate-specific 
antigen (PSA) undetectable.
8. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis.
9. Has a known history of active tuberculosis (TB) (Bacillus tuberculosis).
10. Has an active infection requiring systemic therapy.
11. Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema, 
hypotension, bronchospasm, angioedema or anaphylaxis) to pembrolizumab, 
gemcitabine, carboplatin, or cisplatin or their analogs, and/or to any of their 
excipients.
12. 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.
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
At the time of signing informed 
consent is a known regular user (including “recreational use”) of any illicit drug(s) or 
had a recent history (within the last year) of drug or alcohol abuse.
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of pembrolizumab or 180 days after the last dose of chemotherapy 
treatment.
15. Has received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another coinhibitory T-cell receptor (e.g., CTLA-4, OX-40, 
CD137).
16. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
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17. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
18. Has received a live virus vaccine within 30 days of planned start of trial therapy.
19. Has known active CNS metastases and/or carcinomatous meningitis.  Subjects with 
previously treated brain metastases may participate provided they are radiologically 
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically 
stable and without requirement of steroid treatment for at least 14 days prior to first 
dose of trial treatment.
20. Has symptomatic ascites or pleural effusion; a subject who is clinically stable 
following treatment for these conditions is eligible.
21. Has had a prior allogeneic stem cell or bone marrow transplant.
Trial Treatment
The treatments to be used in this trial are outlined below in Table 4. 
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Table 4
Trial Treatments
Drug
Dose/ Potency
Cycle 
Length
Route of 
Administration
Regimen
Use
Pembrolizumab Regimens:
Pembrolizu-
mab 
(MK-3475)
200 mg
Q3W
IV infusion
Day 1 of 
each 3-
week cycle
Pembro 
Monotherapy: 
Experimental 
regimen
Pembro + 
Chemotherapy: 
Experimental 
regimen
Chemotherapy Regimens:
Gemcitabine
1000 mg/m2
Q3W
IV infusion
Day 1 and 
8 of each 3-
week cycle
Pembro + 
Chemotherapy: 
Experimental 
regimen 
Chemotherapy 
alone: 
Comparator 
PLUS
Cisplatin
70 mg/m2
Q3W
IV infusion
Day 1 (or 
Day 2)a of 
each 3-
week cycle
Pembro + 
Chemotherapy: 
Experimental 
regimen
Chemotherapy
alone: 
Comparator
OR
Carboplatin 
(to be used 
only in 
subjects who 
are ineligible 
for cisplatin)
AUC 5b
(or AUC 4.5)b 
Q3W
IV infusion
Day 1 (or 
Day 2)a of 
each 3-
week cycle
Pembro + 
Chemotherapy: 
Experimental 
regimen
Chemotherapy
alone: 
Comparator
Abbreviations: AUC=area under the curve; IV=intravenous; Q3W=every 3 weeks. 
a Day 1 is the preferred day of dosing; however, treatment may be given on Day 2 if required per local 
guidelines.
b AUC 5 is preferred dose; however, AUC 4.5 is acceptable if required per local guidelines.
Note: A subject can switch from cisplatin to carboplatin during the course of the trial if required by clinical 
factors such as impairment of renal function. 
A maximum of 6 cycles of chemotherapy should be 
administered.
Trial Treatment should begin within 3 days of randomization.
All supplies indicated in Table 4 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
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For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
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
Dose Selection (Preparation)
Dose selection rationale has been provided in Section 4.2.2 – Rationale for Dose 
Selection/Regimen/Modification. 
Details 
on 
preparation 
and
administration 
of 
pembrolizumab are provided in the Pharmacy Manual.
Carboplatin will be prepared and administered per local guidelines and practices.
AUC 5 (Using Calvert formula).  Carboplatin dose not to exceed 750 mg for AUC 5 and 
675 mg for AUC 4.5
Calvert Formula:
Total Dose (mg) = (target AUC) × (CrCl + 25)
The estimated GFR used in the Calvert formula should not exceed 125 mL/min
Maximum carboplatin dose (mg) = 
Target AUC 5 (mg∙min/mL) × (125 + 25) = 5 × 150 mL/min = 750 mg
Target AUC 4.5 (mg∙min/mL) × (125 + 25) = 4.5 × 150 mL/min = 675 mg
Cisplatin will be prepared and administered per local guidelines and practices.
Gemcitabine will be prepared and administered per local guidelines and practices.
Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
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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 monotherapy, coformulations, or IO combinations are provided in Table 5.
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1-2 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
Recurrent Grade 2 
or Grade 3 or 4 
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.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring 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
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
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 
discontinue a
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 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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
Myocarditis
Grade 1 
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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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 6.
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE 
Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption 
not 
indicated; 
intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the 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 pembrolizumab
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 
participant's study record.
5.2.1.2.2 Dose Modifications for Cisplatin or Carboplatin
Dose modifications for cisplatin or carboplatin will be implemented according to local 
guidelines and practices.
5.2.1.2.3 Dose Modifications for Gemcitabine
Dose modifications for gemcitabine will be implemented according to local guidelines and 
practices.
5.2.1.2.4 Dose Modifications for Combination Therapy or Chemotherapy
All components of the regimen should be administered together.  If one of the components in 
the regimen is interrupted/delayed, other medications in the regimen should also be 
interrupted/delayed.  If one or all of the chemotherapy components in the combo arm is 
discontinued, subjects can continue with pembrolizumab up to the full 35 cycles.  Dose 
modifications or dose interruptions should not be used to resolve Grade 2 or Grade 3 AEs of 
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anemia or leukopenia that are related to chemotherapy.  To ensure that subjects can receive 
adequate SOC chemotherapy dosing, standard supportive care measures (e.g., erythrocyte 
infusion, thrombocyte infusion, G-CSF, and erythropoietin) should be utilized first before 
dose modification if there are no other reasons to modify SOC dosing for chemotherapy 
agents.
Timing of Dose Administration
Study treatment will be administered after all procedures/assessments have been completed
(as detailed in Section 6.0 – Trial Flow Chart), and in the following order: pembrolizumab 
infusion will be administered first, followed by premedication for the assigned chemotherapy
(if applicable; see Section 5.6.2 – Supportive Care Guidelines for Chemotherapy-related 
Adverse Events) and then administration of chemotherapy, according to local guidelines and 
practices.
After Cycle 1 Day 1, trial treatment may be administered up to 3 days before or after the 
scheduled dosing date for administrative reasons per investigator’s judgment.
Pembrolizumab
MK-3475 200 mg will be administered as a 30-minute IV infusion every 3 weeks. Sites 
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).
The Pharmacy Manual contains specific instructions for MK-3475 dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Cisplatin/Gemcitabine
Cisplatin will be administered as an IV infusion on Day 1 of a 3-week cycle according to 
local guidelines and procedures.  Cisplatin may be administered on Day 2, if required per 
local guidelines; however, Day 1 is the preferred day for treatment administration.  
Gemcitabine will be administered as an IV infusion on Days 1 and 8 of a 3-week cycle,
according to local guidelines and procedures.
Carboplatin/Gemcitabine
Carboplatin will be administered as an IV infusion on Day 1 of a 3-week cycle according to 
local guidelines and practices. Carboplatin may be administered on Day 2, if required as per 
local guidelines; however, Day 1 is the preferred day for treatment administration.  
Gemcitabine will be administered as an IV infusion on Days 1 and 8 of a 3-week cycle, 
according to local guidelines and procedures.
Trial Blinding 
Trial treatment will be open-label. Access to the allocation schedule for summaries or 
analyses will be restricted to an unblinded external statistician and, as needed, an external 
scientific programmer performing the DMC interim analyses, who will have no other 
responsibilities associated with the study.
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Imaging data for the primary analysis will be centrally reviewed by BICR without knowledge 
of subject treatment assignment.
The trial team at the Sponsor consisting of clinical, statistical, statistical programming and 
data management personnel will not be blinded to subject-level PD-L1 biomarker results
obtained at baseline to monitor PD-L1 prevalence.
Randomization
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 3 treatment arms.  
Subjects will be assigned randomly in a 1:1:1 ratio to one of the treatment arms below:
1. Pembro only
2. Combo, either with

Cisplatin and gemcitabine, or 

Carboplatin and gemcitabine
3. Chemo only, either 

Cisplatin and gemcitabine, or 

Carboplatin and gemcitabine
Investigators must select 1 chemotherapy treatment option (cisplatin or carboplatin) before 
randomization to use in the event that the subject is randomized either to the combo 
treatment arm or the chemo only treatment arm. As of 21-FEB-2018, subjects who have 
tumors that are PD-L1 CPS <10% will be randomized only to combo arm or chemo only 
arm. There is no change to randomization for subjects who have tumors that are PD-L1 CPS 
≥10%.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:

Chemotherapy drug: Investigator choice cisplatin or carboplatin

PD-L1 expression (CPS ≥10% or CPS <10%)
Concomitant Medications/Vaccinations (Allowed and Prohibited)
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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Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF),
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  Note that subjects receiving bone resorptive therapy (including, but not limited to 
bisphosphonate or RANK-L inhibitor) must have been on stable doses for ≥4 weeks prior to 
first dose of trial treatment.
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 the first dose of trial treatment and up to 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 –
Assessing and Recording Adverse Events.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including re-treatment for post-CR relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case-by-case basis after consultation with the Sponsor
(except during screening).

Live vaccines within 30 days prior to the first dose of pembrolizumab treatment and 
while participating in the trial if in 1 of the pembrolizumab-containing regimen 
groups (combo or pembro only).  Examples of live vaccines include, but are not 
limited to, the following:  measles, mumps, rubella, varicella/zoster, yellow fever, 
rabies, BCG, and typhoid vaccine.  Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
o
If precluded by local regulations, live vaccines should not be given for 
120 days after the last dose of pembrolizumab is administered.

Any chronic immunological-suppressive treatment for any reason other than the 
management of AEs, as described in Section 5.2.1.2.1 (Table 5).
Note:  Inhaled or topical steroids are allowed, and systemic steroids at doses 
≤10 mg/day prednisone or equivalents are allowed, as described in Section 5.2.1.2.1, 
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and immune suppressants are allowed as prophylaxis for contrast allergy for imaging 
procedures.

Any medication prohibited in combination with chemotherapy as described in the 
respective product labels for cisplatin, carboplatin, and gemcitabine.
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 medically necessary.
The exclusion criteria describe other medications prohibited in this trial.
Rescue Medications & Supportive Care
Supportive Care Guidelines for Subjects Receiving Pembrolizumab
See Section 5.2.1.2.1 - Dose Modifications for Pembrolizumab
Supportive Care Guidelines for Chemotherapy-related Adverse Events
Cisplatin/gemcitabine-related and GC-related AEs should be managed according to local 
guidelines and practices.
Diet/Activity/Other Considerations
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.
For this trial, male subjects will be considered to be of nonreproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Female subjects will be considered of nonreproductive potential if they meet 1 of the 
following criteria:

She is postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women <45 years of age who are not using hormonal 
contraception or hormonal replacement therapy, a high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a postmenopausal
state). In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.

She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion at least 6 weeks prior to screening;

She has a congenital or acquired condition that prevents childbearing.
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Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, for the course of the trial through 120 days after the 
last dose of pembrolizumab or 180 days after chemotherapy treatment, by complying with 
one of the following (refer to Appendix 12.5 for country-specific requirements):

Practice abstinence from heterosexual activity;
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and European 
Research Councils (ERCs)/Institutional Review Boards (IRBs).  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, postovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.

Use (or have their partner use) acceptable contraception during heterosexual activity.
Acceptable methods of contraception are‡:

Single method (one of the following is acceptable):

intrauterine device (IUD)

vasectomy of a female subject’s male partner

contraceptive rod implanted into the skin

Combination method (requires use of 2 of the following):

diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

cervical cap with spermicide (nulliparous women only)

contraceptive sponge (nulliparous women only)

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection.
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region.
Subjects should be informed that taking the trial medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the trial.  To participate in the trial, 
subjects of childbearing potential must adhere to the contraception requirements (described 
above) from the day of trial medication initiation (or 14 days prior to the initiation of trial 
medication for oral contraception) for the course of the trial through 120 days after the last 
dose of pembrolizumab or 180 days after chemotherapy treatment. If there is any question 
that a subject of childbearing potential will not reliably comply with the requirements for 
contraception, that subject should not be entered into the trial. For women of childbearing 
potential, monthly pregnancy testing should be conducted as per local regulations where 
applicable.
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Below are the required contraceptives for countries where the health authority requests
compliance with the Clinical Trial Facilitation Group Guidance:
Subjects should use birth control methods that can achieve a failure rate of less than 1% per
year when used consistently and correctly and are considered as highly effective birth control
methods. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

Oral

Injectable

Implantable

IUD

Intrauterine hormone-releasing system

Bilateral tubal occlusion

Vasectomized partner

Sexual abstinence
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab or
carboplatin, cisplatin or gemcitabine, the subject will immediately be removed from study 
treatment.  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 an SAE
(e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication 
to the mother or newborn). The trial 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 trial 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 – Reporting of Pregnancy and Lactation to the Sponsor.
Subjects should then be followed for Survival Follow-up. (Refer to Section 7.1.5.3.4)
Use in Nursing Women
It is unknown whether pembrolizumab, carboplatin, and gemcitabine are excreted in human 
milk. Cisplatin 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 breastfeeding are not eligible for enrollment.
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Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment    
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment will still continue to participate in the trial as specified in 
Section 6.0 - Trial Flow Chart and Section 7.1.5.3. – Posttreatment Visits 
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment, but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
The subject has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, placed the subject at unnecessary risk from continued 
administration of study treatment.
o
The subject has a confirmed positive serum pregnancy test. Refer to Section 5.7.3 – Use 
in Pregnancy.
o
Investigator’s decision to withdraw subject.
o
Verified radiographic disease progression by BICR.
Note: For unconfirmed radiographic progression, refer to Section 7.1.2.8.2 – Tumor 
Imaging During the Trial.
o
Unacceptable adverse experiences as described in Section 7.2.
Note: Subjects on the combo arm who discontinue one or all components of 
chemotherapy due to toxicity or AEs prior to the full 6 cycle chemotherapy treatment 
regimen, can continue with pembrolizumab up to the full 35 cycles.
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
o
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment
o
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 5.2.1.2
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o
A confirmed positive serum pregnancy test
o
Noncompliance with trial treatment or procedure requirements
o
Investigator’s decision to withdraw the subject
o
Completion of 35 treatments (approximately 2 years) with pembrolizumab
Note: The number of treatments is calculated starting with the first dose.  Subjects who stop 
the combination or pembrolizumab after receiving 35 doses may be eligible for re-treatment 
if they progress after stopping trial treatment provided they meet the requirements detailed in
Section 7.1.5.2.1 - Second Course Phase (Re-treatment Period). Subjects may be re-treated 
in the Second Course Phase (Re-treatment) for up to an additional 17 cycles (approximately 
1 year).
o
Discontinuation of treatment in subjects enrolled to the pembro only or the combo
arm may be considered for subjects who have attained a confirmed CR and have been
treated for at least 8 cycles (at least 24 weeks), receiving at least 2 doses of 
pembrolizumab beyond the date when initial CR was declared.  Subjects in the 
combo arm must have received at least 4 cycles of chemotherapy to ensure that 
subjects receive adequate SOC.
o
Administrative reasons.
For subjects who are discontinued from treatment, but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
For subjects who are discontinued from treatment, but continue to be monitored in the trial, 
see Section 6.0 – Trial Flow Chart, and Section 7.1.5.3 – Posttreatment Visits for those 
procedures to be completed at each specified visit.
Subjects may be allowed to begin treatment again if deemed medically appropriate.
Withdrawal from the Trial
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject must be withdrawn from the trial if:
○
The subject or subject’s legally acceptable representative withdraws consent from the 
trial.
○
The subject is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 7.1.4 – Other Procedures.
Treatment After Initial Radiologic Progression
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of immunotherapeutic agents such as pembrolizumab which 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 
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responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.  Standard RECIST 1.1 may, 
thus, not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. Based on an analysis of patients with melanoma enrolled in KN001, 7% of 
evaluable patients experienced delayed or early tumor pseudoprogression. Of note, patients
who had PD by RECIST 1.1, but not by immune-related Response Criteria had longer OS 
than patients with PD by both criteria.  Additionally, the data suggest that RECIST 1.1 may 
underestimate the benefit of pembrolizumab in approximately 15% of patients.  These 
findings support the need to apply a modification to RECIST 1.1 that takes into account the 
unique patterns of atypical response in immunotherapy and enables treatment beyond initial 
radiographic progression.  Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to 
account for the unique tumor response seen with immuno-therapeutics as described in [52]. 
The assessment of unidimensional target lesions and response categories per irRECIST are 
identical to RECIST 1.1.  However, Merck has implemented an adaptation related to new 
lesions, nontarget and tumor burden assessment to confirm radiographic progression.
irRECIST will be used by local site investigators to assess tumor response and progression, 
and to make treatment decisions by a BICR in support of PFS endpoint.
For further information on irRECIST, see Section 7.1.2.10.
Discontinuation of Trial Therapy After Complete Response
Discontinuation of treatment may be considered for subjects on the pembrolizumab arms
(combo and pembro only) who have attained a confirmed CR and have been treated for at 
least 8 cycles (at least 24 weeks) with pembrolizumab, and had at least 2 cycles of
pembrolizumab beyond the date when the initial CR was declared.  Subjects on the 
combination treatment must have received at least 4 cycles of chemotherapy.
These subjects should remain on study and continue in the Follow-up period of the trial with 
protocol-specified disease assessments, including imaging, as outlined in the Trial Flow 
Chart (see Section 6.0).  Subjects who then experience radiographic disease progression may 
be eligible for up to 1 year (17 cycles) of additional treatment with pembrolizumab at the 
discretion of the investigator, if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open.  Additional details are provided in Section 7.1.5.2.1.  Response 
or progression in the Second Course Phase will not count toward the OS and PFS of the 
primary endpoint in this trial.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
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).  Upon study completion, participants are discontinued and enrolled in a 
pembrolizumab extension study.
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Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. The trial may be stopped early for futility or safety at the recommendation of the 
external DMC.
2. Quality or quantity of data recording is inaccurate or incomplete.
3. Poor adherence to protocol and regulatory requirements.
4. Incidence or severity of adverse drug reaction in this or other trials indicates a 
potential health hazard to subjects.
5. Plans to modify or discontinue the development of the trial drug.
In the event of Sponsor decision to no longer supply trial drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
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6.0 TRIAL FLOW CHART
Initial Treatment Phase – Pembrolizumab Only (Pembro Only)
Trial Period:
Screening
Phase
Screening
Phase
Treatment Cycles a
End of 
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening (Visit 1)
1
2
3
4
To be repeated 
beyond 8 cycles a
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-
upb
Survival 
Follow-
up
5
6
7
8
Scheduling Window (Days)
-42 to -1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from 
last 
dose
(+3 
days)
Every 9 
or 
12 weeks
(±7 days)
Every 
12 weeks
(±7 days)
Administrative Procedures
Informed Consent
X c
Informed Consent for Future Biomedical 
Research
X d
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
Obtain randomization number and trial drug 
assignment using IVRS/IWRS
X e
Trial Treatment Administration
X
X
X
X
X
X
X
X
Posttrial Anticancer Therapy Status
X
X
X f
Survival Status f
˂-------------------------------------------------------------------------------------------˃
X f
Clinical Procedures/Assessments
Review Adverse Events g
X
X
X
X
X
X
X
X
X
X
X g
X g
12-Lead ECG (Locally Performed)
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
Height, Weight, and Vital Signs (T, P, RR, 
BP) h
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status 
X
X
X
X
X
X
X
X
X
X
X
X
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Trial Period:
Screening
Phase
Screening
Phase
Treatment Cycles a
End of 
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening (Visit 1)
1
2
3
4
To be repeated 
beyond 8 cycles a
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-
upb
Survival 
Follow-
up
5
6
7
8
Scheduling Window (Days)
-42 to -1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from 
last 
dose
(+3 
days)
Every 9 
or 
12 weeks
(±7 days)
Every 
12 weeks
(±7 days)
Laboratory Procedures/Assessments: Analysis performed by LOCAL laboratory
Pregnancy Test i
X  j
PT/INR and aPTT
X j
CBC with Differential
X  j
X
X
X
X
X
X
X
X
X
Comprehensive Chemistry Panel
X  j
X
X
X
X
X
X
X
X
X
Urinalysis k
X  j
X k
X
T3, FT4, and TSH
X  j
X k
X
Laboratory Procedures/Assessments: analysis performed by CENTRAL laboratory
Blood for RNA Analyses l
X
X
X
X
Blood for Plasma Biomarker Analyses l
X
X
X
Blood for Serum Biomarker Analyses l
X
X
X
Blood for Genetic Analysis m
X
Efficacy Measurements
Tumor Imaging n
X n
X
X
X 
X
Tumor Tissue Collection
Archival 
or 
Newly 
Obtained 
Tissue 
Collection for Biomarker Analysis o
Xo
Patient-reported Outcomes
EuroQol EQ-5D p
X
X
X
X
X
X
X
EORTC QLQ-C30 p
X
X
X
X
X
X
X
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Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; BP=blood pressure; discon=discontinuation; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECI=event of clinical interest; ECOG=Eastern Cooperative Oncology Group; EuroQol=European Quality of Life; FT4=free thyroxine; 
EORTC=European Organisation for Research and Treatment of Cancer Quality of Life; ePRO=electronic patient-reported outcomes; FBR=future biomedical 
research; INR=International Normalized Ratio; IRB/IEC=institutional review board/independent ethics committee; IVRS/IWRS=interactive voice response 
system/integrated web response system; P=pulse; pembro=pembrolizumab; PT=prothrombin time; Q9W=every 9 weeks; Q12W=every 12 weeks; 
RNA=ribonucleic acid; RR=respiratory rate; SAE=serious adverse event; T=temperature; T3=triiodothyronine; TSH=thyroid-stimulating hormone.
a
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment 
cycles are 3 weeks.  Imaging should be performed at 9 weeks (63 days ±7) from randomization until Week 54 and every 12 weeks (84 days ±7) thereafter, 
regardless of any treatment delays.
b
Subjects who complete the protocol-required cycles of study intervention or who discontinue study therapy without documented disease progression should 
enter Efficacy Follow-up and continue disease monitoring per study schedule (i.e., Q9W before Week 54 or Q12W after Week 54). See Section 7.1.2.8.3 for 
more details.
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 the specified time frame.
d
Signing the informed consent for FBR samples is optional.  Detailed instructions for the collection and management of specimens for FBR are provided in the 
Procedures Manual and Section 12.2.
e
The window for each visit is ±3 days unless otherwise noted.  Cycle 1 treatment must be given within 3 days of randomization.
f
After the start of new anticancer treatment or documented disease progression, the subject should be contacted approximately every 12 weeks (84 days ±7) to 
assess for survival status.  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all 
participants who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status 
(excluding participants that have a death event previously recorded).
g
After the end of treatment, each subject will be followed for 30 days for AE monitoring. SAEs will be collected for 90 days after the trial treatment or 30 days 
after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All drug-related SAEs and ECIs will be reported regardless of 
time frame.
h
Height will be measured at the screening visit only. Refer to Section 7.1.2.4.
i
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test performed by the local trial site laboratory will be required. Monthly pregnancy testing should 
be conducted as per local regulations where applicable. Refer to Appendix 12.5 for country-specific requirements.
j
Laboratory tests for screening and determining eligibility are to be performed within 14 days prior to the first dose of trial treatment. Refer to Section 7.1.3.2 
for details regarding laboratory tests.
k
Urinalysis and thyroid tests (T3, FT4, and TSH) are to be repeated every 4 cycles after Cycle 5 (Cycles 9, 13, 17, etc.).
l
Blood for RNA analyses should be collected predose on Day 1 of Cycle 1, Cycle 2, Cycle 5 and again at discontinuation. Blood for plasma and serum 
biomarker analyses should be collected predose on Day 1 of Cycle 1, Cycle 2, and again at discontinuation. See Procedures Manual. Any leftover samples 
from the RNA analyses, plasma biomarker analyses, and serum biomarker analyses will be stored for FBR if the subject signs the FBR consent.
m
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at 
that site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If 
the sample is collected, leftover extracted DNA will be stored for FBR if the subject signs the FBR consent. If the planned genetic analyses are not approved, 
but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
08BFSJ


Product:  MK-3475 
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Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
n
The initial tumor imaging will be performed within 28 days prior to randomization.  Refer to Section 7.1.2.8 for details on tumor imaging and assessment of 
disease. 
o
Baseline tumor tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy. Refer to Section 7.1.2.11. Detailed 
instructions for tissue collection, process and shipment are provided in the Procedures Manual.
p
It is strongly recommended that ePROs are administered prior to drug administration, AE evaluation, and disease status notification starting with EuroQol EQ-
5D, followed by EORTC QLQ-C30. Refer to Section 7.1.2.7 for details on collection of ePROs.
08BFSJ


Product:  MK-3475 
63
Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
Pembrolizumab + Chemotherapy (Combo)
Trial Period:
Screening 
Phase
Treatment
Cycles a
End of
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 b
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-
upc
Survival
Follow-up
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days)
-42 to 
-1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 
or 12 
weeks 
(±7 days)
Every 
12 week 
(±7 days)
Administrative Procedures
Informed Consent
X d
Informed Consent for Future
Biomedical Research
X e
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical
History
X
Prior and Concomitant
Medication Review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Obtain randomization 
number and trial drug 
assignment using 
IVRS/IWRS
X f
Pembro + Chemo 
X
X
X
X
X
X
X
X
X
X
X
X
Posttrial Anticancer Therapy 
Status
X
X
X g
Survival Status g
˂-----------------------------------------------------------------------------------------------------------------˃
X g
08BFSJ


Product:  MK-3475 
64
Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
Trial Period:
Screening 
Phase
Treatment
Cycles a
End of
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 b
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-
upc
Survival
Follow-up
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days)
-42 to 
-1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 
or 12 
weeks 
(±7 days)
Every 
12 week 
(±7 days)
Clinical
Procedures/Assessments
Review Adverse Events h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X h
X h
12-Lead ECG (Local)
X
Full Physical Examination
X
X
Directed Physical
Examination 
X
X
X
X
X
X
X
X
X
X
X
X
Height, Weight, and Vital 
Signs (T, P, RR, BP) i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: LOCAL laboratory
Pregnancy Test j
X k
PT/INR and aPTT 
X k
CBC with Differential 
X k
X
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Chemistry   
Panel
X k
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis l
X k
X l
X
T3, FT4, and TSH l
X k
X l
X
08BFSJ


Product:  MK-3475 
65
Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
Trial Period:
Screening 
Phase
Treatment
Cycles a
End of
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 b
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-
upc
Survival
Follow-up
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days)
-42 to 
-1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 
or 12 
weeks 
(±7 days)
Every 
12 week 
(±7 days)
Laboratory Procedures/Assessments:  Analysis performed by CENTRAL laboratory 
Blood for RNA Analyses m
X
X
X
X
Blood for Plasma Biomarker
Analyses m
X
X
X
Blood for Serum Biomarker 
Analyses m
X
X
X
Blood for 
Genetics Analysis n
X
Efficacy Measurements
Tumor Imaging o
X o
X
X p
X
Tumor Tissue Collection
Archival or Newly Obtained 
Tissue Collection for 
Biomarker analysis q
X q
08BFSJ


Product:  MK-3475 
66
Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
Trial Period:
Screening 
Phase
Treatment
Cycles a
End of
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 b
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-
upc
Survival
Follow-up
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days)
-42 to 
-1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 
or 12 
weeks 
(±7 days)
Every 
12 week 
(±7 days)
Patient-reported Outcomes
EuroQol EQ-5D r
X
X
X
X
X
X
EORTC QLQ-C30 r
X
X
X
X
X
X
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; BP=blood pressure; chemo=chemotherapy; combo=pembro+chemo+SOC; 
discon=discontinuation; DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECI=event of clinical interest; ECOG=Eastern Cooperative Oncology Group; 
EuroQol=European Quality of Life; FT4=free thyroxine; EORTC=European Organisation for Research and Treatment of Cancer Quality of Life; ePRO= 
electronic patient-reported outcomes; FBR=future biomedical research; INR=International Normalized Ratio; IRB/IEC=institutional review 
board/independent ethics committee; IVRS/IWRS=interactive voice response system/integrated web response system; P=pulse; Pembro=pembrolizumab; 
PT=prothrombin time; Q9W=every 9 weeks; Q12W=every 12 weeks; RNA=ribonucleic acid; RR=respiratory rate; SAE=serious adverse event; 
T=temperature; T3=triiodothyronine; TSH=thyroid-stimulating hormone.
a
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Day 1 is 
the preferred day of treatment administration for both cisplatin and carboplatin; however, these chemotherapy treatments may be given on Day 2 if 
required by local guidelines. Treatment cycles are 3 weeks.  Imaging should be performed at 9 weeks (63 days ±7) from randomization and until Week 54 
and every 12 weeks (84 days ±7) thereafter, regardless of any treatment delays.
b
Subjects in chemotherapy plus pembrolizumab treatment arm will continue receiving pembrolizumab treatment and continue repeating Treatment Cycles 
Visits in the Trial Flow Chart.
c
Subjects who complete the protocol-required cycles of study intervention or who discontinue study therapy without documented PD should enter Efficacy 
Follow-up and continue disease monitoring per study schedule (i.e., Q9W before Week 54 or Q12W after Week 54). See Section 7.1.2.8.3 for more 
details. 
d
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 the specified time frame.
e
Signing the informed consent for FBR samples is optional.  Detailed instructions for the collection and management of specimens for FBR are provided in 
the Procedures Manual and Section 12.2.
f
The window for each visit is ±3 days unless otherwise noted.  Cycle 1 treatment must be given within 3 days of randomization.
g
After the start of new anticancer treatment or documented disease progression, the subject should be contacted approximately every 12 weeks (84 days ±7) 
to assess for survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for 
their survival status (excluding participants that have a death event previously recorded).
08BFSJ


Product:  MK-3475 
67
Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
Trial Period:
Screening 
Phase
Treatment
Cycles a
End of
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 b
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-
upc
Survival
Follow-up
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days)
-42 to 
-1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 
or 12 
weeks 
(±7 days)
Every 
12 week 
(±7 days)
h
After the end of treatment, each subject will be followed for 30 days for AE monitoring. SAEs will be collected for 90 days after the trial treatment or 30 
days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All drug-related SAEs and ECIs will be reported 
regardless of time frame. 
i
Height will be measured at the screening visit only. Refer to Section 7.1.2.4.  Weight, and vital signs (T, P, RR, and BP) will also be measures during 
cycles repeating after Cycle 6 for pembrolizumab administration.
j
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test performed by the local trial site laboratory will be required. Monthly pregnancy testing 
should be conducted as per local regulations where applicable. Refer to Appendix 12.5 for country-specific requirements.
k
Laboratory tests for screening and determining eligibility are to be performed within 14 days prior to the first dose of trial treatment. Refer to Section 
7.1.3.2 for details regarding laboratory tests.
l
Urinalysis and thyroid tests (T3, FT4, and TSH) are to be repeated every 4 cycles after Cycle 5 (Cycles 9, 13, 17, etc.).
m Blood for RNA analyses should be collected predose on Day 1 of Cycle 1, Cycle 2, Cycle 5 and again at discontinuation. Blood for plasma and serum 
biomarker analyses should be collected predose on Day 1 of Cycle 1, Cycle 2, and again at discontinuation. See Procedures Manual. Any leftover 
samples from the RNA analyses, plasma biomarker analyses and serum biomarker analyses will be stored for FBR research if the subject signs the FBR 
consent 
n
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be 
collected at that site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for 
these purposes. If the sample is collected, leftover extracted DNA will be stored for FBR if the subject signs the FBR consent. If the planned genetic 
analyses are not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
o
The initial tumor imaging will be performed within 28 days prior to randomization. Refer to Section 7.1.2.8 for details on tumor imaging and assessment 
of disease. 
p
In subjects who discontinue study therapy without confirmed PD by the site per irRECIST, tumor imaging should be performed at the time of treatment 
discontinuation (± 4 weeks). If previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, then additional tumor imaging at 
treatment discontinuation is not required.
q
Baseline tumor tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy. Refer to Section 7.1.2.12. 
Detailed instructions for tissue collection, process and shipment are provided in the Procedures Manual.  
r
It is strongly recommended that ePROs are administered prior to drug administration, AE evaluation, and disease status notification starting with EuroQol 
EQ-5D, followed by EORTC QLQ-C30. Refer to Section 7.1.2.7 for details on collection of ePROs.
08BFSJ


Product:  MK-3475 
68
Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
Chemotherapy Only (Chemo Only)
Trial Period:
Screening 
Phase
Treatment
Cycles a
End of
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 b
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-
upc
Survival 
Follow-up
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days)
-42 to 
-1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 or 
12 weeks 
(±7 days)
Every 
12 weeks
(±7 days)
Administrative Procedures
Informed Consent
X d
Informed Consent for Future
Biomedical Research
X e
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical 
History
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Obtain randomization 
number and trial drug 
assignment using 
IVRS/IWRS
X f
Chemo only Administration
X
X
X
X
X
X
X
X
X
X
X
X
Posttrial Anticancer Therapy 
Status
X
X
X g
Survival Status g
˂-------------------------------------------------------------------------------------------------------------˃
X g
08BFSJ


Product:  MK-3475 
69
Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
Trial Period:
Screening 
Phase
Treatment
Cycles a
End of
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 b
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-
upc
Survival 
Follow-up
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days)
-42 to 
-1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 or 
12 weeks 
(±7 days)
Every 
12 weeks
(±7 days)
Clinical
Procedures/Assessments
Review Adverse Events h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X h
X h
12-Lead ECG (Local)
X
Full Physical Examination 
X
X
Directed Physical
Examination 
X
X
X
X
X
X
X
X
X
X
X
X
Height, Weight, and Vital 
Signs (T,P, RR, BP) i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: LOCAL laboratory
Pregnancy Test j
X k
PT/INR and aPTT 
X k
CBC with Differential
X k
X
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Chemistry
Panel
X k
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X k
X 
X
T3, FT4, and TSH 
X k
08BFSJ


Product:  MK-3475 
70
Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
Trial Period:
Screening 
Phase
Treatment
Cycles a
End of
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 b
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-
upc
Survival 
Follow-up
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days)
-42 to 
-1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 or 
12 weeks 
(±7 days)
Every 
12 weeks
(±7 days)
Laboratory Procedures/Assessments:  Analysis performed by CENTRAL laboratory
Blood for RNA Analyses i
X
X
X
X
Blood for Plasma Biomarker
Analyses i
X
X
X
Blood for Serum Biomarker 
Analyses i
X
X
X
Blood for 
Genetics Analysis m
X
Efficacy Measurements
Tumor Imaging n
X n
X
X o
X
Tumor Tissue Collection
Archival or Newly Obtained 
Tissue Collection for 
Biomarker analysis p
X p
08BFSJ


Product:  MK-3475 
71
Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
Trial Period:
Screening 
Phase
Treatment
Cycles a
End of
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 b
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-
upc
Survival 
Follow-up
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days)
-42 to 
-1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 or 
12 weeks 
(±7 days)
Every 
12 weeks
(±7 days)
Patient-reported Outcomes
EuroQol EQ-5D q
X
X
X
X
X
X
EORTC QLQ-C30 q
X
X
X
X
X
X
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; BP=blood pressure; chemo=chemotherapy; discon=discontinuation; 
DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECI=event of clinical interest; ECOG=Eastern Cooperative Oncology Group; EuroQol=European 
Quality of Life; FT4=free thyroxine; EORTC=European Organisation for Research and Treatment of Cancer Quality of Life; ePRO= electronic patient-
reported outcomes; FBR=future biomedical research; INR=International Normalized Ratio; IRB/IEC=institutional review board/independent ethics committee; 
IVRS/IWRS=interactive voice response system/integrated web response system; P=pulse; Pembro=pembrolizumab; PK=pharmacokinetic(s); PT=prothrombin 
time; Q9W=every 9 weeks; Q12W=every 12 weeks; RNA=ribonucleic acid; RR=respiratory rate; SAE=serious adverse event; T=temperature; 
T3=triiodothyronine; TSH=thyroid-stimulating hormone. 
a
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Day 1 is 
the preferred day of treatment administration for both cisplatin and carboplatin; however, these chemotherapy treatments may be given on Day 2 if 
required by local guidelines. Treatment cycles are 3 weeks. Imaging should be performed at 9 weeks (63 days ±7) from randomization and until Week 54 
and every 12 weeks (84 days ±7) thereafter, regardless of any treatment delays.
b
Subjects in the chemo only treatment arm will discontinue treatment after 6 cycles of trial drug administration.  These subjects would then be followed 
according to Posttreatment procedures.
c
Subjects who complete the protocol-required cycles of study intervention or who discontinue study therapy without documented PD should enter Efficacy 
Follow-up and continue disease monitoring per study schedule (i.e., Q9W before Week 54 or Q12W after Week 54). See Section 7.1.2.8.3 for more details. 
d
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 the specified time frame. 
e
Signing the informed consent for FBR samples is optional.  Detailed instructions for the collection and management of specimens for FBR are provided in 
the Procedures Manual and Section 12.2.
f
The window for each visit is ±3 days unless otherwise noted.  Cycle 1 treatment must be given within 3 days of randomization.
g
After the start of new anticancer treatment or documented disease progression, the subject should be contacted approximately every 12 weeks (84 days ±7) 
to assess for survival status.
Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for 
their survival status (excluding participants that have a death event previously recorded).
08BFSJ


Product:  MK-3475 
72
Protocol/Amendment No.: 361-10 
MK-3475-361-10 Final Protocol
10-Jun-2021
Confidential
Trial Period:
Screening 
Phase
Treatment
Cycles a
End of
Treatment
Posttreatment Visits
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 b
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-
upc
Survival 
Follow-up
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days)
-42 to 
-1
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 or 
12 weeks 
(±7 days)
Every 
12 weeks
(±7 days)
h
After the end of treatment, each subject will be followed for 30 days for AE monitoring. SAEs will be collected for 90 days after the trial treatment or 30 
days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All drug-related SAEs and ECIs will be reported 
regardless of time frame.  
i
Height will be measured at the screening visit only. Refer to Section 7.1.2.4.
j
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test performed by the local trial site laboratory will be required. Monthly pregnancy testing 
should be conducted as per local regulations where applicable. Refer to Appendix 12.5 for country-specific requirements.
k
Laboratory tests for screening and determining eligibility are to be performed within 14 days prior to the first dose of trial treatment. Refer to Section 
7.1.3.2 for details regarding laboratory tests.
l
Blood for RNA analyses should be collected predose on Day 1 of Cycle 1, Cycle 2, Cycle 5 and again at discontinuation. Blood for plasma and serum 
biomarker analyses should be collected predose on Day 1 of Cycle 1, Cycle 2, and again at discontinuation. See Procedures Manual. Any leftover samples 
from the RNA analyses, plasma biomarker analyses and serum biomarker analyses will be stored for FBR research if the subject signs the FBR consent 
m
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected 
at that site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these 
purposes. If the sample is collected, leftover extracted DNA will be stored for FBR if the subject signs the FBR consent. If the planned genetic analyses 
are not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
n
The initial tumor imaging will be performed within 28 days prior to randomization. Refer to Section 7.1.2.8 for details on tumor imaging and assessment of 
disease. 
o
In subjects who discontinue study therapy without confirmed PD by the site per irRECIST, tumor imaging should be performed at the time of treatment 
discontinuation (± 4 weeks). If previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, then additional tumor imaging at 
treatment discontinuation is not required.
p
Baseline tumor tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy. Refer to Section 7.1.2.12.
Detailed instructions for tissue collection, process and shipment are provided in the Procedures Manual.  
q
It is strongly recommended that ePROs are administered prior to drug administration, AE evaluation, and disease status notification starting with EuroQol 
EQ-5D, followed by EORTC QLQ-C30. Refer to Section 7.1.2.7 for details on collection of ePROs.
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Second Course Phase (Re-treatment for Pembrolizumab [Pembro Only and Combo] Arms ONLY)
Trial Period:
Treatment Cycles a
End of 
Treatment
Posttreatment Visits
Treatment Cycle/Title
1
2
3
4
To be repeated beyond 
8 cycles a
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-up b
Survival 
Follow-up
5
6
7
8
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 or 
12 weeks
(±7 days)
Every 12 weeks
(±7 days)
Administrative Procedures
Eligibility Criteria c
X
Concomitant Medication Review 
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administration d
X
X
X
X
X
X
X
X
Posttrial Anticancer Therapy Status
X
X
X e
Survival Status e
˂-------------------------------------------------------------------------------------------------------------------˃
X e
Clinical Procedures/Assessments
Review Adverse Events 
X
X
X
X
X
X
X
X
X
X f
X f
Full Physical Examination 
X
X
Directed Physical Examination 
X
X
X
X
X
X
X
Weight and Vital Signs 
(T, P, RR, BP)
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status 
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: Analysis performed by LOCAL laboratory
Pregnancy Test –Urine or Serum g
X
CBC with Differential 
X h
X
X
X
X
X
X
X
X
X
Comprehensive Chemistry Panel 
X h
X
X
X
X
X
X
X
X
X
T3, FT4, and TSH 
X h
X i
X
PT/INR and aPTT 
X h
Urinalysis 
X
X i
X
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Trial Period:
Treatment Cycles a
End of 
Treatment
Posttreatment Visits
Treatment Cycle/Title
1
2
3
4
To be repeated beyond 
8 cycles a
End of 
Treatment 
Visit
Safety
Follow-up
Efficacy 
Follow-up b
Survival 
Follow-up
5
6
7
8
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
At time of 
Discon
30 days 
from last 
dose 
(+3 days)
Every 9 or 
12 weeks
(±7 days)
Every 12 weeks
(±7 days)
Efficacy Measurements
Tumor Imaging j
X
X
X
X j
X j
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; BICR=blinded independent central review; BP=blood pressure; CBC=complete 
blood count; CR=complete response; discon=discontinuation; ECI=event of clinical interest; ECOG=Eastern Cooperative Oncology Group; FT4=free 
thyroxine; INR=International Normalized Ratio; P=pulse; PT=prothrombin time; Q9W=every 9 weeks; Q12W=every 12 weeks; RR=respiratory rate; 
SAE=serious adverse event; SIM=site imaging manual; T=temperature; T3=triiodothyronine; TSH=thyroid-stimulating hormone.
a
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  
Treatment cycles are 3 weeks.  Imaging should be performed at 9 weeks (63 days ±7) from start of treatment until Week 54 and every 12 weeks (84 days ±7) 
after Week 54, regardless of any treatment delays.
b
Subjects who complete the protocol-required cycles of study intervention or who discontinue study therapy without documented PD should enter Efficacy 
Follow-up and continue disease monitoring per study schedule (i.e., Q9W before Week 54 or Q12W after Week 54). See Section 7.1.2.8.3 for more details. 
c
Subjects who either a) attain a CR and discontinue treatment, or b) discontinue treatment after receiving 35 administrations on pembrolizumab for reasons 
other than disease progression or intolerability may restart trial treatment if they meet the criteria specified in Section 7.1.5.2.1.
d
Subjects who restart treatment should resume at the same dose and cycle interval which they were receiving prior to discontinuation.
e
After the start of new anticancer treatment or documented disease progression, the subject should be contacted approximately every 12 weeks (84 days ±7) 
to assess for survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for 
their survival status (excluding participants that have a death event previously recorded).
f
After the end of treatment, each subject will be followed for 30 days for AE monitoring.  SAEs will be collected for 90 days after the trial treatment or 
30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier. All drug-related SAEs and ECIs will be reported 
regardless of time frame.
g
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test performed by the local trial site laboratory will be required. Monthly pregnancy testing 
should be conducted as per local regulations where applicable.
h
See Section 7.1.3.2 for details regarding laboratory tests.
i
Urinalysis, and thyroid tests (T3, FT4, and TSH) to be repeated every 4 cycles after Cycle 5 (Cycles 9, 13, 17, etc.).
j
A scan must be performed within 28 days prior to restarting treatment with pembrolizumab. Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts. Refer to Section 7.1.2.8 for details on tumor imaging and assessment of disease. The processes for image collection and 
transmission for BICR are in the SIM.
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7.0 TRIAL PROCEDURES
Trial Procedures
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
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. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place.
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 Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
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.
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. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee.
Medical history will include all active conditions, and any condition diagnosed within the 
prior 10 years that are considered to be clinically significant by the investigator.  Details 
regarding the subject’s urothelial bladder cancer will be recorded separately and not listed as 
medical history.
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.
Prior anticancer treatment for urothelial bladder cancer will be recorded separately and not 
listed as a prior medication.
The investigator or qualified designee will review and record all prior anticancer treatments
including systemic treatments, radiation, and surgeries, regardless of the time prior to first
dose of trial treatment.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial treatment and 30 days after the last dose of trial treatment. All medications 
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related to reportable SAEs should be recorded as defined in Section 7.2 – Assessing and 
Recording Adverse Events.
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 treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1 – Screening.  
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/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 treatment/randomization number.
In a situation where rerandomization of the participants is planned (eg, study extension 
periods), the rerandomization will be based on a new randomization schedule; however, each 
participant will retain his/her original treatment/randomization number. Only the study 
intervention regimen associated with the rerandomization period or phase may change.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for ≥12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
Administration of trial medication will be monitored by the investigator and/or trial staff.
The total volume of pembrolizumab infused will be compared with the total volume prepared 
to determine compliance to each dose of pembrolizumab administered. The instructions for 
preparing and administering pembrolizumab will be provided in the Pharmacy Manual.
Clinical Procedures/Assessments
Tumor Tissue Collection and Correlative Blood Sampling
Either an archival FFPE tumor sample or a newly obtained core or excisional biopsy (fine 
needle aspirate not adequate) must be submitted to a central laboratory for characterization of 
PD-L1 expression. PD-L1 expression will be evaluated prospectively in this trial. The tumor 
tissue must be received by the central vendor and be deemed adequate for evaluation prior to 
subject randomization. If new scientific data emerge indicating that an existing biopsy or 
surgical specimen is suboptimal for identification of subjects, only new biopsies will be 
acceptable for determination of PD-L1 status.
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Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in Section 6.0 – Trial Flow Chart, and more frequently if 
clinically indicated. AEs will be graded and recorded throughout the trial and during the 
Follow-up Period according to National Cancer Institute (NCI) CTCAE Version 4.0 (see 
Section 12.4).
Toxicities will be characterized in terms including seriousness, causality, 
toxicity grading, and action taken with regard to trial treatment.
Please refer to Section 7.2 – Assessing and Recording Adverse Events for detailed 
information regarding the assessment and recording of AEs.
Physical Examination
7.1.2.3.1 Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical examination are described in Section 6.0 – Trial 
Flow Chart. After the first dose of trial treatment new clinically significant abnormal 
findings should be recorded as AEs. Refer to Appendix 12.5 for country-specific
requirements.
7.1.2.3.2 Directed Physical Examination
For cycles that do not require a full physical examination per the Trial Flow Chart (Section 
6.0), the investigator or qualified designee will perform a directed physical examination as 
clinically indicated prior to trial treatment administration.
New clinically significant 
abnormal findings should be recorded as AEs. Refer to Appendix 12.5 for country-specific
requirements.
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment, at trial discontinuation, and during the 
Follow-up Period as specified in the Trial Flow Chart (Section 6.0). Vital signs include 
temperature, pulse, respiratory rate, weight, and blood pressure. Height will be measured at 
the screening visit only.
12-Lead Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures once at screening. Clinically significant abnormal findings should be recorded as 
medical history.  Additional ECGs may be performed as clinically necessary.
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status at screening, prior to each 
cycle of trial treatment and during the Follow-up Period as specified in the Trial Flow Chart
(Section 6.0). Section 12.3 shows the flow criteria for ECOG PS.
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Patient-reported Outcomes
The EuroQol EQ-5D and EORTC QLQ-C30 questionnaires will be administered by trained 
trial site personnel and completed electronically by subjects to record PROs.
It is strongly recommended that electronic patient-reported outcomes (ePROs) be
administered prior to drug administration, AE evaluation, and disease status notification. 
The ePROs are completed in the following order: EuroQol EQ-5D first and then EORTC 
QLQ-C30 at the time points specified in the Trial Flow Chart (Section 6.0) and briefly 
summarized below.
All PROs (EuroQol EQ-5D, EORTC QLQ-C30) are completed at Cycle 1, Cycle 2, Cycle 3, 
Cycle 4, then every 3 cycles for the first 54 weeks and every 4 cycles thereafter (e.g., 
Cycle 7, 10, 13, 16, 19, 23, 27, 31, 35) until treatment discontinuation and the 30-day 
post-treatment Safety Follow-up Visit. If the subject does not complete the ePROs, the 
MISS_MODE form must be completed to capture the reason the assessment was not 
performed.
Tumor Imaging and Assessment of Disease
The process for image collection and transmission for BICR can be found in the Site Imaging 
Manual (SIM).
Tumor imaging should be acquired by computed tomography (CT), which is strongly 
preferred.  Magnetic resonance imaging (MRI) should be used when CT is contraindicated or 
for imaging of the brain. The same imaging technique regarding modality and use of contrast 
should be used in a subject throughout the trial to optimize the visualization of existing and 
new tumor burden.
All scheduled images for all study subjects from the sites will be submitted to the BICR. In 
addition, imaging (including other modalities) that are obtained at an unscheduled time point 
to determine disease progression, as well as imaging obtained for other reasons, but captures 
radiologic progression, should be submitted to the BICR as well.
The BICR will verify PD following local site investigator-assessed first radiologic evidence 
of PD.  Expedited verification of radiologic PD by BICR will be communicated to the study 
site and Sponsor (Refer to Section 7.1.2.10).
Local review of imaging will be used for subject management.  The BICR team will receive 
radiologic images during the course of the trial and will perform a retrospective analysis of 
response to treatment.
7.1.2.8.1 Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
randomization. The site trial team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1. The screening images must be submitted for BICR
retrospective review.
Scans performed as part of routine clinical management are acceptable for use as screening 
tumor imaging if they are of diagnostic quality and performed within 28 days prior to the 
date of randomization and can be assessed by the site radiologist.
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Local site investigator/radiology assessment based on RECIST 1.1 will be used to determine 
subject eligibility.  Although RECIST 1.1 references to a maximum of 5 target lesions in 
total and 2 per organ, Merck allows a maximum of 10 target lesions in total and 5 per organ, 
if clinically relevant to enable a broader sampling of tumor burden.
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases, i.e., without evidence of progression by imaging; (confirmed by MRI if 
MRI was used at prior imaging, or confirmed by CT imaging if CT was used at prior 
imaging) for at least 4 weeks prior to randomization. Any neurologic symptoms must have 
returned to baseline, and subjects must have no evidence of new or enlarging brain
metastases, and have not used steroids for brain metastases at least 7 days prior to trial 
initiation as per local site assessment.
This exception does not include carcinomatous 
meningitis, as subjects with carcinomatous meningitis are excluded regardless of clinical 
stability.
7.1.2.8.2 Tumor Imaging During the Trial
The first on-trial imaging assessment should be performed at 9 Weeks (63 days ±7), from the 
date of randomization for the first year (through Week 54 ±7) or more frequently if clinically 
indicated. Subjects who remain on treatment beyond 54 weeks will have imaging performed 
every 12 weeks (84 days ±7) thereafter.  Imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts. In determining response to treatment or
progression, investigators must evaluate all target and nontarget lesions and search for new 
lesions at each imaging time point. For subjects who have stable brain metastases and who 
have undergone brain imaging at baseline, brain imaging should be performed if a 
site-assessed complete response was achieved.
Response
Per RECIST 1.1, PR and CR should be confirmed by a repeat tumor imaging assessment 
4 weeks or longer from the date the response was first documented.  The tumor imaging for 
confirmation of response may be performed 4 weeks after the first indication of a response, 
or at the next scheduled scan (i.e., 9 weeks or 12 weeks later, depending on the year of 
treatment), whichever is clinically indicated.  Subjects will then return to regular scheduled 
imaging every 9 weeks or 12 weeks depending on the year of treatment, starting with the 
next scheduled imaging time point. Subjects who obtain a confirmation scan do not need to 
undergo the next scheduled tumor imaging if it is <4 weeks later; tumor imaging may resume 
at the subsequent scheduled imaging time point.
Progression
Radiographic progression will be determined according to RECIST 1.1. Subsequently, per 
irRECIST (Section 7.1.2.10 – irRECIST Assessment of Disease), disease progression in 
subjects treated with pembrolizumab should be confirmed by the site at least 4 weeks after 
central verification of site-assessed first radiologic evidence of PD in clinically stable
subjects. Subjects who have unconfirmed disease progression and are clinically stable may 
continue on treatment at the discretion of the site investigator until progression is confirmed 
by the site provided they have met the conditions detailed in Section 7.1.2.10. Subjects who 
obtain a confirmation scan do not need to undergo the next scheduled tumor imaging if it is 
<4 weeks later. Tumor imaging may resume at the subsequent scheduled imaging time point 
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if clinically stable. Subjects who have confirmed disease progression as assessed by the site 
will discontinue treatment.  Exceptions are detailed in Section 7.1.2.10.
If a subject with confirmed radiographic progression is clinically stable or clinically 
improved, and there is no further increase in the tumor dimensions at the confirmatory scan, 
an exception may be considered to continue treatment upon consultation with the Sponsor.  
To continue treatment, clinically stable subjects should also have at the confirmatory scan no 
further increase in the target lesions, no unequivocal increase in nontarget lesions, and no
worsening in size of an initial new lesions or the development of additional new lesions 
(non-worsening PD).
Imaging should continue to be performed until verified by BICR (unless the site’s principal 
investigator [PI] elects to continue treatment and follow irRECIST), the start of new 
anti-cancer treatment, or withdrawal of consent or death, whichever occurs first. 
All
supplemental imaging must be submitted to the BICR.
7.1.2.8.3 End of Treatment and Follow-up of Tumor Imaging
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4-week window). If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory. 
In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the 
same imaging schedule used while on treatment, (every 9 weeks [63 days ±7] for the first 
54 weeks or every 12 weeks [84 days ±7]) thereafter to monitor disease status until the start 
of new anticancer treatment, disease progression, death, or the end of the trial, whichever 
occurs first.
7.1.2.8.4 Second Course (Re-treatment) Tumor Imaging
Before a participant may enter the Second Course Phase, BICR verification of PD must have 
occurred.  The PD imaging may also be used as the Second Course baseline imaging if it is 
within 28 days prior to restarting treatment and otherwise meets the baseline standards 
outlined in the SIM.  Local reading (Investigator assessment with site radiology reading) will 
be used to determine eligibility.
All Second Course imaging should be submitted to the 
central imaging vendor for quality control, storage, and possible retrospective review, though 
BICR verification of PD will not occur during Second Course Phase.
The first on-trial imaging assessment should be performed at 9 weeks (63 days ±7) after the 
restart of treatment up to 54 weeks. Subsequent tumor imaging should be performed every 
12 weeks (84 days ±7) or more frequently if clinically indicated.
Per irRECIST if tumor imaging shows initial PD (Section 7.1.2.10 – irRECIST Assessment 
of Disease), tumor assessment should be repeated ≥4 weeks later to confirm PD with the 
option of continuing treatment while awaiting radiologic confirmation of progression.  
Subjects who obtain a confirmation scan do not need to undergo scheduled tumor imaging if 
it is <4 weeks later and may wait until the next scheduled imaging time point if clinically 
stable.
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Imaging should continue to be performed until disease progression, the start of new 
anti-cancer treatment, withdrawal of consent, death, or notification by the Sponsor, 
whichever occurs first. Disease progression may be confirmed at least 4 weeks after the first 
tumor imaging indicating PD in clinically stable subjects.  Additional irRECIST detail is 
described in Section 7.1.2.10.
In subjects who discontinue trial treatment and will not continue to have scans performed in 
follow-up (e.g., subject is discontinuing treatment due to documented disease progression), 
final assessment tumor imaging should be performed at the time of treatment discontinuation 
(±4-week window).  If a previous scan was obtained within 4 weeks prior to the date of 
discontinuation, then a scan at treatment discontinuation is not mandatory.  In subjects who 
discontinue trial treatment due to documented disease progression, this is the final required 
tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 
9 weeks (63 days ±7) for the first 54 weeks and then every 12 weeks (84 days ±7) thereafter 
until the start of new anticancer treatment, disease progression, death, or the end of the trial, 
whichever occurs first.
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be applied by BICR as the primary measure for assessment of tumor 
response, date of disease progression, and as a basis for all protocol guidelines related to 
disease status (e.g., discontinuation of trial therapy). Although RECIST 1.1 references a 
maximum of 5 target lesions in total and 2 per organ, the Sponsor allows a maximum of 
10 target lesions in total and 5 per organ, if clinically relevant to enable a broader sampling 
of tumor burden.  Initial tumor imaging showing site-assessed PD should be submitted to the 
central imaging vendor immediately for verification of PD by BICR.
The site will be 
notified if the BICR verifies PD using RECIST 1.1.
Figure 2 illustrates the imaging flow involving verification of PD for clinically stable 
subjects.
irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs. 
irRECIST will be used by the site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions. This data will be collected in the clinical database. Treatment efficacy 
based on irRECIST as assessed by BICR will be evaluated retrospectively.
When feasible, subjects in the treatment arms receiving pembrolizumab should not be 
discontinued until progression 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 or at a later time point and then experience 
subsequent response.  Subjects who are deemed clinically unstable are not required to have 
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repeat tumor imaging for confirmation of PD.  Tumor flare includes any of the following 
scenarios:

Worsening of existing target lesion(s)

Worsening of existing nontarget lesion(s)

Development of new lesion(s)
In subjects who have shown initial evidence of radiological PD by RECIST 1, as verified by 
BICR, it is at the discretion of the PI whether to continue a subject on trial treatment until 
repeat imaging is obtained (using irRECIST for subject management, see Table 7 and Figure 
2).
This clinical judgment decision by the site investigator should be based on the subject’s 
overall clinical condition, including PS, clinical symptoms, and laboratory data.  Subjects 
may receive trial treatment and tumor assessment should be repeated ≥4 weeks later to
confirm PD by irRECIST per site assessment.  Clinical stability is defined as the following:
1. Absence of symptoms and signs indicating clinically significant progression of
disease, including worsening of laboratory values.
2. No decline in ECOG PS.
3. Absence of rapid progression of disease.
4. Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention.
Any subject deemed clinically unstable should be discontinued from trial treatment at 
central verification of site-assessed first 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, the local site 
investigator should consider all target and nontarget lesions as well as any incremental new 
lesion(s).
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST:

Target lesion sum of diameters is <20% or <5 mm absolute increase compared with
nadir.

Nontarget disease resulting in initial PD is stable or qualitatively improved.

New lesion resulting in initial PD is stable or qualitatively improved.

No incremental new lesion(s) since last evaluation.

No incremental new nontarget lesion progression since last evaluation.
If repeat imaging does not confirm PD by irRECIST as assessed by the local site investigator 
and the subject continues to be clinically stable, treatment may continue and follow the 
regular imaging schedule.
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Disease progression will be considered to be “confirmed” at repeat imaging if ANY of the 
following occur (as assessed by irRECIST):

Target lesion sum of diameters remains ≥20% and at least 5 mm absolute increase 
compared with nadir.

Nontarget disease resulting in initial PD is qualitatively worse.

New lesion resulting in initial PD is qualitatively worse.

Additional new lesion(s) since last evaluation.

Additional new nontarget 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.
Note: If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks apart 
demonstrating PD), by irRECIST, but the subject is achieving a clinically meaningful 
benefit, and there is no further increase in the tumor burden at the confirmatory tumor 
imaging, an exception to continue treatment may be considered following consultation with 
the Sponsor. In this case, if treatment is continued, tumor imaging should continue to be 
performed following the intervals outlined in Section 6.0 Trial Flowchart and be submitted 
for BICR.
Additional details about irRECIST are referenced in Merck TIP Sheet for RECIST 1.1 and
irRECIST.
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Table 7
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic evidence 
of PD by RECIST 1.1, 
which has been verified 
by 
the 
blinded 
independent 
central 
review
Repeat 
imaging 
at 
4 weeks
at site
to 
confirm PD
May continue trial 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 every
9
weeks 
(every 
12 
weeks after 12 months)
Continue trial treatment at 
the 
site
investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart trial 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.
Abbreviations: CR=complete response; irRECIST=immune-related RECIST; N/A=not applicable; PD=progressive disease; PR=partial response; RECIST=Response Evaluation 
Criteria in Solid Tumors; SD=stable disease.
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Figure 2
Flow Chart for Imaging After First Site-Identified Progression of Disease
RECIST 1.1
st
1  radiologic (imaging) evidence of PD
assessed by site
Site submits all required imaging for Blinded Independent
Central Review (BICR), and requests verification of PD
NO = BICR queries
BICR quality 
check-- do 
images PASS?
YES = BICR provides 
email notice of 
verification of PD in
3-5 business days
NO = PD not verified 
Subject should 
remain on trial 
treatment
Does BICR 
verify PD per 
RECIST 1.1?
YES=PD is verified 
Subject may 
remain on trial
treatment per site PI
1. Subject to resume 
imaging schedule per 
protocol, if clinically 
indicated
2. Site should
continue to document 
their assessment of
PD and submit for 
verification of PD until 
centrally verified
NO=Site DOES NOT 
confirm PD per 
irRECIST
Repeat tumor 
imaging at ≥ 4 weeks
Does SITE 
confirm PD 
per 
irRECIST?
YES=Site
confirms
PD by irRECIST
irRECIST
1. Subject MAY remain on study drug at 
site PI’s discretion.
2. Regular tumor imaging is followed;
unscheduled imaging should be 
obtained, if clinically indicated... 
manage subject by irRECIST
3. Submit all tumor imaging to BICR
1.Subject discontinues trial 
treatment. Upon sponsor 
consultation -exception is 
possible.
2.Tumor imaging done, ONLY
if needed for End of 
Treatment (if previous scan
was done > 4 weeks
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Tumor Tissue Collection and Correlative Blood Sampling
Either an archival FFPE tumor sample or a newly obtained core or excisional biopsy (fine 
needle aspirate not adequate) must be submitted to a central laboratory for characterization of 
PD-L1 expression, which will be evaluated prospectively in this trial. The tumor tissue must 
be received by the central vendor and be deemed adequate for evaluation prior to subject 
randomization. If new scientific data emerge that indicate an existing biopsy or surgical 
specimen is suboptimal for identification of subjects, only new biopsies will be acceptable 
for determination of PD-L1 status.
Tumor Tissue Collection: PD-L1 Status
All subjects should submit either a newly obtained core or excisional biopsy or archival 
tissue (fine needle aspirate is not adequate for both archival and new tissue samples) to a 
central laboratory for characterization of PD-L1 status prior to treatment allocation.
Submission of FFPE tumor tissue sample blocks is preferred; if submitting unstained slides, 
the slides should be freshly cut and submitted to the testing laboratory within 14 days from 
the site slide section date; otherwise a new specimen will be requested.
If the sample is determined to be nonevaluable prior to testing by the central laboratory, a 
new sample should be submitted if available.  This may include additional cut slides that are 
outside the 14-day window noted above.
Individual subject PD-L1 status will not be disclosed to investigative sites or trial subjects.
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Procedures Manual.
If the subject signs the Future Biomedical Research consent, any leftover samples that would 
be ordinarily discarded at the end of the main trial will be retained for Future Biomedical 
Research.
Laboratory Procedures/Assessments
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 pretrial to posttrial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.  Safety laboratory results must be reviewed by the investigator or qualified designee 
and found to be acceptable prior to each dose of trial treatment.
Serum/Urine Pregnancy Test
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, will be tested for pregnancy within 72 hours of receiving the 
first dose of trial medication and must be excluded in the event of a positive or borderline-
positive test result. If a urine test is positive or borderline, a serum pregnancy test will be 
required.  The results of the pregnancy testing will not be recorded. Refer to Appendix 12.5
for country-specific requirements.
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Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 8. Refer to 
Appendix 12.5 for country-specific requirements.
Table 8
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine) a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR) b
Platelet Count
Alanine aminotransferase
Protein
aPTT b
White Blood Cell 
(total and 
differential) g
Aspartate aminotransferase
Specific gravity 
Total triiodothyronine (T3)c
Red Blood Cell 
Count
Carbon dioxide (CO2 or 
Bicarbonate) d
Microscopic 
examination, if 
abnormal results 
are noted 
Free thyroxine (FT4)
Absolute 
Neutrophil Count
Calcium
Thyroid-stimulating hormone 
Absolute 
Lymphocyte 
Count
Chloride
Blood for RNA analyses
Creatinine
Blood for plasma biomarker 
analyses
Glucose
Blood for serum biomarker 
analyses
Magnesium
Blood for genetic analysis
Phosphorus
Potassium
Sodium
Total Bilirubin
Direct bilirubin, if total bilirubin is 
elevated above the upper limit of 
normal
Total protein
Blood urea nitrogen g
Uric acid
a Perform on women of childbearing potential only.  Urine pregnancy test is preferred.  If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.  For women of childbearing potential, 
monthly pregnancy testing should be conducted as per local regulations where applicable.
b Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any 
subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the trial.
c Total T3 is preferred; if not available, free T3 may be tested.
d
If these tests are not performed as part of standard of care in your region then these tests do not need to be performed
e Blood draws for thyroid function tests should be performed prior to dosing at the scheduled time point; however,
results can be reviewed after dosing.
f Blood Urea Nitrogen is preferred; if not available, urea may be tested.
g For white blood cell counts (absolute or %) can be provided as per institutional standards.
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Laboratory safety tests will be performed within 2 weeks prior to the first dose of trial 
treatment. After Cycle 1, predose laboratory procedures can be conducted up to 72 hours 
prior to dosing.  An exception is thyroid serologies, which may be performed within 28 days 
prior to first dose.  Subjects eligible for trial re-treatment should have imaging performed 
within 28 days and laboratory tests performed within 14 days prior to the first dose of trial 
treatment in the Second Course Phase.  After Cycle 1, in both the Initial Treatment Phase and 
the Second Course Phase, predose laboratory safety tests can be conducted up to 72 hours 
prior to dosing unless otherwise noted on the flow charts.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment. Unresolved abnormal laboratory test results that are drug-related AEs should be 
followed until resolution. Laboratory tests do not need to be repeated after the end of 
treatment if results are within normal range.
Pharmacokinetic/Pharmacodynamic Evaluations
The collection of PK and ADA samples is being discontinued, as consistent results have been 
seen in PK and ADA across multiple indications including urothelial carcinoma (based on 
data from KN045 and KN052). KN361 evaluates pembrolizumab in combination with small 
molecule drugs, which are not likely to impact pembrolizumab concentrations in any 
clinically meaningful way. Therefore, PK and ADA data from KN045 and KN052 support 
discontinuation of PK and ADA in KN361. Overall, the PK profile of pembrolizumab is 
consistent with that of other humanized mAbs, which typically have a low CL and a limited 
central volume of distribution (Vc).  The observed incidence of treatment-emergent ADA in 
evaluable subjects based on a pooled analysis of multiple indication is low (<2%).  In 
addition, total incidence rate of treatment-emergent neutralizing positive subjects is also low 
(<0.5%).
Blood samples collected for PK and ADA from subjects enrolled under the base protocol 
may be stored. Analyses will be performed only if required.  
Pharmacokinetic data may also be analyzed using nonlinear mixed effects modeling.  Based 
on PK data obtained in this trial as well as PK data obtained from other trials, a population 
PK analysis may be performed to characterize PK parameters (Clearance, Volume of 
Distribution) and evaluate the effect of extrinsic and intrinsic factors to support the proposed 
dosing regimen. Pharmacokinetic data will also be used to explore the exposure-response 
relationships for pembrolizumab antitumor activity/efficacy as well as safety in the proposed 
patient population, if feasible. The results of these analyses, if performed, will be reported 
separately.
7.1.3.3.1 Exploratory Drug-drug Interaction Analysis
As pembrolizumab is an IgG4 antibody that is administered parentally and cleared by 
catabolism, drug-drug interactions are not anticipated to affect exposure of pembrolizumab, 
cisplatin, gemcitabine and carboplatin.  Therefore, no investigation of drug-drug interaction 
is conducted in this protocol.
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Blood for RNA Analyses, Plasma Biomarker Analyses, and Serum Biomarker 
Analyses
Sample collection, storage, and shipment instructions for blood for RNA analyses, plasma 
biomarker analyses and serum biomarker analyses samples will be provided in the 
Procedures Manual.
Any leftover samples from the RNA analyses, plasma biomarker 
analyses and serum biomarker analyses will be stored for Future Biomedical Research if the 
subject signs the Future Biomedical Research consent.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual. 
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
o
Leftover DNA for future research.
o
Leftover main trial tumor
o
Leftover RNA from blood for RNA analyses
o
Leftover plasma from blood for plasma biomarker analyses
o
Leftover serum from blood for serum biomarker analyses
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end of treatment visit should be performed at the time of discontinuation.  
Any adverse events 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.  Subjects who discontinue from trial treatment for any reason 
listed in Section 5.8 – Subject Withdrawal/Discontinuation Criteria should return to the site 
for a Safety Follow-up Visit (described in Section 7.1.5.3.2). Thereafter, subjects who 
discontinued for confirmed radiographic disease progression by BICR should then proceed to 
the Survival Follow-up Phase of the trial (described in Section 7.1.5.3.4 – Survival Follow-
up Assessments). All other subjects should remain on trial and should continue trial-related 
disease assessments including imaging on schedule until 1) the start of new anticancer
treatment, 2) confirmed radiographic disease progression by the BICR, 3) death, or 4) the end 
of trial, whichever comes first.
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 
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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.
Blinding/Unblinding
This is an open-label trial; there is no blinding for this trial.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
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:

Laboratory equipment as required for inclusion laboratory tests and trial assessments

Imaging equipment- as required for trial objectives

Infusion equipment- as required for administering drug product.
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Pharmacy 
Manual and SIM.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
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Screening
Approximately 42 days prior to enrollment, potential subjects will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5.1 – Entry Criteria.  Visit 
requirements are outlined in Section 6.0 – Trial Flow Chart.
After providing main trial consent, subjects will be assigned a screening number.  Subjects 
must sign the main trial consent prior to submitting existing tissue samples and/or 
undergoing a new biopsy. Requirements pertaining to submission of tissue samples are
found in Section 7.1.2.8 – Tumor Imaging and Assessment of Disease.
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 the specified time 
frame.
Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment, except for the following:

Informed consent form (ICF) signed within 42 days. ICF must be signed prior to 
completing any protocol-specified procedure.

ICF
for Future Biomedical Research (optional) signed within 42 days of 
randomization.

Archival or Newly Obtained Tissue Collection for biomarker analysis to be obtained
within 42 days prior to randomization.

Laboratory tests are to be performed within 2 weeks of trial initiation.

For women of reproductive potential, a urine pregnancy test will 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 will be required (performed by the
local trial site laboratory).
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.
The Subject Identification Card will be updated with the screening number.
Treatment Period
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related
details are provided in Section 7.1 – Trial Procedures.
7.1.5.2.1 Second Course Phase (Re-treatment Period)
Subjects who stop pembro only or combo with stable disease (SD), partial response (PR), or 
CR, may be eligible for up to 1 year (17 cycles) of pembrolizumab if they experience disease 
progression after stopping pembro only or combo treatment.  This re-treatment is termed the
Second Course Phase of this trial and is only available if the trial remains open and the 
subject meets the following conditions.
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EITHER
o
Stops initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1

Is treated for at least 8 cycles
with pembrolizumab before 
discontinuing therapy.

Received at least 2 treatments with pembrolizumab beyond the date 
when the initial CR was declared.

If enrolled to the combo
arm received at least 4 cycles of 
chemotherapy.
OR
o
Subject has SD, PR, or CR and stops pembrolizumab treatment after 35 cycles
of trial treatment for reasons other than disease progression or intolerability.
AND
o
Experiences a BICR verification of radiographic disease progression after 
stopping their initial treatment with pembrolizumab.
o
Does not receive any anticancer
treatment since the last dose of 
pembrolizumab.
o
Has a performance status of 0, 1, or 2 on the ECOG Performance Scale.
o
Demonstrates adequate organ function as detailed in Section 5.1.2 – Subject 
Inclusion Criteria.
o
Female subjects of childbearing potential should have a negative urine or
serum pregnancy test within 72 hours prior to receiving re-treatment with trial
medication.
o
Female subjects of childbearing potential should be willing to use 2 methods 
of birth control or be surgically sterile, or abstain from heterosexual activity 
for the course of the trial through 120 days after the last dose of 
pembrolizumab or 180 days after chemotherapy treatment. (Reference Section 
5.7.2 – Contraception).  Subjects of child bearing potential are those who have 
not been surgically sterilized or have not been free from menses for >1 year.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
o
Male subjects should agree to use an adequate method of contraception 
starting with the first dose of trial therapy for the course of the trial through 
120 days after the last dose of pembrolizumab or 180 days after chemotherapy 
treatment.  (Reference Section 5.7.2 – Contraception).
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
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o
Does not have a history or current evidence of any condition, therapy, or
laboratory abnormality that might interfere with the subject’s participation for 
the full duration of the trial or is not in the best interest of the subjects to 
participate, in the opinion of the treating investigator.
Subjects who restart treatment will be re-treated at the same dose frequency as when they last 
received pembrolizumab.  Treatment will be administered for up to 1 additional year.
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
Posttreatment Visits
7.1.5.3.1 Discontinuation Visit
The Discontinuation Visit should occur at the time study treatment is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow-up Visit, procedures do not need to be repeated.
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures. Additional details regarding 
subject withdrawal and discontinuation are presented in Section 5.8
–
Subject 
Withdrawal/Discontinuation Criteria.
7.1.5.3.2 Safety Follow-up Visit
The mandatory 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 anticancer treatment, 
whichever comes first.
All AEs that occur prior to the Safety Follow-up Visit should be recorded.  Subjects with an 
AE of Grade >1 will be followed until the resolution of the AE to Grade 0 to 1 or until the 
beginning of a new anticancer therapy, whichever occurs first.  Serious AEs that occur within 
90 days of the end of treatment or before initiation of a new anticancer treatment should also 
be followed up and recorded
Subjects who are eligible for re-treatment with pembrolizumab (as described in 
Section 7.1.5.2.1 – Second Course Phase) may have up to 2 Safety Follow-up Visits, 1 after 
the Treatment Period and 1 after the Second Course Phase.
Procedures and assessments performed at the Safety Follow-up Visit and beyond should 
follow guidelines described in Section 6.0 – Trial Flow Chart.  All AEs that occur within the 
30-day Safety Follow-up Visit should be recorded. In subjects who start another anticancer
therapy before 30 days after discontinuation of trial therapy, the Safety Follow-up Visit 
should occur prior to the subject receiving another cancer therapy.
7.1.5.3.3 Efficacy Follow-up
Subjects who complete the protocol-required cycles of study intervention or who discontinue 
trial treatment for a reason other than disease progression will remain on trial, will move into 
the Efficacy Follow-up, and will have tumor imaging to monitor disease status (including 
VS, ECOG, anticancer treatment and AE assessments, as outlined in the flow chart) every 
9 weeks (63 days ±7) after randomization for the first 54 weeks and then every 12 weeks 
(84 days ±7) thereafter. Every effort should be made to collect information regarding disease 
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status until the start of new anticancer therapy, disease progression, death, end of study, or if 
the subject begins re-treatment with pembrolizumab as detailed in Section 7.1.5.2.1 – Second 
Course Phase. Information regarding poststudy anticancer treatment will be collected if new 
treatment is initiated. Subjects who completed all efficacy assessments and/or will not have 
further efficacy assessments must enter the Survival Follow-up Phase. 
Subjects who are eligible to receive re-treatment with pembrolizumab according to the 
criteria in Section 7.1.5.2.1 will move from the Efficacy Follow-Up Phase to the Second 
Course Phase when they experience disease progression. Details are provided in Section 6.3
– Trial Flow Chart for Second Course Phase (Re-treatment for Pembrolizumab arms ONLY)
for re-treatment with pembrolizumab.
7.1.5.3.4 Survival Follow-up Assessments
Once a subject experiences confirmed disease progression or starts a new anticancer therapy, 
the subject moves into the Survival Follow-up Phase and should be contacted approximately
every 12 weeks (84 days +/-7) to assess for survival status until death, withdrawal of consent, 
or the end of the study, whichever occurs first. This can be performed in a variety of 
manners including phone, email, chart review, or review of public records. 
Post-trial 
treatments and the subject’s response to them will also be collected.
The first survival follow-up assessment should be scheduled as described below: 
For subjects who discontinue treatment intervention and who will not enter the Efficacy 
Follow-up Phase, the first survival follow-up assessment will be scheduled 12 weeks after the 
discontinuation visit and/or Safety Follow-up Visit (whichever is last).  
For subjects who completed assessments in the Efficacy Follow-up Phase, the first survival 
follow-up assessment will be scheduled 12 weeks after the last Efficacy Assessment 
Follow-up Visit has been performed.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested at any time during the course of the study by the 
Sponsor.  For example, updated survival status may be requested prior to, but not limited to 
an external DMC review, interim and/or final analysis.  Upon Sponsor notification, all 
participants who do not/will not have a scheduled study visit or study contact during the 
Sponsor defined time period will be contacted for their survival status (excluding participants 
that have previously recorded a death event in the collection tool).
Assessing and Recording Adverse Events
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 
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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 clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or 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. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event 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).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
An overdose for all other trial treatments will be defined as any dose exceeding the 
prescribed dose by 20%. In the event of overdose, the subject should be observed closely for 
signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated.
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by ≥1,000 mg (5 times the dose). No specific information is 
available on the treatment of overdose of pembrolizumab. 
In the event of overdose, 
pembrolizumab should be discontinued and 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 
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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 by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
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.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or 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.  
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any AEs 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 another important medical event. 
Note: In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same timeframe as SAEs to 
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meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 9 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any SAEs, or follow-up to a SAE, including death due to any cause
other than progression of the cancer under study (reference Section 7.2.3.3 for additional 
details), that occurs to any subject must be reported within 24 hours to the Sponsor if it 
causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including, but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any SAE, or follow up to a SAE, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), whether or not related to the Sponsor’s product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines.
Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any SAE, 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 
following consent through the end of the specified Safety Follow-up period specified in the 
paragraph above, or at any time outside the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor.  
All subjects with SAEs must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures 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).
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3 – Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under trial.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under trial will be forwarded to Global Safety as an SAE within 
24 hours of determination that the event is not progression of the cancer under trial.
Evaluating Adverse Events
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.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
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Table 9
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) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. 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 
Sponsor’s 
Product
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 the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Trial Steering Committee
This trial will be conducted in consultation with a Trial Steering Committee.  The Trial 
Steering Committee comprises:

Sponsor personnel 

Investigators participating in the trial 

Consulting therapeutic-area experts and clinical trialists 
The Trial Steering Committee will include the PI and co-PI of the study, the representative 
regional senior investigators and help with recommendations and advice regarding 
enrollment and trial-specific questions. The Trial Steering Committee will work with the 
Sponsor clinical lead of the study to support the conduct of the study.
Specific details regarding responsibilities and governance of the Trial Steering Committee 
will be described in a separate charter.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
DMC regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
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Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the trial.  If, after the 
trial has begun, but prior to any database lock for any interim or final analysis of the primary 
endpoints of the trial, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH [International Council for Harmonisation] Guideline E-9).  Changes to exploratory 
or other nonconfirmatory analyses made after the protocol has been finalized, but prior to 
unblinding/final database lock, will be documented in a supplemental Statistical Analysis 
Plan (sSAP) and referenced in the Clinical Study Report (CSR) for the trial.  Post hoc 
exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan (SAP) are summarized below. 
The 
comprehensive plan is provided in Sections 8.2 to 8.12.
Key Elements of the Statistical Analysis Plan
Trial Design Overview
A Phase III randomized controlled clinical trial of 
pembrolizumab (MK-3475) with or without platinum-
based combination chemotherapy versus chemotherapy 
alone in subjects with advanced urothelial carcinoma.
Treatment Assignment
A total of approximately 990 eligible subjects will be 
randomized to receive pembrolizumab combined with 
chemotherapy (combo), pembrolizumab alone (pembro 
only), and chemotherapy alone (chemo only) with 1:1:1 
allocation ratio (approximately 330 subjects in each arm).
Randomization will be stratified for the following factors:
1. Chemotherapy: Cisplatin or Carboplatin
2. PD-L1 expression (CPS ≥10% or CPS <10%)
This is an open-label trial.
As of 21-FEB-2018, subjects who have tumors that are
PD-L1 CPS <10% will only be randomized to the combo 
arm or chemo only arm. There will be no change to 
randomization for subjects who have tumors that are
PD-L1 CPS ≥10%. 
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Analysis Populations
Efficacy: Intention-to-treat Population (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
1. Progression-free Survival (PFS) per RECIST 1.1 as 
assessed by BICR for all subjects.
2. Overall survival (OS) for PD-L1 CPS ≥10% and all 
subjects, respectively.
Key 
Secondary 
Endpoints
Objective Response Rate (ORR) per RECIST 1.1 as 
assessed by BICR for all subjects
Statistical Methods for 
Key Efficacy Analyses
The primary hypotheses will be evaluated by comparing 
combo to chemo only with respect to PFS; combo to 
chemo only, and pembro only to chemo only with respect 
to OS using a stratified log-rank test. Estimation of the 
hazard ratio (HR) will be performed using a Cox 
regression model. Event rates over time will be estimated 
within each treatment group using the Kaplan-Meier 
method.
Statistical Methods for 
Key Safety Analyses
The analysis of safety results will follow a tiered 
approach. The tiers differ with respect to the analyses that 
will be performed. No Tier 1 events are defined for this 
trial. Tier 2 parameters will be assessed via point estimates 
with 95% CIs provided for between-group comparisons; 
only point estimates by treatment group are provided for 
Tier 3 safety parameters. The between-treatment CIs will 
be calculated using the Miettinen and Nurminen method
[53]. No formal treatment comparisons with p-values will 
be conducted.
Interim Analyses
Two interim efficacy analyses will be performed in this 
trial.  Results will be reviewed by an external DMC.  Details 
are provided in Section 8.7. 

Timing: The first interim analysis will be performed
when approximately 347 PFS events have been 
observed in combo and chemo only arms in all 
subjects. 
The second interim analysis will be 
performed when approximately 357 OS events have 
been observed in combo and chemo only arms in all 
subjects.  Testing: Inferential analyses for PFS will 
be provided for all subjects and for OS will be 
provided for PD-L1 CPS ≥10% and all subjects.
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Multiplicity
The Type I error rate over the multiple treatment 
comparisons and multiple primary endpoints and key 
secondary endpoints will be strongly controlled by the 
graphical approach of Maurer and Bretz [54]. 
The 
primary and key secondary hypotheses are divided into 2 
sets related to PFS and OS/ORR, respectively. 
A 
Bonferroni approach is used to control the Type I error 
rate alpha at 2.5% (one-sided), with respectively 0.5% and 
2% allocated to PFS and OS initially. The hypotheses 
related to ORR will be tested after all OS related 
hypotheses are successfully tested. Within each set, a step-
down approach is used to control the Type I error rate. 
The Type I error allocated to a set of hypotheses that is
successfully tested will be re-distributed for the testing of 
hypotheses in another set.
Sample Size and Power 
The planned sample size is 990 subjects.  For the OS 
analysis in all subjects, the trial has about 94% power to 
show
that 
pembrolizumab 
in 
combination 
with 
chemotherapy is superior to chemotherapy at an initially 
assigned one-sided 2.0% alpha level when the underlying 
HR is 0.7.
The PFS analysis in all subjects has 
approximately 97% power to show that combo is superior 
to chemo only at an initially assigned one-sided 0.5% 
alpha level when the underlying HR is 0.675.
Abbreviations:
BICR=blinded 
independent 
central 
review; 
chemo=chemotherapy 
only+SOC; 
CI=confidence interval; Combo=pembrolizumab+chemotherapy+SOC; CPS=Combined Positive Score for 
PD-L1 
positivity; 
DMC=data 
monitoring 
committee; 
PD-L1=programmed 
death-ligand 
1; 
pembro=pembrolizumab only; PFS=progression-free survival; RECIST=Response Evaluation Criteria in 
Solid Tumors.
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this trial will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for trial treatment 
assignment for this protocol, and the randomization will be implemented in IVRS.
Although the trial is open-label, analyses or summaries generated by randomized treatment 
assignment, and actual treatment received status will be limited and documented. In addition, 
BICR evaluation of imaging data will be performed.
The external DMC will serve as the primary reviewer of the unblinded results of the interim 
analyses and will make recommendations for discontinuation of the trial or modification to 
an EOC of the Sponsor. Depending on the recommendation of the external DMC, the 
Sponsor may prepare a regulatory submission. 
If the external DMC recommends 
modifications to the design of the protocol or discontinuation of the trial, this EOC and 
limited additional Sponsor personnel may be unblinded to results at the treatment level to act 
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on these recommendations. Additional logistical details, revisions to the above plan and data 
monitoring guidance will be provided in the DMC Charter.
Hypotheses/Estimation
Objectives and hypotheses of the trial are stated in Section 3.0 – Objective(s) and 
Hypothesis(es).
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
Efficacy Endpoints
Primary
Progression-free survival – RECIST 1.1 by BICR
Progression-free-survival is defined as the time from randomization to the first documented 
disease progression per RECIST 1.1 based on BICR or death due to any cause, whichever 
occurs first. See Section 8.6 – Statistical Methods for the censoring rules.
Overall Survival
Overall survival is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.
Key Secondary
Objective Response Rate – RECIST 1.1 by BICR
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a CR or PR. Responses are based on BICR per RECIST 1.1.
Information on other efficacy endpoints will be provided in sSAP. 
Safety Endpoints
Safety measurements are as described in Section 7.1.2 – Clinical Procedures/Assessments.
Analysis Populations
Efficacy Analysis Populations
The intention-to-treat (ITT) population will serve as the primary population for the analysis 
of efficacy data in this trial.
Subjects will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the ITT population.  Details on the approach to handling 
missing data are provided in Section 8.6 – Statistical Methods.
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Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this trial.  The ASaT population consists of all randomized subjects who received at least 
1 dose of trial treatment. Subjects will be included in the treatment group corresponding to 
the trial treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects this will be the treatment group to which they are randomized.  
For subjects who take incorrect trial treatment for only part of the treatment period, AEs will 
be analyzed based on the period when the correct treatment occurs. In addition, a narrative 
will be included to describe any AEs that occur during the time the subjects receive the 
incorrect treatment. Subjects who take incorrect trial treatment for the entire treatment 
period will be included in the treatment group corresponding to the trial treatment actually 
received.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of trial
treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 8.6 – Statistical Methods.
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 8.6.2 – Statistical 
Methods for Safety Analyses. 
Efficacy results that will be deemed to be statistically 
significant after consideration of the Type I error control strategy are described in 
Section 8.8 – Multiplicity. Nominal p-values computed for other efficacy analyses should be 
interpreted with caution due to potential issues of multiplicity, sample size, etc.
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and key secondary 
objectives.  Methods related to other objectives will be described in the sSAP.
Table 11
summarizes the primary analysis approach for primary and key secondary efficacy endpoints.
Progression-free Survival (PFS) 
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., hazard ratio) between the 
treatment arms. The HR and its 95% confidence interval (CI) from the stratified Cox model 
with Efron’s method of tie handling and with a single treatment covariate will be reported. 
The stratification factors used for randomization (see Section 5.4 – Stratification) will be 
applied to both the stratified log-rank test and the stratified Cox model.  Note that the 
stratified analyses for primary and secondary objectives will use the stratification information 
collected in the IVRS.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
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documented. For the primary analysis, for subjects who have PD or death documented after 
≤ 1 missed disease assessment and before new anticancer therapy, if any, then these subjects 
will be counted as having events at date of documented PD or death. For subjects who have 
PD or death documented immediately after ≥2 consecutive missed disease assessments or 
after new anticancer therapy, if any, then the PFS will be censored at last disease assessment 
prior to the earlier date of ≥2 consecutive missed disease assessment and new anticancer
therapy, if any. For subjects who have no PD and no death, the PFS will be censored at last 
disease assessment unless there is new anticancer treatment initiated, when the PFS will be 
censored at last disease assessment before new anticancer treatment. Sensitivity analyses will 
be performed for comparison of PFS based on the investigator’s assessment.
To evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 2 sensitivity 
analyses will be performed with a different set of censoring rules. For the first sensitivity 
analysis, all PD or death will be counted as an event; all no PD and no death will be censored 
at the last disease assessment. For the second sensitivity analysis, not only all PD or death 
will be counted as an event, no PD and no death will be counted as an event as well, except 
that the subject is still in treatment or discontinues the treatment due to complete response
and no new anticancer therapy is initiated. If a subject meets multiple criteria for censoring, 
the censoring criterion that occurs earliest will be applied. The details of censoring rules for 
primary and sensitivity analyses are summarized in Table 10.
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Table 10
Censoring Rules for Primary and Sensitivity Analysis of PFS
Primary 
Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death documented 
after ≤ 1 missed disease 
assessment, and before new 
anticancer therapy, if any
Progressed at 
date of 
documented PD 
or death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
PD or death documented 
immediately after ≥2 
consecutive missed disease 
assessments or after new 
anticancer therapy, if any
Censored at last 
disease 
assessment 
prior to 
the earlier date 
of ≥2 
consecutive 
missed disease 
assessment and 
new anticancer
therapy, if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
No PD and no death; and 
new anticancer treatment is 
not initiated
Censored at last 
disease 
assessment 
Censored at last 
disease assessment 
Progressed at treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at 
last disease assessment 
if still on study 
treatment or completed 
study treatment.
No PD and no death; new 
anticancer treatment is 
initiated
Censored at last 
disease 
assessment 
before new 
anticancer 
treatment 
Censored at last 
disease assessment
Progressed at date of 
new anticancer 
treatment
Abbreviation: PD=progressive disease.
Overall Survival (OS) 
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., the hazard ratio). The HR and its 95% CI from 
the stratified Cox model with a single treatment covariate will be reported. The stratification 
factors used for randomization (see Section 5.4 – Stratification) will be applied to both the 
stratified log-rank test and the stratified Cox model. Subjects in the control arm may switch 
to another anti-PD-1 treatment following the verification of PD by BICR.
Exploratory 
analyses to adjust for the effect of treatment switching to other PD-1 therapies on OS may be 
performed based on recognized methods, e.g., the Rank Preserving Structural Failure Time 
model proposed by Robins and Tsiatis [55], etc., based on an examination of the 
appropriateness of the data to the assumptions required by the methods.
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Objective Response Rate
Stratified Miettinen and Nurminen’s method will be used for comparison of the ORR 
between 2 treatment groups. The difference in ORR and its 95% CI from the stratified 
Miettinen and Nurminen’s method with strata weighting by sample size will be reported. 
The stratification factors used for randomization (see Section 5.4 – Stratification) will be 
applied to the analysis.
Table 11
Analysis Strategy for Primary and Key Secondary Efficacy Objectives
Endpoint/Variable†
(Description, Time
Point)
Statistical Method†
Analysis Population
Missing Data 
Approach
Primary Endpoint
PFS per RECIST 1.1
as accessed by 
BICR
Testing: Stratified† Log-rank test
Estimation: Stratified Cox model with 
Efron’s tie handling method
ITT
Primary 
censoring rule
Sensitivity 
analysis 1
Sensitivity 
analysis 2
OS
Testing: Stratified† Log-rank test
Estimation: Stratified Cox model with 
Efron’s tie handling method
ITT
Censored at date 
the subject was 
known to be 
alive
Key Secondary Endpoint
ORR per RECIST 
1.1as accessed by 
BICR
Testing: Stratified Miettinen and 
Nurminen method
ITT
Subjects with 
missing data are 
considered 
nonresponders
Abbreviations: ITT=intention-to-treat population; ORR=objective response rate; OS=overall survival; PFS=progression-
free survival; RECIST 1.1=Response Evaluation Criteria in Solid Tumors; BICR=blinded independent central review(er)
† The primary endpoints are under control of Type I error. They will be analyzed for 2 populations: all subjects and 
PD-L1 CPS ≥10% subjects, respectively. Statistical models are described in further detail in the text. For stratified 
analyses, the stratification factors used for randomization (see Section 5.4) will be applied to the analysis model.
The strategy to address multiplicity issues with regard to interim analyses and multiple 
endpoints is described in Section 8.7 – Interim Analyses and in Section 8.8 – Multiplicity.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 12). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) and events that meet predefined limits of change in laboratory, vital signs, and 
ECG parameters are either prespecified as Tier 1 endpoints or will be classified as belonging 
to Tier 2 or Tier 3 based on observed proportions of subjects with an event.
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Tier 1 Events
Safety parameters or AEOSIs that are identified a priori constitute Tier 1 safety endpoints 
that will be subject to inferential testing for statistical significance. AEs that are immune-
mediated or potentially immune-mediated are well documented and will be evaluated 
separately; however, these events have been characterized consistently throughout the 
pembrolizumab clinical development program, and determination of statistical significance is 
not expected to add value to the safety evaluation. Similarly, the combination of 
pembrolizumab and chemotherapy has not been associated with any new safety signals. 
Therefore, there are no Tier 1 events for this protocol.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of subjects with events using the Miettinen and Nurminen method [53], an 
unconditional, asymptotic method. 
Membership in Tier 2 requires that at least 10% of subjects in any treatment group exhibit the 
event; all other AEs and predefined limits of change will belong to Tier 3. The threshold of at 
least 10% of subjects was chosen for Tier 2 events because the population enrolled in this 
study is in critical condition and usually experiences various AEs of similar types regardless 
of treatment; events reported less frequently than 10% of participants would obscure the 
assessment of the overall safety profile and add little to the interpretation of potentially 
meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of participants in 1 of 
the treatment groups) and SAEs (≥5% of participants in 1 of the treatment groups) will be 
considered Tier 2 endpoints. Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in safety 
review, not as a formal method for assessing the statistical significance of the between-group 
differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Table 12
Analysis Strategy for Safety Endpoints
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Specific AE (≥10% of subjects in one of the treatment 
groups)
X
X
Any Grade 3 to 5 AE (≥5% of subjects in one of the 
treatment groups)
X
X
Any SAE (≥5% of subjects in one of the treatment groups)
X
X
Tier 3
Any AE
X
Change from baseline results (laboratory test toxicity grade)
X
Abbreviations: AE=adverse event; CI=confidence interval; SAE=serious adverse event; X=results will be 
provided.
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Time to First Grade 3 to 5 AE
In addition to the tiered approach, exploratory analysis may be performed on the time to the 
first Grade 3 to 5 AE. Time to first Grade 3 to 5 AE is defined as the time from the first day 
of study treatment to the first event of Grade 3 to 5 AE. For subjects without a Grade 3 to 5 
AE, the time to first Grade 3 to 5 AE is censored at 30 days after the last dose of study 
treatment. The Kaplan-Meier method will be used to estimate the curve of time to first Grade 
3 to 5 AE.  The treatment difference in time to first Grade 3 to 5 AE will be assessed by the 
stratified log-rank test. A stratified Cox proportional hazard model with Efron's method of tie 
handling will be used to assess the magnitude of the treatment difference (i.e., the hazard 
ratio).  The hazard ratio and its 95% confidence interval from the stratified Cox model with a 
single treatment covariate will be reported. The same stratification factors used for 
randomization will be applied to both the stratified log-rank test and the stratified Cox model.  
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened and randomized, and the 
primary reasons for screening failure and discontinuation, will be displayed.  Demographic 
variables (such as age), baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
Interim Analyses
Safety Interim Analysis
A safety assessment will take place after 10 subjects in the combo arm have completed 
2 cycles of therapy. If the majority of the enrolled subjects (more than 80%) require a dose 
modification of platinum and/or gemcitabine by the end of the second cycle, the dose of the 
chemotherapies may be reduced for the remainder of the trial. If 9 or 10 of the first 
10 subjects require 2 dose modifications of platinum and/or gemcitabine by the end of the 
second cycle, the Sponsor will consider discontinuing or modifying the treatment dose levels
in the combination arm. Although there is no plan to evaluate efficacy data at the safety 
interim analysis, an administrative alpha-spending of 0.0001 will be imposed for this 
analysis.
Efficacy Interim Analysis
Two interim efficacy analyses will be conducted. Both PFS and OS will be analyzed at the 
time of the interim analysis in the combo arm, pembro only arm, and chemo only arm.
The first interim analysis will be performed if 1) all subjects are enrolled; and 
2) approximately 347 PFS events have been observed in the combo and chemo only arms in 
all subjects. The information fraction of PFS events observed is around 0.65. This is 
projected to occur around 20 months after the trial starts.
The second interim analysis will be performed if approximately 357 OS events have been 
observed among the combo and chemo only treatment arms in all subjects.  The information 
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fraction of OS events observed is around 0.85. This is projected to occur around 28 months 
after the trial starts.
To account for potential delayed treatment effect, which was observed with immunotherapy 
study data external to this study, the final analysis (FA) will take place when all of the 
following requirements are met: 1) at least 22 months after the last subject is randomized; 
2) approximately 616 OS events have been observed among the 3 treatment arms in all 
subjects; and 3) approximately 208 OS events have been observed in pembrolizumab 
monotherapy and chemo only arms in PD-L1 CPS ≥10. The additional follow-up time is 
incorporated into the trial to ensure that the FA is conducted at an appropriate time to 
characterize the potential benefit of immunotherapy, where the treatment effect is most 
pronounced toward the tail of the survival curve. The FA is projected to occur around 
42 months after the trial starts.
Table 13 summarizes the decision guidance for the interim analysis and the FA. The stopping 
boundary shows the values of statistics at the decision boundary across which the 
corresponding null hypotheses will be rejected. The boundary information corresponds to 
tests of the primary hypotheses at each possible Type I error level (please see Section 8.8 –
Multiplicity for details on possible alpha levels for each test). The actual alpha allocated at 
the interim analysis is based on the Hwang-Shih-DeCani alpha-spending function with 
gamma parameter (-4) for OS and Pocock alpha-spending function for PFS.
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Table 13
Decision Guidance (Boundary Z Statistic, P-Value, and Approximate Hazard Ratio) for the Interim and Final Analysis of 
PFS and OS
Hypothesis
Alpha 
Level for 
Hypothesis 
(Alpha at 
IA) a
IA1
IA2
FA
Boundary
Boundary
Boundary
Z 
Statistic
p-value
Approximate 
Observed 
HR at 
Boundary
Z statistic
p-value
Approximate 
Observed 
HR at 
Boundary
Z statistic
p-value
Approximate Observed 
HR at Boundary
H1
0.50%
2.8002
0.0026
0.7398
2.8002
0.0026
0.7741
2.8002
0.0026
0.7843
2.50%
2.2001
0.0139
0.789
2.2001
0.0139
0.8176
2.2001
0.0139
0.8261
H2
2%
2.7336
0.0031
0.6995
2.3469
0.0095
0.7796
2.1266
0.0167
0.8122
2.50%
2.6593
0.0039
0.7061
2.2601
0.0119
0.7865
2.0307
0.0211
0.8196
H3a
2%
2.7336
0.0031
0.6597
2.3469
0.0095
0.7703
2.1266
0.0167
0.8168
2.50%
2.6593
0.0039
0.6703
2.2601
0.0119
0.7816
2.0307
0.0211
0.8289
H3b
2%
2.7336
0.0031
0.6018
2.3469
0.0095
0.702
2.1266
0.0167
0.7441
2.50%
2.6593
0.0039
0.6096
2.2601
0.0119
0.7108
2.0307
0.0211
0.7537
H4a
2%
2.7336
0.0031
0.7717
2.3469
0.0095
0.8593
2.1266
0.0167
0.8949
2.50%
2.6593
0.0039
0.7795
2.2601
0.0119
0.8674
2.0307
0.0211
0.9035
H4b
2%
2.7336
0.0031
0.7021
2.3469
0.0095
0.7815
2.1266
0.0167
0.8139
2.50%
2.6593
0.0039
0.7084
2.2601
0.0119
0.7883
2.0307
0.0211
0.8212
Abbreviations: HR=hazard ratio; IA1=first interim analysis; IA2=second interim analysis; FA=final analysis
a Except for the initially assigned alpha for H1 and H2, all other alphas are conditional on the outcomes of other hypotheses tests from the multiplicity control.
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Please note that the HRs are approximations and the actual alpha levels and interim analysis 
boundaries will be determined from the actual number of events observed at the time of the 
interim analyses and the corresponding alpha-spending function. The boundaries for the FA
will be adjusted according to the actual alpha spent at the interim analyses and the actual 
number of events observed at the interim analyses and FA.
More details on the FA are in Section 8.9 – Sample Size and Power Calculations.
Results of the interim analyses will be reviewed by an external DMC. Depending on the 
recommendation of the DMC, the Sponsor may prepare a regulatory submission if any of the 
primary objectives are met at interim analysis. Further details of interim analyses will be 
incorporated into the DMC Charter.
Multiplicity
The multiplicity strategy specified in this section will be applied to the primary hypotheses 
on superiority for PFS, superiority and noninferiority in OS, and key secondary hypotheses 
of superiority of ORR.
The overall Type I error across the testing of the PFS, OS, and ORR hypotheses is strongly 
controlled at =2.5% (one-sided).
The multiplicity strategy will follow the graphical 
approach of Maurer and Bretz [54].  Figure 3 provides the multiplicity strategy for the trial.
The arrows on the diagram show how the Type I error allocated to a null hypothesis that is 
successfully rejected will be redistributed for the testing of the other hypotheses. Please note 
that the arrows do not necessarily indicate the testing order.
The primary hypotheses are 
divided into a set for PFS testing and a second set for OS/ORR testing. A Bonferroni 
approach is used to control the Type I error rate alpha at 2.5% (1-sided), with 0.5% and 2% 
initially allocated to the PFS and OS/ORR set, respectively.
Within the PFS set, the hypotheses H1 will be tested. The alpha allocated to the PFS set will 
be shifted to the OS/ORR set if the null hypothesis of H1 is rejected at the interim or final 
analysis, and the alpha level for testing OS/ORR hypotheses at the interim and final analysis 
will be adjusted using the Hwang-Shih-DeCani alpha-spending function with gamma 
parameter (-4).
Within the OS/ORR set, a step-down approach will be used to control the Type I error rate.
The primary OS hypotheses will be tested in the order of H2, H3a, H3b, H4a, and H4b based 
on the order of projected power and corresponding relationship between noninferiority and 
superiority tests. The noninferiority hypotheses are tested before corresponding superiority 
hypotheses.  The superiority in ORR will be tested after the superiority in all OS related 
hypotheses is shown. After demonstrating the superiority in ORR, the alpha will be shifted 
from the OS/ORR set to the PFS set.  In the PFS set, when the hypothesis H1 is tested, the 
possible alpha levels are 0.5% and 2.5% corresponding to without and with alpha level 
shifted from the OS/ORR set, respectively.  In the OS/ORR set, when a hypothesis is tested, 
the possible alpha levels are 2% and 2.5% corresponding to without and with alpha level 
shifted from the PFS set, respectively.
Please note that both PFS and OS/ORR endpoints have initially been assigned an alpha level, 
0.5% for PFS and 2% for OS/ORR set. Therefore, if the PFS hypothesis H1 is not rejected, 
only PFS testing will be stopped and there will be no impact on OS/ORR testing with its 
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initially assigned alpha and vice versa. Furthermore, if the null hypothesis in the PFS set H1 
is rejected, then the initially assigned alpha level 0.5% will be recycled to the OS/ORR set 
and the hypotheses in the OS/ORR set will be tested at alpha level equal to 2.5%. The 
consequence of this recycling is that some null hypotheses in the OS/ORR set that could not 
be rejected at the alpha level equal to 2% might be rejected with a higher alpha level (2.5%). 
Similarly, if all null hypotheses related to OS/ORR are rejected, then the alpha level 2% will 
be recycled to the PFS set and increase the power of testing PFS related hypothesis H1.
Figure 3
Multiplicity Strategy
Abbreviations: 
chemo=chemotherapy
only+SOC; 
Combo=pembrolizumab
+chemotherapy+SOC; 
FWER=family-wise error rate; ORR=objective response rate; OS=overall survival; PD-L1=programmed death-
ligand 1; pembro=pembrolizumab only; PFS=progression-free survival; SOC=standard of care.
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The ORR hypotheses in all subjects will be tested following a group sequential approach.  
The 2 ORR hypotheses are initially assigned Type I error rates of 0% and thus, cannot be
tested unless the null hypothesis of H4b (superiority of OS pembro only vs chemo only in all 
subjects) is successfully rejected.  The ORR hypothesis of pembro only vs chemo only in all 
subjects can only be tested after the ORR hypothesis of combo vs chemo only in all subjects 
is successful.  Depending on the results from the primary hypotheses testing, the ORR 
hypothesis can be tested at different Type I error levels.  The nominal Type I error rates for 
the interim analyses and final analysis allowing tight control of the overall Type I error will 
be distributed by an alpha-spending function of Hwang-Shih-DeCani with gamma parameter 
(-4) based on the information fraction.  The information fraction for ORR analysis is 
determined by the proportion of subjects who have “mature ORR information”, defined as 
subjects who enrolled at least 27 weeks prior to the interim data cutoff date and thus had an 
opportunity to have at least 3 scheduled scans if not discontinued.  Only subjects with 
“mature ORR information” will be included into the ORR analysis.
Sample Size and Power Calculations
This trial was designed to randomize a total of approximately 990 subjects into the combo, 
pembro only, and chemo only arms with a 1:1:1 ratio. Beginning on 21-FEB-2018, subjects 
who had tumors that were PD-L1 CPS <10% were only randomized to the combo arm or 
chemo only arm. There was no change to randomization for subjects who had tumors that 
were PD-L1 CPS ≥10%. As a result of this change, there will be a small imbalance leading 
to more subjects in the combo and chemo only arms and fewer subjects in the pembro only
arm. Among all subjects, approximately 50% were expected to be PD-L1 CPS ≥10%.
The interim analyses of the OS and PFS trial endpoints will be event driven (ie, the testing of 
the OS and PFS hypotheses are conducted upon accumulating a preset number of events).
The FA will take place when all of the following requirements are met: 1) at least 22 months 
after the last subject is randomized; 2) approximately 616 OS events have been observed 
among the 3 treatment arms in all subjects; and 3) approximately 208 OS events have been 
observed in pembrolizumab monotherapy and chemo only arms in PD-L1 CPS ≥10.
The sample size was calculated based on the following assumptions: 1) A total of 
990 subjects and among them 495 are PD-L1 CPS ≥10% 2) both OS and PFS follow 
exponential distributions and with median of 13.5 and 7.5 months, respectively, in the chemo 
only arm; 3) the HRs are listed in Table 14; 4) a yearly dropout rate for OS and PFS is 2% 
and 5%, respectively; and 5) the noninferiority margin is set at HR equal to 1.1.
Table 14
Assumptions of Hazard Ratios for Superiority between Different Conditions
PFS all subjects Combo vs Chemo only
0.675
OS all subjects Combo vs Chemo only
0.7
OS PD-L1 CPS ≥10% Pembro only vs Chemo only
0.65
OS all subjects Pembro only vs Chemo only
0.75
Abbreviations: chemo=chemotherapy+SOC; 
combo=pembrolizumab+chemotherapy+SOC; PD-L1=programmed death-ligand 1; 
pembro=pembrolizumab; PFS=progression-free survival; OS=overall survival.
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The assumptions on median survival months were based upon historical data.
The 
noninferiority margin was based on the 25% of the effect of the assumed effect [56] of 
chemotherapy versus placebo with a HR of 0.7 (FDA Guidance for Non-Inferiority Clinical 
Trials) [57]. In addition, the HR 1.1 is also the lower bound of the range of margin for 
noninferiority cancer trials that used time-to-event primary outcomes [58].
Table 15 shows the approximate power of primary hypotheses tests under specific scenarios. 
Please note that this is marginal power for each hypothesis. Depending on the actual 
outcomes from the multiplicity control, a hypothesis could be tested at more than one alpha 
level. Please see Section 8.8 – Multiplicity for details on possible alpha levels.  The other
detailed information on boundary, and HR, etc. is shown in Table 13.
Table 15
Power of Primary Hypotheses Tests
Hypothesis
Alpha Level†
Power†
H1: PFS, all subjects superiority, 
Combo vs Chemo Only
0.5%
97%
2.5%
99%
H2: OS, all subjects, superiority, 
Combo vs Chemo Only
2%
94%
2.5%
95%
H3a: OS, PD-L1 CPS ≥10%, 
noninferiority, 
Pembro Only vs Chemo Only
2%
95%
2.5%
96%
H3b: OS, PD-L1 CPS ≥10%, 
superiority, Pembro Only vs Chemo 
Only
2%
85%
2.5%
87%
H4a: OS, all subjects, noninferiority, 
Pembro Only vs Chemo Only
2%
97%
2.5%
97.5%
H4b: OS, all subjects, superiority, 
Pembro Only vs Chemo Only
2%
81%
2.5%
84%
Abbreviations: chemo=chemotherapy+SOC; combo= pembrolizumab+chemotherapy+SOC; H=Hypothesis; 
PD-L1=programmed death-ligand 1; pembro=pembrolizumab; PFS=progression-free survival; OS=overall 
survival.
† Except for the initially assigned alpha for H1 and H2, all other alphas and powers are conditional on the 
outcomes of other hypotheses from the multiplicity control.
Note that power of noninferiority tests is based on the same hazard ratio assumptions as used in the 
corresponding superiority tests
Please note that the actual power may be adjusted based on the actual number of events 
observed at the time of the FA.
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of each subgroup.  The 
following are examples of classification variables:

Age category (<65 vs ≥65 years)

Sex (female, male)
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
PD-L1 subgroup (CPS ≥10% vs CPS <10%)

ECOG (0/1 vs 2)

Chemotherapy drug (Investigator choice of cisplatin or carboplatin)

Smoking status (never vs former vs current)
Note that the subgroup identification information will be based on the actual value in the 
database.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the trial. Compliance 
with trial treatment administration will be measured by subjects: 1) receiving unscheduled 
trial agent infusions/injections; 2) missing an infusion/injection. Numbers and percentages of 
subjects and infusion/injection visits with any deviation in these measures will be reported 
for the ITT population.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity 
will also be summarized as appropriate.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
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 16. 
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.
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Table 16
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional 
Information
Pembrolizumab 
(MK-3475) 100 mg/4 mL
Solution for infusion
Provided centrally by the 
Sponsor
Gemcitabine 1000 mg
Lyophilized powder
for IV infusion
Provided centrally by the 
Sponsor or locally by the trial 
site, subsidiary, or designee 
Carboplatin 10 mg/mL
Solution for infusion
Provided centrally by the 
Sponsor or locally by the trial 
site, subsidiary, or designee 
Cisplatin 1 mg/mL
Solution for infusion
Provided centrally by the 
Sponsor or locally by the trial 
site, subsidiary, or designee 
All supplies indicated in Table 16 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 16 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
All supplies will be provided open-label. Pembrolizumab will be provided as nonkitted single 
vials or as single/multi vials in a kit box. The other products will be provided as a kit with a 
single vial.
Clinical Supplies Disclosure
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
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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Discard/Destruction/Returns and Reconciliation
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, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the 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
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.
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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
By signing this protocol, the investigator recognizes that certain personal identifying 
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;
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
The Sponsor is required to record the name and address of each IRB/IEC 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
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 
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allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
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 Council for Harmonisation of Technical 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 
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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 
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.
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Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  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 FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
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 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
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
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
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 
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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. 
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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with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8.
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unfit for cisplatin-based chemotherapy. Lancet Oncol. 2011 Mar;12(3):211-4.
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Dash A, Galsky MD, Vickers AJ, Serio AM, Koppie TM, Dalbagni G, et al.
Impact of renal impairment on eligibility for adjuvant cisplatin-based 
chemotherapy in patients with urothelial carcinoma of the bladder. Cancer. 2006 
Aug 1;107(3):506-13.
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Galsky MD, Chen GJ, Oh WK, Bellmunt J, Roth BJ, Petrioli R, et al. 
Comparative 
effectiveness 
of 
cisplatin-based 
and 
carboplatin-based 
chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol 
2012;23(2):406-10.
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Antonia SJ, Gettinger SN, Man Chow LQ, Juergens RA, Borghaei H, Shen Y, et 
al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-
line NSCLC: Interim phase I results [abstract]. J Clin Oncol. 2014;32 Suppl 
1:5s. Abstract no. 8023.
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[33]
Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. 
Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 
1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated 
Advanced 
Non-Small-Cell 
Lung 
Cancer. 
J 
Clin 
Oncol. 
2015 
Jun 
20;33(18):2004-12.
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Papadimitrakopoulou V, Patnaik A, Borghaei H, Stevenson J, Gandhi L, Gubens 
MA, et al. Pembrolizumab (pembro; MK-3475) plus platinum doublet 
chemotherapy (PDC) as front-line therapy for advanced non-small cell lung 
cancer (NSCLC): KEYNOTE-021 cohorts A and C [abstract]. J Clin Oncol. 
2015 May 29;33(Suppl). Abstract no. 8031.
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Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. 
Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment 
in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-
blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54.
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Plimack ER, Bellmunt J, Gupta S, Berger R, Montgomery B, Heath K, et al. 
Pembrolizumab (MK-3475) for advanced urothelial cancer: updated results and 
biomarker analysis from KEYNOTE-012. Poster session presented at: 2015 
ASCO Annual Meeting; 2015 May 29-Jun 2; Chicago, IL.
[37]
Petrylak DP, Powles T, Bellmunt J, Braiteh FS, Loriot Y, Zambrano CC, et al. A 
phase Ia study of MPDL3280A (anti-PDL1): updated response and survival data 
in urothelial bladder cancer (UBC) [abstract]. Abstracts of the 2015 ASCO 
Annual Meeting; 2015; Chicago, IL: ASCO; 2015. p. 1-2.
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Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et 
al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N 
Engl J Med 2012;366(26):2443-54.
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Bellmunt J, Mullane SA, Werner L, Fay AP, Callea M, Leow JJ, et al. 
Association of PD-L1 expression on tumor-infiltrating mononuclear cells and 
overall survival in patients with urothelial carcinoma. Ann Oncol. 2015 
Apr;26(4):812-7.
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Bellmunt J, de Wit R, Albanell J, Baselga J. A feasibility study of carboplatin 
with fixed dose of gemcitabine in ‘unfit’ patients with advanced bladder cancer. 
Eur J Cancer 2001;37:2212-5.
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Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, et al. A 
prospective randomized trial comparing MVAC and CISCA chemotherapy for 
patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5.
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Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, et al. 
Treatment of patients with metastatic urothelial cancer "unfit" for cisplatin-based 
chemotherapy. J Clin Oncol 2011;29(17):2432-8.
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[43]
Lei AQ, Cheng L, Pan CX. Current treatment of metastatic bladder cancer and 
future directions. Expert Rev Anticancer Ther. 2011 Dec;11(12):1851-62.
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Bamias A, Lainakis G, Kastritis E, Antoniou N, Alivizatos G, Koureas A, et al. 
Biweekly carboplatin/gemcitabine in patients with advanced urothelial cancer 
who are unfit for cisplatin-based chemotherapy: report of efficacy, quality of life 
and geriatric assessment. Oncology. 2007;73(5-6):290-7.
[45]
Linardou H, Aravantinos G, Efstathiou E, Kalofonos C, Anagnostopoulos A, 
Deliveliotis C, et al. Gemcitabine and carboplatin combination as first-line 
treatment in elderly patients and those unfit for cisplatin-based chemotherapy 
with advanced bladder carcinoma: Phase II study of the Hellenic Co-operative 
Oncology Group. Urology 2004;64(3):479-84.
[46]
Food and Drug Administration (CDER, CBER). Guidance for industry: clinical 
trial endpoints for the approval of cancer drugs and biologics. Silver Spring: 
U.S. Department of Health and Human Services; 2007. 19 p.
[47]
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. 
The European Organization for Research and Treatment of Cancer QLQ-C30: a 
quality-of-life instrument for use in international clinical trials in oncology. J 
Natl Cancer Inst 1993;85(5):365-76.
[48]
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol 
group. Ann Med 2001;33:337-43.
[49]
Mehanna HM, Morton RP. Patients’ views on the utility of quality of life 
questionnaires in head and neck cancer: a randomised trial. Clin Otolaryngol 
2006;31:310-6.
[50]
Proakis AG, Harris GB. Comparative penetration of glycopyrrolate and atropine 
across the blood-brain and placental barriers in anesthetized dogs. 
Anesthesiologists 1978;48(5):339-44.
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Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, 
Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic 
urothelial carcinoma who have progressed following treatment with platinum-
based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 Mar 
4. [Epub ahead of print].
[52]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: 
immune-related response criteria using unidimensional measurements. Clin 
Cancer Res. 2013 Jul 15;19(14):3936-43.
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Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
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Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20.
[55]
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials 
using rank preserving structural failure time models. Commun Stat-Theor M 
1991;20(8):2609-31.
[56]
Food and Drug Administration (CDER, CBER). Guidance for Industry: non-
Inferiority clinical trials. Silver Spring: U.S. Department of Health and Human 
Services; 2010. 63 p.
[57]
CDER, CBER.  Guidance for Industry Non-Inferiority Clinical Trials.
[58]
Riechelmann RP, Alex A, Cruz L, Bariani GM, Hoff PM. Non-inferiority cancer 
clinical trials: scope and purposes underlying their design. Ann Oncol. 2013 
Jul;24(7):1942-7.
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
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
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.3 – Future Biomedical 
Research 
Sample 
Collection7.1.3.3 
–
Future 
Biomedical 
Research 
Sample 
Collection7.1.3.3 – Future Biomedical Research Sample Collection7.1.3.3 – Future 
Biomedical Research Sample Collection7.1.3.3 – Future Biomedical Research Sample 
Collection7.1.3.3 – Future Biomedical Research Sample Collection7.1.3.3 – Future 
Biomedical Research Sample Collection7.1.3.3 – Future Biomedical Research Sample 
Collection will be used to study various causes for how subjects may respond to a 
drug/vaccine.  Future biomedical research specimen(s) will be stored to provide a 
resource for future trials conducted by the Sponsor 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 the Sponsor or those working for 
or with the Sponsor.
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 Future 
Biomedical Research.
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, 
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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.  
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.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
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.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical 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.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol and consent. Future Biomedical Research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
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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 the Sponsor using the designated 
mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent 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 the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
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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. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For Future Biomedical Research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor 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.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Council for Harmonisation: 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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ECOG Performance Status Categories 
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J 
Clin Oncol. 1982;5:649-655 http://ecog-acrin.org/resources/ecog-performance-status
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Common Terminology for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI CTCAE Version 4.0 will be 
utilized for AE reporting. (http://ctep.cancer.gov/reporting/ctc.html).
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Country-specific Requirements
France-specific Requirements
Section 5.1.2 Inclusion Criteria
Estimated creatinine clearance is used as an assessment of renal function.
Renal
Estimated creatinine clearance (CrCl) a
(estimated GFR can be used in place of estimated 
CrCl)
≥30 mL/min 
(Note: Subjects are ineligible for cisplatin if 
their estimated creatinine clearance 
<60 mL/min)
a Estimated CrCl should be calculated per institutional standard.
Section 7.1.3.2 Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Estimated creatinine clearance is used as an assessment of renal function.
Chemistry
Estimated Creatinine Clearance
Section 5.1.3 Exclusion Criteria
For subjects that will receive cisplatin if randomized to a chemotherapy arm:
Exclusion Criterion #22: Subjects with estimated creatinine clearance <60 mL/min are not 
eligible for treatment with cisplatin according to the SmPC of the product.
Exclusion Criterion #23: Subjects with Grade ≥2 audiometric hearing loss (25 decibels in
2 consecutive wave ranges) are not eligible for treatment with cisplatin according to the 
SmPC of the product.
Section 5.7.2 Contraception
For women of childbearing potential, a pregnancy test should be conducted prior to Day 1 of 
each cycle
Section 7.1.2.3.1 Full Physical Examination
An audiogram will be included as part of the screening examination.
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Section 7.1.2.3.2 Directed Physical Examination
Audiograms will be included in the directed physical examinations as necessary, as 
determined by the investigator (ie, if subject experiences a hearing-related AE).
Section 7.1.3.1 Serum/Urine Pregnancy Test
Pregnancy testing will continue to be performed prior to each cycle and at the time of 
discontinuation from study treatment.
Section 7.1.3.2 Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
a
For women of childbearing potential, pregnancy testing will continue prior to each cycle 
and at the time of discontinuation from study treatment.
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List of Abbreviations
Abbreviation/Term
Definition
AE
Adverse Event
ADA
Antidrug Antibodies
ALT
Alanine Aminotransferase
aPTT
Activated Partial Thromboplastin Time
ASaT
All Subjects as Treated
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BCG
Bacillus Calmette-Guerin(Tuberculosis vaccine)
BICR
Blinded independent central review(er)
Chemo
In this trial, cisplatin+gemcitabine or carboplatin+gemcitabine (the 
latter only in cisplatin-ineligible subjects) plus SOC
CI
Confidence Interval
Cis
Carcinoma in situ
CNS
Central Nervous System
Combo
In 
this 
trial, 
pembrolizumab 
plus
chemotherapy
(cisplatin+gemcitabine or carboplatin+gemcitabine [the latter only 
in cisplatin-ineligible subjects] plus SOC)
CPS
Combined Positive Score
for PD-L1 positivity
(combined 
expression of tumor cells and inflammatory markers)
CR
Complete Response
CrCl
Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Protein-4
DCR
Disease Control Rate (CR, PR, and SD)
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DRAE
Drug-Related Adverse Event
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire
eEQ-5D
eEuroQol-5 Dimensions
ePRO
Electronic Patient-Reported Outcome
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Abbreviation/Term
Definition
ERC
Ethics Review Committee
ESMO
European Society of Medical Oncology
EuroQol
European Quality of Life
FA
Final analysis
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
Formalin-Fixed, Paraffin-Embedded
GC
Gemcitabine/Carboplatin
GCP
Good Clinical Practice
GEM
Gemcitabine
HIV
Human Immunodeficiency Virus
HR
Hazard ratio
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IgV
Immunoglobulin Variable
IHC
Immunohistochemistry
irAE
Immune-related adverse event
IRB
Institutional Review Board
IrRECIST
Immune-related RECIST
ITT
Intention-To-Treat Population
IUD
Intrauterine Device
IV
Intravenous
IVD
In Vitro Diagnostic
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
KN
Keynote
mAb
Monoclonal Antibody
MCAVI
Gemcitabine plus carboplatin or methotrexate plus carboplatin plus 
vinblastine 
Mg
Milligram
Mg/kg
Milligram per Kilogram
MK-3475
(formerly 
SCH90045)
Merck designation for pembrolizumab
mL
milliliter
MRI
Magnetic Resonance Imaging
MSI
Microsatellite instability
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MVAC
Methotrexate/Vinblastine/Doxorubicin/Cisplatin
NA or N/A
Not Applicable
NCCN
National Comprehensive Cancer Network
NCI
(US) National Cancer Institute
NMIBC
Nonmuscle Invasive Bladder Cancer
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Abbreviation/Term
Definition
NSCLC
Non–Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-Counter (nonprescription)
PD
Progressive Disease
PD-1
Programmed Cell Death 1
PD-L1
Programmed Cell Death-Ligand 1
Pembro
Pembrolizumab (only)
PFS
Progression-free Survival
PI
Principal investigator
PIN
Personal Identification Number
PK
Pharmacokinetic(s)
PR
Partial Response
PRO
Patient-Reported Outcome 
PS
Performance Status
PT
Prothrombin Time
PS
Performance Status
PSA
Prostate-specific Antigen
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RR
Response Rate
SAE
Serious Adverse Event(s)
SAP
Statistical Analysis Plan
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SOC
Standard of Care
SOP
Standard Operating Procedure
sSAP
Supplemental Statistical Analysis Plan
T1DM
Type 1 Diabetes Mellitus
TIL
Tumor-Infiltrating Lymphocyte
TSH
Thyroid-Stimulating Hormone
US
United States
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
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 – TRIAL PROCEDURES (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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