A Phase III Randomized Clinical Trial of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel or Vinflunine in Subjects With Recurrent or Progressive Metastatic Urothelial Cancer
Phase: PHASE3
Conditions: Urothelial Cancer
Sponsor: Merck Sharp & Dohme LLC

Product:  MK-3475 
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase III Randomized Clinical Trial of Pembrolizumab (MK-3475) versus Paclitaxel, 
Docetaxel or Vinflunine in Subjects with Recurrent or Progressive Metastatic Urothelial 
Cancer
IND NUMBER:  122753
EudraCT NUMBER:  2014-002009-40
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
Trial Diagram........................................................................................................ 14
Crossover for Subjects in Control Arm to Pembrolizumab 200 mg Q3W 
Arm ........................................................................................................................ 15
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 16
Primary Objective(s) & Hypothesis(es).............................................................. 16
Secondary Objective(s) & Hypothesis(es)........................................................... 18
Exploratory Objectives......................................................................................... 19
4.0
BACKGROUND & RATIONALE.......................................................................... 19
Background ........................................................................................................... 19
Pharmaceutical and Therapeutic Background .................................................... 19
Pre-clinical and Clinical Trials ........................................................................... 20
Ongoing Clinical Trials....................................................................................... 21
Information on Other Trial-Related Therapy...................................................... 21
Rationale................................................................................................................ 21
Rationale for the Trial and Selected Subject Population .................................... 21
Rationale for Dose Selection/Regimen/Modification......................................... 23
Rationale for the Use of Comparator........................................................... 24
Rationale for Endpoints ...................................................................................... 24
Efficacy Endpoints....................................................................................... 24
4.2.3.1.1
Primary.................................................................................................. 24
4.2.3.1.2
Secondary.............................................................................................. 25
PD-L1 Expression .......................................................................... 25
4.2.3.1.3
Exploratory ........................................................................................... 25
Patient Reported Outcomes............................................................ 25
Safety Endpoints.......................................................................................... 26
Planned Exploratory Biomarker Research................................................... 27
Future Biomedical Research........................................................................ 28
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Benefit/Risk ........................................................................................................... 28
5.0
METHODOLOGY ................................................................................................... 29
Entry Criteria........................................................................................................ 29
Diagnosis/Condition for Entry into the Trial...................................................... 29
Subject Inclusion Criteria.................................................................................... 29
Subject Exclusion Criteria .................................................................................. 32
Trial Treatment(s) ................................................................................................ 34
Dose Selection/Modification .............................................................................. 35
Dose Selection (Preparation) ....................................................................... 35
Dose Modification for Pembrolizumab (MK-3475).................................... 35
5.2.1.2.1
Dose Modification for Standard Treatment with Paclitaxel, 
Docetaxel or Vinflunine........................................................................ 40
Specific Dose Modifications for Vinflunine .................................. 42
Specific Dose Modifications for Paclitaxel.................................... 43
Specific Dose Modifications for Docetaxel ................................... 44
Timing of Dose Administration.......................................................................... 45
Pembrolizumab (MK-3475)......................................................................... 45
Paclitaxel...................................................................................................... 45
Docetaxel ..................................................................................................... 45
Vinflunine .................................................................................................... 46
Trial Blinding/Masking....................................................................................... 46
Randomization or Treatment Allocation............................................................ 46
Stratification.......................................................................................................... 47
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 47
Acceptable Concomitant Medications ................................................................ 47
Prohibited Concomitant Medications.................................................................. 48
Rescue Medications & Supportive Care............................................................. 49
Supportive Care Guidelines for Pembrolizumab (MK-3475)............................. 49
Supportive Care Guidelines for Paclitaxel, Docetaxel and Vinflunine .............. 49
Diet/Activity/Other Considerations..................................................................... 50
Diet...................................................................................................................... 50
Contraception...................................................................................................... 50
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Use in Pregnancy ................................................................................................ 51
Use in Nursing Women....................................................................................... 51
Subject Withdrawal/Discontinuation Criteria................................................... 51
Treatment after Initial Radiologic Progression................................................... 53
Discontinuation of Study Therapy after CR ....................................................... 54
Crossover Phase.................................................................................................. 55
Safety Follow-up Visit........................................................................................ 55
Duration of Follow-up ........................................................................................ 55
Survival Follow-up ............................................................................................. 55
Subject Replacement Strategy............................................................................. 56
Beginning and End of the Trial ........................................................................... 56
Clinical Criteria for Early Trial Termination ................................................... 56
6.0
TRIAL FLOW CHART ........................................................................................... 57
Initial Treatment Phase........................................................................................ 57
Second Course Phase (Retreatment) for Pembrolizumab (MK-3475) Arm 
Only........................................................................................................................ 60
Crossover Phase for Control Arm Only ............................................................. 62
7.0
TRIAL PROCEDURES ........................................................................................... 64
Trial Procedures ................................................................................................... 64
Administrative Procedures.................................................................................. 64
Informed Consent......................................................................................... 64
7.1.1.1.1
General Informed Consent.................................................................... 64
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 65
Inclusion/Exclusion Criteria ........................................................................ 65
Subject Identification Card .......................................................................... 65
Medical History ........................................................................................... 65
Prior and Concomitant Medications Review............................................... 65
7.1.1.5.1
Prior Medications.................................................................................. 65
Prior Treatment Details for Urothelial Cancer............................... 65
7.1.1.5.2
Concomitant Medications..................................................................... 66
Subsequent Anti-Cancer Therapy Status........................................ 66
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Assignment of Screening Number............................................................... 66
Assignment of Randomization Number....................................................... 66
Trial Compliance (Medication/Diet/Activity/Other)................................... 66
Clinical Procedures/Assessments........................................................................ 67
Adverse Event (AE) Monitoring.................................................................. 67
12-Lead Electrocardiogram ......................................................................... 67
Physical Exam.............................................................................................. 67
7.1.2.3.1
Full Physical Exam ............................................................................... 67
7.1.2.3.2
Directed Physical Exam........................................................................ 68
Vital Signs.................................................................................................... 68
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 68
Tumor Imaging and Assessment of Disease................................................ 68
7.1.2.6.1
Initial Tumor Imaging........................................................................... 68
7.1.2.6.2
Tumor Imaging During Trial ................................................................ 69
7.1.2.6.3
Bone Scans............................................................................................ 69
7.1.2.6.4
Assessment of Disease.......................................................................... 70
Tumor Tissue Collection and Correlative Blood Sampling......................... 70
Patient Reported Outcomes (PROs)............................................................. 71
Crossover Phase Assessments and Procedures............................................ 71
Laboratory Procedures/Assessments .................................................................. 71
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 72
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 73
Future Biomedical Research........................................................................ 73
Other Procedures................................................................................................. 73
Withdrawal/Discontinuation........................................................................ 73
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 74
Blinding/Unblinding .................................................................................... 74
Calibration of Critical Equipment................................................................ 74
Visit Requirements.............................................................................................. 74
Screening...................................................................................................... 75
Treatment Period.......................................................................................... 75
7.1.5.2.1
Second Course Phase (Retreatment Period) ......................................... 75
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7.1.5.2.2
Crossover Phase.................................................................................... 77
Inclusion Criteria for Crossover from Control Arm to 
Pembrolizumab ....................................................................................... 77
Exclusion Criteria for Crossover from Control Arm to 
Pembrolizumab ....................................................................................... 78
Post-Treatment Visits................................................................................... 78
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 78
7.1.5.3.2
Follow-up Visits ................................................................................... 79
7.1.5.3.3
Survival Follow-up ............................................................................... 79
Survival Status ............................................................................................. 80
Assessing and Recording Adverse Events .......................................................... 80
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 81
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 81
Immediate Reporting of Adverse Events to the Sponsor.................................... 82
Serious Adverse Events ............................................................................... 82
Events of Clinical Interest............................................................................ 83
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 84
Evaluating Adverse Events................................................................................. 84
Sponsor Responsibility for Reporting Adverse Events ...................................... 87
Trial Governance and Oversight......................................................................... 87
Scientific Advisory Committee........................................................................... 87
Executive Oversight Committee......................................................................... 87
Data Monitoring Committee............................................................................... 87
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 88
Statistical Analysis Plan Summary ..................................................................... 88
Efficacy Analyses ............................................................................................... 88
Safety Analyses................................................................................................... 89
Power and Sample Size....................................................................................... 89
Interim Analysis.................................................................................................. 90
Statistical Analysis Plan ....................................................................................... 90
Responsibility for Analyses/In-House Blinding ................................................. 90
Hypotheses/Estimation ....................................................................................... 91
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Analysis Endpoints ............................................................................................. 91
Efficacy Endpoints....................................................................................... 91
Safety Endpoints.......................................................................................... 92
Analysis Population ............................................................................................ 92
Efficacy Analysis Population....................................................................... 92
Safety Analysis Populations ........................................................................ 93
Statistical Methods.............................................................................................. 93
Statistical Methods for Efficacy Analyses................................................... 93
8.2.5.1.1
Progression-Free Survival (PFS) .......................................................... 93
8.2.5.1.2
Overall Survival (OS) ........................................................................... 96
8.2.5.1.3
Objective Response Rate (ORR) .......................................................... 97
8.2.5.1.4
Response Duration................................................................................ 97
8.2.5.1.5
Exploratory Analyses............................................................................ 97
Statistical Methods for Safety Analyses ...................................................... 98
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses..................................................................................................... 100
Multiplicity ....................................................................................................... 100
Sample Size and Power Calculation ................................................................. 104
Subgroup Analyses and Effect of Baseline Factors.......................................... 106
Interim Analysis................................................................................................ 106
PFS and Interim OS Analysis .................................................................... 107
Final OS Analysis ...................................................................................... 110
Compliance (Medication Adherence)............................................................... 110
Extent of Exposure............................................................................................ 110
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 111
Investigational Product ...................................................................................... 111
Packaging and Labeling Information ............................................................... 111
Clinical Supplies Disclosure............................................................................... 111
Storage and Handling Requirements................................................................ 111
Returns and Reconciliation................................................................................ 112
Standard Policies................................................................................................. 112
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10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 112
Confidentiality..................................................................................................... 112
Confidentiality of Data ..................................................................................... 112
Confidentiality of Subject Records................................................................... 112
Confidentiality of Investigator Information...................................................... 113
Confidentiality of IRB/IEC Information........................................................... 113
Compliance with Financial Disclosure Requirements..................................... 113
Compliance with Law, Audit and Debarment ................................................. 114
Compliance with Trial Registration and Results Posting Requirements...... 116
Quality Management System............................................................................. 116
Data Management............................................................................................... 116
Publications ......................................................................................................... 117
11.0
LIST OF REFERENCES....................................................................................... 119
12.0
APPENDICES......................................................................................................... 125
Merck Code of Conduct for Clinical Trials...................................................... 125
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 127
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 134
Abbreviations ...................................................................................................... 145
ECOG Performance Status................................................................................ 147
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 148
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
Evaluating Response in Solid Tumors .............................................................. 149
Strong Inhibitors and Strong Inducer  of CYP3A4......................................... 150
QT Prolongation Medications............................................................................ 151
13.0
SIGNATURES......................................................................................................... 153
Sponsor's Representative ................................................................................... 153
Investigator.......................................................................................................... 153
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values........................................................ 30
Table 2
Trial Treatment ....................................................................................................... 34
Table 3
Dose Modification Guidelines for Drug-Related Adverse Events ......................... 36
Table 4
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines............................................................................................................... 39
Table 5
Dose Modification Guidelines for Drug-Related Adverse Events on the Active 
Comparator Arm..................................................................................................... 40
Table 6
Vinflunine Dose Modification for Drug-Related Adverse Events ......................... 43
Table 7
Paclitaxel Dose Modification for Drug-Related Adverse Events........................... 44
Table 8
Docetaxel Dose Modification for Drug-Related Adverse Events .......................... 44
Table 9
Imaging and Treatment After 1st Radiologic Evidence of PD............................... 54
Table 10 Laboratory Tests..................................................................................................... 72
Table 11 Evaluating Adverse Events .................................................................................... 85
Table 12
Censoring Rules for Primary and Sensitivity Analyses of PFS ............................ 95
Table 13 Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints ........ 97
Table 14 Analysis Strategy for Safety Parameters.............................................................. 100
Table 15 Cumulative Alpha Spending ................................................................................ 102
Table 16 Summary of Timing, Sample Size and Decision Guidance at the Planned PFS 
and OS Analyses .................................................................................................. 108
Table 17 Summary of Futility Boundary at the Planned Interim Analyses on OS ............. 109
Table 18 Summary of Revised Efficacy Decision Guidance (Selected Scenarios) ............ 109
Table 19 Product Descriptions ............................................................................................ 111
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LIST OF FIGURES
Figure 1
Trial Design
15
Figure 2
Type I Error Reallocation Strategy Following Closed Testing Principle
103
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
2.2
Trial Diagram Figure 1
Replaced with new diagram
New diagram shows survival 
follow-up and the extension 
study
5.2.1
Table 3.  Dose Modification 
Guidelines for Drug-Related 
Adverse Events
Replaced with new table
New table reflects changes to 
dose 
modification 
recommendations
5.2.1
5.6.1
Table 4 Pembrolizumab Infusion 
Reaction Dose modification and 
Treatment Guidelines
Moved from Section 5.6.1 to Section 
5.2.1
New 
organization 
of 
dose 
medication 
and 
infusion
reaction guidelines
7.1.5.3.3
Survival Follow-up
Removed text describing survival 
status
Created new subsection 7.1.5.4 
Survival Status
7.1.5.4
Survival Status
New section and language added to 
state that survival may be requested for 
subjects during any phase of the study
Survival information may be 
collected during any phase of 
the study, not only during 
survival follow-up.
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
5.10
Trial Summary, Duration of 
Participation
Beginning and End of the Trial
Added 
language 
regarding 
the 
potential for subjects to be enrolled in 
an extension study if one becomes 
available.
Enrolling in an extension may 
be available to subjects at the 
conclusion of this study
4.2.2
Rationale for Dose 
Selection/Regimen/Modification
Replaced text describing KN001 with 
current information regarding the 200 
mg Q3W dose
The 200 mg Q3W dose is now 
the 
approved 
dose 
of 
pembrolizumab
6.1
Initial Treatment Phase
Survival status row and table footnote 
revised to detail updates in survival 
sweep collection
Survival status can be assessed 
at any time throughout the trial
6.2
Second Course Phase (Retreatment) 
for Pembrolizumab (MK-3475) 
Arm Only
Survival status row and table footnote 
revised to detail updates in survival 
sweep collection
Survival status can be assessed 
at any time throughout the trial
6.3
Crossover Phase for Control Arm 
Only
Survival status row and table footnote 
revised to detail updates in survival 
sweep collection
Survival status can be assessed 
at any time throughout the trial
7.1.3.2
Pharmacokinetic/Pharmacodynamic 
Evaluations
Removed ADA/PK sample collection
The 200 mg Q3W dose is now 
the approved standard dose of 
pembrolizumab
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1.0 TRIAL SUMMARY
Abbreviated Title
Ph 3 trial of Pembrolizumab (MK-3475) vs paclitaxel, docetaxel or 
vinflunine in recurrent/progressive metastatic urothelial cancer
Trial Phase
Phase III
Clinical Indication
Metastatic or locally advanced/unresectable urothelial cancer that has 
recurred or progressed following platinum-based chemotherapy
Trial Type
Interventional
Type of control
Active control without placebo
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
A)
Pembrolizumab (MK-3475) 200 mg every 3 weeks
B)
Investigator’s choice of:
-Paclitaxel 175 mg/m2 every 3 weeks;
-Docetaxel 75 mg/m2 every 3 weeks OR
-Vinflunine 320 mg/m2 every 3 weeks
Number of trial subjects
Approximately 470 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 30 months
from the time the first subject signs the informed consent until the last 
subject’s last 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 contact.  After a 
screening phase of 42 days, each subject will receive treatment based on 
the arm to which they have been randomized. Treatment on trial will 
continue until disease progression is confirmed by the investigator/site 
radiologist, unacceptable adverse event(s), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to 
withdraw the subject, subject withdrawals consent, pregnancy of the 
subject, noncompliance with trial treatment or procedures requirements, 
subject receives 24 months of trial treatment (pembrolizumab (MK-
3475)
arm only), or administrative reasons. Subjects on the 
pembrolizumab (MK-3475) arm who attain a complete response may 
consider stopping trial treatment if they meet criteria for holding therapy. 
Subjects receiving pembrolizumab (MK-3475) who stop trial treatment 
after receiving 24 months of trial treatment for reasons other than disease 
progression or intolerability, or subjects who attain a complete response 
and stop trial treatment may be eligible for up to one year of retreatment 
upon experiencing disease progression.  The decision to retreat will be at 
the discretion of the investigator only if they meet the criteria for 
retreatment after experiencing disease progression and the trial is 
ongoing. After the end of treatment each subject will be followed for 30 
days for adverse event monitoring (serious adverse events and events of 
clinical interest will be collected for 90 days after the end of treatment).  
Subjects who discontinue for reasons other than disease progression will 
have post-treatment follow-up every 6 weeks for disease status until 
disease progression is confirmed by the investigator/site radiologist, 
initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up. All subjects will be followed by telephone 
for overall survival every 12 weeks until death, withdrawal of consent, or 
the end of the trial.  
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Following demonstration of a survival benefit in the interim analysis, 
eligible subjects who were allocated to the control arm who experienced 
disease progression will be provided with the opportunity to crossover to 
pembrolizumab 200 mg every three weeks (Q3W).
Once the participant has achieved the study objective or study has ended, 
the participant is discontinued from this study and will be enrolled in an 
extension study to continue protocol defined assessments and treatment.
Randomization Ratio
1:1
A list of abbreviations used in this document can be found in Section 12.4.
2.0 TRIAL DESIGN
Trial Design
This is a randomized, active-controlled, multi-site, open-label trial of pembrolizumab (MK-
3475) in subjects with metastatic or locally advanced/unresectable urothelial cancer that has 
recurred or progressed following platinum-containing chemotherapy, to be conducted in 
conformance with Good Clinical Practices.
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 trial design is depicted in Figure 1.
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*Subjects who meet the eligibility criteria described in Section 7.1.5.2.2 may receive pembrolizumab 200 mg 
IV Q3W for up to 2 years.
Note: 
The overall proportion of subjects receiving vinflunine in the control arm is capped at approximately 
35%.  Vinflunine will only be a comparator option in countries where vinflunine is approved for the treatment 
of metastatic urothelial cancer.  Docetaxel will only be a comparator option for subjects with a total bilirubin 
≤1x ULN, and an AST and/or ALT ≤ 1.5x ULN if alkaline phosphatase is also >2.5x ULN.
Figure 1
Trial Design
Crossover for Subjects in Control Arm to Pembrolizumab 200 mg Q3W Arm
The study’s interim analysis results demonstrated that pembrolizumab 200 mg every 3 weeks 
(Q3W) was associated with superior overall survival (OS) compared to the control arm 
(investigator’s choice: paclitaxel, docetaxel or vinflunine) in the overall study population. 
Based on the positive outcome of the OS analysis, subjects in the control arm, who 
experience disease progression, will have the opportunity to participate in the Crossover 
Phase with pembrolizumab 200 mg Q3W if inclusion/exclusion criteria defined in Section 
7.1.5.2.2 are met.
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
(1) Objective: To evaluate progression-free survival (PFS) per RECIST 1.1 by blinded 
independent radiologists’ review of all subjects with recurrent/progressive metastatic 
urothelial cancer treated with pembrolizumab (MK-3475) compared to paclitaxel, 
docetaxel or vinflunine.
Hypotheses (H1):  Pembrolizumab (MK-3475) prolongs PFS per RECIST 1.1 by 
blinded independent radiologists’ review in all subjects with recurrent/progressive 
metastatic urothelial cancer compared to paclitaxel, docetaxel or vinflunine.
(2) Objective:  To evaluate the overall survival (OS) of all subjects with metastatic or 
locally advanced/unresectable urothelial cancer that has recurred or progressed 
following platinum-based chemotherapy (recurrent/progressive metastatic urothelial 
cancer), when treated with pembrolizumab (MK-3475) compared to paclitaxel, 
docetaxel or vinflunine.
Hypothesis (H2):  Pembrolizumab (MK-3475) prolongs OS in all subjects with 
recurrent/progressive metastatic urothelial cancer compared to paclitaxel, docetaxel
or vinflunine.
(3) Objective: 
To evaluate the PFS per RECIST 1.1 by blinded independent 
radiologists’ review of subjects with platinum-refractory recurrent/progressive 
metastatic PD-L1 positive urothelial cancer treated with pembrolizumab compared to 
paclitaxel, docetaxel or vinflunine.
Hypotheses (H3):  Pembrolizumab prolongs PFS per RECIST 1.1 by blinded 
independent 
radiologists’ 
review
in 
subjects 
with 
platinum-refractory 
recurrent/progressive metastatic PD-L1 positive urothelial cancer compared to 
paclitaxel, docetaxel or vinflunine.
(4) Objective:  To evaluate the OS of subjects with platinum-refractory metastatic or 
locally advanced/unresectable PD-L1 positive urothelial cancer, when treated with 
pembrolizumab compared to paclitaxel, docetaxel or vinflunine.
Hypothesis (H4):  Pembrolizumab prolongs OS in subjects with platinum-refractory 
recurrent/progressive metastatic PD-L1 positive urothelial cancer compared to 
paclitaxel, docetaxel or vinflunine.
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(5) Objective: 
To evaluate the PFS per RECIST 1.1 by blinded independent 
radiologists’ review of subjects with platinum-refractory recurrent/progressive 
metastatic PD-L1 strongly positive urothelial cancer treated with pembrolizumab 
compared to paclitaxel, docetaxel or vinflunine.
Hypotheses (H5):  Pembrolizumab prolongs PFS per RECIST 1.1 by blinded 
independent 
radiologists’ 
review
in 
subjects 
with 
platinum-refractory 
recurrent/progressive metastatic PD-L1 strongly positive urothelial cancer compared 
to paclitaxel, docetaxel or vinflunine.
(6) Objective:  To evaluate the OS of subjects with platinum-refractory metastatic or 
locally advanced/unresectable PD-L1 strongly positive urothelial cancer, when 
treated with pembrolizumab compared to paclitaxel, docetaxel or vinflunine.
Hypothesis (H6):  Pembrolizumab prolongs OS in subjects with platinum-refractory 
recurrent/progressive metastatic PD-L1 strongly positive urothelial cancer compared 
to paclitaxel, docetaxel or vinflunine.
The study is considered to have met its primary objective if the pembrolizumab arm is 
superior to paclitaxel, docetaxel or vinflunine at an interim or final analysis in any of the 
following:
H1: PFS in all subjects (regardless of PD-L1 expression)
H2: OS in all subjects (regardless of PD-L1 expression)
H3: PFS in subjects with PD-L1 Positive expression
H4: OS in subjects with PD-L1 Positive expression
H5: PFS in subjects with PD-L1 Strongly Positive expression
H6: OS in subjects with PD-L1 Strongly Positive expression
PD-L1 positive is defined as combined proportion score (CPS) of ≥1%. The specific cutoff 
of PD-L1 strongly positive has been independently determined by data outside of the 
current study to be CPS ≥10%.
Data from KN052 demonstrated a clinically meaningful response rate and durable responses 
in all subjects, including those who were considered to be PD-L1 negative (CPS <1%).  
Response rates were also meaningfully increased when a CPS cutpoint of 10% was applied. 
In contrast, the magnitude of enrichment using a 1% CPS cutpoint in this population was not 
clinically meaningful. Based on these observations from KN052, a single CPS cutpoint of 
10% has been identified for urothelial cancer.
Therefore, in the second interim analysis 
(IA2) and final analysis, only primary hypotheses of PD-L strongly positive subjects and all 
subjects will be included in the multiplicity controlled statistical testing.   
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Secondary Objective(s) & Hypothesis(es)
(1) Objective:  To evaluate the safety and tolerability profile of pembrolizumab (MK-
3475) in subjects with recurrent/progressive metastatic urothelial cancer.
(2) Objective: To evaluate the objective response rate (ORR) per RECIST 1.1 by 
independent radiologists’ review in PD-L1 strongly positive, PD-L1 positive and 
all subjects with recurrent/progressive metastatic urothelial cancer treated with 
pembrolizumab (MK-3475) compared to paclitaxel, docetaxel or vinflunine.
Hypothesis:  Pembrolizumab (MK-3475) improves ORR per RECIST 1.1 by 
independent radiologists’ review in PD-L1 strongly positive, PD-L1 positive and 
all subjects with recurrent/progressive metastatic urothelial cancer compared to 
paclitaxel, docetaxel or vinflunine.
(3) Objective:  To evaluate PFS per modified RECIST by independent radiologists’ 
review of PD-L1 strongly positive, PD-L1 positive, and all subjects with 
recurrent/progressive metastatic urothelial cancer treated with pembrolizumab (MK-
3475) compared to paclitaxel, docetaxel or vinflunine.
Hypothesis: pembrolizumab (MK-3475) prolongs PFS per modified RECIST by 
blinded central radiology review in PD-L1 strongly positive, PD-L1 positive and all 
subjects with recurrent/progressive metastatic urothelial cancer compared to 
paclitaxel, docetaxel or vinflunine.
(4) Objective: To evaluate the objective response rate (ORR) per modified RECIST by 
independent radiologists’ review in PD-L1 strongly positive, PD-L1 positive and 
all subjects with recurrent/progressive metastatic urothelial cancer treated with 
pembrolizumab (MK-3475) compared to paclitaxel, docetaxel or vinflunine.
Hypothesis:  Pembrolizumab (MK-3475) improves ORR per modified RECIST by 
independent radiologists’ review in PD-L1 strongly positive, PD-L1 positive and 
all subjects with recurrent/progressive metastatic urothelial cancer compared to 
paclitaxel, docetaxel or vinflunine.
(5) Objective: To evaluate response duration per RECIST 1.1 by independent 
radiologists' review in PD-L1 strongly positive, PD-L1 positive and all subjects
with recurrent/progressive metastatic urothelial cancer treated with pembrolizumab 
(MK-3475) compared to paclitaxel, docetaxel or vinflunine.
(6) Objective: To evaluate PFS per RECIST 1.1 from randomization to specific time 
points (6 months, 12 months) by independent radiologists’ review in PD-L1 
strongly positive, PD-L1 positive and all subjects with recurrent/progressive 
metastatic urothelial cancer treated with pembrolizumab (MK-3475) compared to 
paclitaxel, docetaxel or vinflunine.
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Exploratory Objectives 
(1) Objective: To evaluate changes in health-related quality-of-life assessments from 
baseline in subjects with recurrent/progressive metastatic urothelial cancer using the 
EORTC QLQ-C30. 
(2) Objective:
  To characterize utilities in previously-treated subjects with 
recurrent/progressive metastatic urothelial cancer using the EuroQol EQ-5D.
(3) Objective: To investigate the relationship between PD-L1 expression and response to
pembrolizumab (MK-3475) treatment utilizing newly obtained or archival FFPE
tumor tissue.
(4) Objective: To investigate the relationship between pembrolizumab (MK-3475) 
treatment and biomarkers predicting response (e.g., immunohistochemistry,
proteomic signatures, genetic variation, and gene expression signatures) utilizing 
newly obtained or archival FFPE tumor tissue and blood.
(5) Objective: To evaluate progression free survival as assessed by RECIST 1.1 by 
investigator review in the next line of therapy (PFS2) in subjects treated with 
pembrolizumab (MK-3475) compared to paclitaxel, docetaxel or vinflunine.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pharmaceutical and Therapeutic Background
Pembrolizumab (MK-3475) (previously known as SCH 9000475) is a potent and highly 
selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to 
directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  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 many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [7; 
8].  The structure of murine PD-1 has been resolved [9].  PD-1 and family members are type 
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I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [7; 10; 11; 12].  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 [13; 14].  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells [15; 16].  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [17]   The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors [18; 19; 20; 13].  Both ligands are type I transmembrane receptors containing 
both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic 
regions with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-
cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or 
chronic inflammatory environments.  PD-L2 is thought to control immune T-cell activation 
in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues [13].  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL) 
[21].  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention.
Pre-clinical 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 mono-therapy or in combination with other 
treatment modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [22; 23; 24; 25; 26; 27].  Experiments have confirmed the in 
vivo efficacy of PD-1 blockade as a mono-therapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the Investigator’s Brochure [IB]).
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Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung 
cancer, a number of advanced solid tumor indications including bladder cancer, and 
hematologic malignancies.  For study details please refer to the Investigator’s Brochure.
The safety, tolerability, and antitumor activity of pembrolizumab were assessed in patients 
with recurrent or metastatic urothelial cancer in the KEYNOTE-012 study.  Archival or 
newly obtained tumor samples from pts with advanced carcinoma of the renal pelvis, ureter, 
bladder, 
or 
urethra 
were 
screened 
for 
PD-L1 
expression 
using 
a 
prototype 
immunohistochemistry assay. PD-L1 expression in stroma or ≥1% of tumor cells was 
required for study entry. Patients received pembrolizumab 10 mg/kg every 2 weeks until 
complete response, progression, or unacceptable toxicity. Pts deriving benefit could remain 
on pembrolizumab beyond initial progression. Response was assessed every 8 weeks per 
RECIST v1.1 by independent central review (primary efficacy end point).
A total of 33 patients were enrolled, including 30 with transitional cell histology and 3 with 
nontransitional cell or mixed histology. Median age was 70 y (range 44-85), 70% had an 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 1, 52% received ≥2 
prior therapies for advanced disease, and 21% had liver metastases. A total of 22 patients 
(67%) received ≥3 pembrolizumab doses. A total of 64% of patients reported ≥1 drug-related 
AE, most commonly fatigue (n = 6), peripheral edema (n = 4), and nausea (n = 3); 5 patients 
(15%) reported grade 3-4 drug-related AEs, with only rash seen in >1 patient (n = 2).  29 
patients received ≥1 dose of pembrolizumab and had a baseline scan with measurable disease 
and were evaluable for response. Objective response rate (ORR) by central review was 
27.6% (95% CI 12.7%-47.2%), with 3 (11%) complete responses. Response duration is 16-
40+ week (median not reached), with 6 of 7 responses ongoing. 
Information on Other Trial-Related Therapy
The proposed choice of single agent paclitaxel, docetaxel or vinflunine for the control arm is 
based on common usage, in the second-line setting, input from key opinion leaders, and prior 
precedence in 2nd line (2L) clinical trials. Therefore, these three agents will be used as 
standard treatment options in the comparator arm of this trial.  This allows the investigator to 
select either 1 of the 3 options for subjects randomized to the standard therapy arm.  See 
Section 4.2.2.1 for additional details.
Rationale
Rationale for the Trial and Selected Subject Population
Urothelial (transitional cell) cancer describes a range of tumors that arise from the urothelial 
endothelium, which includes 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 [28]. Urothelial carcinoma is the predominant histologic type of 
bladder cancer in the United States and Western Europe, where it accounts for approximately 
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90 percent of bladder cancers. In other areas of the world, nonurothelial histologies are more 
frequent.
Subjects with metastatic urothelial cancer that has recurred or progressed following 
platinum-based chemotherapy present a challenge. Although a variety of chemotherapeutic 
agents are used in this setting, the prognosis of subjects with recurrent/progressive urothelial 
cancer is generally poor despite these therapies. The median survival in most series is 7 to 9
months, and the median PFS is 3 to 5 months, with limited treatment options and substantial 
morbidity. Single agent or combination therapy using conventional cytotoxic chemotherapy, 
combined with best supportive care, is palliative for subjects with recurrent/ progressive 
urothelial cancer. The most widely used agents include taxanes (paclitaxel, docetaxel), 
pemetrexed, and, in the EU, vinflunine.   There are no approved therapies for 
recurrent/progressive urothelial cancer in the US, while vinflunine is approved in the EU for 
the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract after 
failure of a prior platinum-containing regimen.
After failure of first-line platinum-containing chemotherapy, objective responses to second-
line cytotoxic chemotherapy are uncommon, particularly when contemporary response 
criteria are applied. Objective response rates of 5% to 28% have been reported with agents 
such as paclitaxel, docetaxel, pemetrexed and ifosfamide [29, 30, 31, 32], but few 
randomized, controlled studies have been conducted in the second-line setting.  In single-arm 
studies, PFS and OS have been reported as 4 months and 9 months, respectively, with 
docetaxel; and 2-3 months and 7 months, respectively with paclitaxel [29, 30, 33].  In a Phase 
III trial, 370 previously treated patients were randomly assigned to either vinflunine or best 
supportive care [34]. Compared to best supportive care, treatment with vinflunine resulted in 
a 9% objective response rate and a trend towards increased overall survival that did not reach 
statistical significance in the ITT population (6.9 versus 4.6 months, hazard ratio 0.88, 95% 
CI 0.69-1.12).  
Given the poor outcome of subsequent chemotherapy in bladder cancer patients after failure 
of a platinum-based regimen, the study will enroll all comers, independent of PD-L1 status.
There is, however, emerging evidence of the correlation of PD-L1 expression and clinical 
outcomes of patients with epithelial malignancies (bladder cancer included) treated with PD-
1/PD-L1 agents. Therefore, the study population will be analyzed as a whole, and also taking 
into account PD-L1 positive and PD-L1 strongly positive status.
Of note, PD-L1 positive is defined as combined proportion score (CPS) of >1%. The specific 
cutoff of PD-L1 strongly positive has been independently determined, taking into account 
data outside of the current study (i.e., from protocols Keynote 012, Keynote 052 and 
epidemiologic studies) to be CPS >10%. 
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying Investigators Brochure (IB) and Informed Consent documents.
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Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
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 eight randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every two weeks (Q2W)
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and
•
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 eight randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer, 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 Q3W (KN001 B2, KN001 D, KN002, KN010 and KN021), and three studies 
compared 10 mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2 and KN006). All of 
these studies demonstrated 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 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 
demonstrated 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 
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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 all pembrolizumab protocols.
Rationale for the Use of Comparator
While there is no accepted standard of care for recurrent/progressive metastatic urothelial 
cancer, taxanes, including paclitaxel and docetaxel, are widely utilized in this setting [35].  
National Comprehensive Cancer Care guidelines state that, while no standard therapy exists
for the second-line therapy of urothelial cancer, taxanes are preferred agents for palliation
[36]. Data from single-arm, open label studies support the use of taxanes in subjects with 
progressive/recurrent urothelial cancer, but demonstrate the limited benefit of these 
chemotherapeutic regimens.  A small, open-label study of docetaxel in this patient population 
demonstrated an ORR of 13.3%; (95% CI 3.8%; 30.7%), a median PFS of 4 months, and a
median overall survival of 9 months (95% CI 6 to 12 months) [30]. An open-label study of 
paclitaxel in subjects with progressive/recurrent urothelial cancer demonstrated an ORR of 
10% (95% CI 0%; 20%), a median PFS of 2.2 months and a median overall survival of 7.2 
months [29].  Although no labeled dosing guidelines for these agents are available for 
subjects with urothelial cancer, docetaxel is typically administered at 75 mg/m2 Q3W, 
consistent with the dose for labeled indications. Paclitaxel has frequently been administered 
at Q3W doses of 175-250 mg/m2 or equivalent weekly dosing to subjects with metastatic 
urothelial cancer, including in recent large Phase II and III clinical studies [37, 38].
In a Phase III trial, 370 previously treated urothelial cancer patients were randomly assigned 
to either vinflunine at 280-320mg/m2 Q3W or best supportive care [34]. Compared to best 
supportive care, treatment with vinflunine resulted in a 9% objective response rate and a 
trend towards increased overall survival that did not reach statistical significance in the ITT 
population (6.9 versus 4.6 months, hazard ratio 0.88, 95% CI 0.69-1.12).  PFS was 3 months 
in the vinflunine arm and 1.5 months in the arm that received best supportive care alone.  In a 
multivariate Cox analysis, the addition of vinflunine was independently correlated with 
improved survival. On the basis of these data, vinflunine is has been approved in the EU as 
monotherapy for the treatment of adult patients with advanced or metastatic transitional cell 
carcinoma of the urothelial tract after failure of a prior platinum-containing regimen.
Rationale for Endpoints
Efficacy Endpoints
4.2.3.1.1 Primary
Overall survival (OS) is the gold standard endpoint to demonstrate superiority of 
antineoplastic therapy.  Progression free survival (PFS) may be an acceptable scientific 
endpoint for a randomized Phase III trial to support accelerated approval in a population with 
a high unmet medical need and poor response to currently available therapies, such as in 
subjects with recurrent/progressive urothelial cancer.  RECIST 1.1 will be used to determine 
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the dates of progression as this methodology is accepted by regulatory authorities.  Because 
the treatment assignment is unblinded, images will be read by independent radiologists 
blinded to treatment assignment to minimize bias in the response assessments.  The first on-
study radiographic imaging assessment will be performed at 9 weeks (±7 days) from 
randomization and then every 6 weeks (±7 days) thereafter or more frequently if clinically 
indicated.  
Given emerging evidence of the correlation of PD-L1 expression and clinical outcomes of 
patients with epithelial malignancies (bladder cancer included) treated with PD-1/PD-L1 
agents, the study population will be analyzed as a whole, and also taking into account PD-L1 
positive and PD-L1 strongly positive status. 
Of note, PD-L1 positive is defined as combined proportion score (CPS) of ≥1%. The specific 
cutoff of PD-L1 strongly positive has been independently determined to be CPS >10%, 
taking into account data outside of the current study.
Data from KN052 demonstrated a clinically meaningful response rate and durable responses 
in all subjects, including those who were considered to be PD-L1 negative (CPS <1%).  
Response rates were also meaningfully increased when a CPS cutpoint of 10% was applied. 
In contrast, the magnitude of enrichment using a 1% CPS cutpoint in this population was not 
clinically meaningful. Based on these observations from KN052, a single CPS cutpoint of 
10% for urothelial cancer has been identified.
Therefore, in the second interim analysis 
(IA2) and final analysis, only primary hypotheses of PD-L strongly positive subjects and all 
subjects will be included in the multiplicity controlled statistical testing. 
4.2.3.1.2 Secondary
PD-L1 Expression
PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to explore 
the relationship between tumor PD-L1 expression and response to treatment with 
pembrolizumab (MK-3475).
4.2.3.1.3 Exploratory
Patient Reported Outcomes
EORTC QLQ-C30, EQ-5D and Health Economic Assessment are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability.
EORTC QLQ-C30
EORTC QLQ-C30 was developed to assess the quality of life of cancer subjects. It has been
translated and validated into 81 languages and used in more than 3,000 studies worldwide.  It 
contains 5 functioning scales (physical, role, cognitive, emotional, and social), 3 symptom 
scales (fatigue, nausea, pain) and additional single symptom items. It is scored on a 4 point 
scale (1=not at all, 2=a little, 3= quite a bit, 4=very much). The EORTC QLQ-C30 
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instrument also contains 2 global scales that use 7 point scale scoring with anchors (1=very 
poor and 7=excellent). This assessment will be completed at various time points as specified 
in the study Flow Chart, beginning with Cycle 1 until 30 days post-treatment discontinuation.
eEuroQoL EQ-5D
The eEuroQol-5D (eEQ-5D) is a standardized instrument for use as a measure of health 
outcome.  The eEQ-5D will provide data for use in economic models and analyses including 
developing health utilities or QALYs.  The five health state dimensions in this instrument 
include the following: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression [41].  Each dimension has three 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.  The 
eEQ-5D will always be completed by subjects first before completing the EORTC QLQ-C30 
and is to be completed at various time points as specified in the study Flow Chart, beginning 
with Cycle 1 until 30 days post-treatment discontinuation. 
Health Economic Assessment
The health economic assessment (HEA) form will be completed via an interview with the 
patient by qualified site personnel. The objective of the HEA form is for the site personnel to 
collect information from patients on all the non-study related health care contacts made 
throughout the study.  The HEA is to be completed at various time points as specified in the 
Trial Flow Chart, beginning with Cycle 2 until 30 days post-treatment discontinuation.
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab (MK-3475) in subjects with recurrent/progressive urothelial cancer. The 
primary safety analysis will be based on subjects who experienced toxicities as defined by 
CTCAE criteria. Safety will be assessed by quantifying the toxicities and grades experienced 
by subjects who have received pembrolizumab (MK-3475), including serious adverse events 
(SAEs) and events of clinical interest (ECIs). Safety will be assessed by reported adverse 
experiences using CTCAE, Version 4.0. The attribution to drug, time-of-onset, duration of 
the event, its resolution, and any concomitant medications administered will be recorded. 
AEs will be analyzed including but not limited to all AEs, SAEs, fatal AEs, and laboratory 
changes. Furthermore, specific immune-related adverse events (irAEs) will be collected and 
designated as immune-related events of clinical interest (ECIs) as described in Section 
7.2.3.2. The mandatory Safety Follow-Up Visit should be conducted approximately 30 days 
after the last dose of trial treatment or before the initiation of a new anti-neoplastic 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 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-
neoplastic treatment should also be followed and recorded.
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Planned Exploratory Biomarker Research
Additional biomarker research to identify factors important for pembrolizumab (MK-3475)
therapy may also be pursued.  For example, tumor and blood (including serum and plasma)
samples from this study may undergo proteomic, genomic, metabolomic and transcriptional 
analyses.  Additional research may evaluate factors important for predicting responsiveness 
or resistance to pembrolizumab (MK-3475) therapy and other immunologic targets.
Assays may include but are not be limited to:
Immunohistochemistry
In addition to PD-L1 expression, other exploratory biomarkers (e.g., PD-1 expression, 
markers of T-cell phenotype) may also be evaluated.
Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material (biopsy specimens, 
peripheral blood) will be completed to assess expression of approximately 700 genes and 
attempt to define a gene set critical for clinical response to pembrolizumab (MK-3475).  The 
hypothesis to be tested is that pembrolizumab (MK-3475) induces responses in tumors that 
reflect an inflamed/ immune phenotype based on gene expression signatures capturing PD-
L1 & interferon-gamma transcriptional programs.  Global profiling will also be pursued.  
Expression of individual genes related to the immune system may also be evaluated such as 
immune signatures and critical cytokines (e.g., IL-10). microRNA profiling may also be 
pursued in serum samples.
Proteomic analysis
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released 
into the blood.  Enzyme-linked immunoassay can measure PD-L1 in serum and correlate this 
expression with response to pembrolizumab (MK-3475) therapy, as well as levels of PD-L1 
IHC or protein in the tumor.  Blood would be a less invasive compartment compared to 
tumor from which to measure PD-L1 protein biomarker.  In addition to this specific protein 
biomarker, both tissue and blood derivatives can be subjected to proteomic profiling studies 
using a variety of platforms that could include but are not limited to immunoassay, Liquid 
chromatography/Mass Spectrometry.  This approach could identify novel protein biomarker 
that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Gene Analyses
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to define certain tumor types at the genetic level as being 
‘hypermutated’ or can detect the presence of specific T-cell clones within the tumor 
microenvironment or in the peripheral blood.  There is a potential that the hypermutated state 
and/or increased T-cell clonality may correlate with response to pembrolizumab (MK-3475)
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therapy, and/or that the converse, ‘hypomutated’ state or lack of dominant T-cell clones may 
correlate with non-response.  
In addition, understanding genetic determinants of drug response is an important endeavor 
during medical research.  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 adverse events, the data might inform optimal 
use of therapies in the patient population. This research contributes to understanding genetic 
determinants of efficacy and safety associated with the treatments in this study.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens routinely and 
specifically collected during this clinical trial. This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes. 
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
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5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and Female subjects of at least 18 years of age with recurrent/progressive metastatic 
urothelial cancer will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial. The 
subject may also provide consent/assent for Future Biomedical Research. However, 
the subject may participate in the main trial without participating in Future 
Biomedical Research.
2. Be ≥18 years of age on day of signing informed consent.
3. Have histologically or cytologically-confirmed diagnosis of urothelial cancer of the 
renal pelvis, ureter, bladder, or urethra. Both transitional cell and mixed 
transitional/non-transitional cell
histologies are allowed, but transitional cell 
carcinoma must be the predominant histology.  Subjects with non-urothelial cancer of 
the urinary tract are not allowed.
4. Have had progression or recurrence of urothelial cancer following receipt of a first-
line platinum-containing regimen (e.g. cisplatin , carboplatin):
a.
Received a first-line platinum-containing regimen in the metastatic setting or for 
inoperable locally advanced disease;
or
b. Received adjuvant platinum-containing therapy following cystectomy for 
localized muscle-invasive urothelial cancer, with recurrence/progression ≤12
months following completion of therapy.
or
c.
Received neoadjuvant platinum-containing therapy prior to cystectomy for 
localized muscle-invasive urothelial
cancer, with recurrence
≤12
months 
following completion of therapy.
Note: Primary chemoradiation given for subjects who are not considered surgical 
candidates is not considered a line of therapy for the purpose of this study.
Note: Subjects with locally advanced unresectable disease who subsequently 
become eligible for surgery after platinum-containing therapy are not eligible for 
this study, unless they subsequently have disease recurrence in the metastatic 
setting.
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5. Have received no more than two prior lines of systemic chemotherapy for metastatic
urothelial cancer. Subjects for whom the most recent therapy has been a non-
platinum-based regimen following progression/recurrence on platinum-based therapy 
(i.e. third-line subjects) are eligible if they have progressed/recurred on their most 
recent therapy.
Note: primary chemoradiation for unresectable muscle-invasive bladder cancer
with the aim of bladder preservation will not be considered a prior line of 
systemic therapy for the purposes of determining study eligibility.
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. A 
newly-obtained biopsy is strongly preferred but not required if archival tissue is 
adequate for analysis. Adequacy of the archived or freshly-obtained biopsy specimen 
must be confirmed by the central laboratory during the screening period prior to 
enrollment.
7. Have measureable disease based on RECIST 1.1 as assessed by the investigator/site 
radiologist. Tumor lesions situated in a previously irradiated area are considered 
measureable if progression has been demonstrated in such lesions.
8. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale, as assessed 
within 10 days prior to treatment initiation. Subjects with an ECOG performance 
status of 2 must have a hemoglobin ≥10 g/dL, must not have liver metastases, and 
must have received the last dose of their last prior chemotherapy regimen ≥3 months
(90 days) prior to enrollment.
9. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation.
Table 1 Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L 
Renal
Creatinine OR
Measured 
or 
calculateda
creatinine 
clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5xULN OR
≥30 mL/min for subjects with 
creatinine levels >1.5x institutional ULN
Hepatic
Total bilirubin
≤1.5xULNb OR
Direct bilirubin ≤ULN for subjects with total 
bilirubin levels >1.5xULN
AST (SGOT) and ALT (SGPT)
≤2.5xULNb  OR
≤5xULN for subjects with liver metastases
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System
Laboratory Value
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT) or PTT
≤1.5xULN 
unless 
subject 
is 
receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants
≤1.5xULN 
unless 
subject 
is 
receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants
a Creatinine clearance should be calculated per institutional standard.  For subjects with a baseline 
calculated creatinine clearance below normal institutional laboratory values, a measured baseline 
creatinine clearance should be determined.
b Docetaxel will only be a comparator option for subjects with a total bilirubin ≤1x ULN, and an AST 
and/or ALT ≤1.5x ULN if alkaline phosphatase is also >2.5x ULN.
10. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
11. Female subjects of childbearing potential must be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of pembrolizumab or 180 days after the 
last dose of paclitaxel, docetaxel or vinflunine (Reference Section 5.7.2). Subjects of 
childbearing 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.
12. Male subjects must agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of pembrolizumab 
(MK-3475) or 180 days after the last dose of paclitaxel, docetaxel or vinflunine.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
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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.
2. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks prior to the first dose of trial 
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 the first dose of trial 
treatment. The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor.
4. Has had a prior anti-cancer monoclonal antibody  (mAb) within 4 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to agents administered more than 4 weeks earlier.
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent.
Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an 
exception to this criterion and may qualify for the study.
Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.
6. Has a known additional malignancy that is progressing or requires active treatment. 
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.  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, PSA undetectable.  
7. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment. This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability.
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8. Has an active autoimmune disease requiring systemic treatment within the past 3
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic or immunosuppressive agents. Subjects with vitiligo, 
diabetes Type I, or resolved childhood asthma/atopy would be an exception to this 
rule. Subjects that require intermittent use of bronchodilators, inhaled steroids, or 
local steroid injections would not be excluded from the study. Subjects with 
hypothyroidism stable on hormone replacement or Sjøgren’s syndrome will not be 
excluded from the study.
9. Has active cardiac disease, defined as: 
a.
Myocardial infarction or unstable angina pectoris within 6 months of the first date 
of study therapy.
b. History of serious ventricular arrhythmia (i.e., ventricular tachycardia or 
ventricular fibrillation), high-grade atrioventricular block, or other cardiac 
arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation 
that is well controlled with antiarrhythmic medication); history of QT interval 
prolongation.
c.
New York Heart Association (NYHA) Class III or greater congestive heart 
failure, or left ventricular ejection fraction of < 40%.
10. Has evidence of interstitial lung disease or active non-infectious pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a history of severe hypersensitivity reaction (e.g. generalized rash/erythema, 
hypotension, bronchospasm, angioedema or anaphylaxis) to paclitaxel or to other 
drugs formulated with polyoxyethylated castor oil, to docetaxel or other drugs 
formulated with polysorbate 80, or to vinflunine or other vinca alkaloids.
13. Requires ongoing therapy with a medication that is a strong inhibitor or inducer of the 
CYP3A4 enzymes (a common list of such agents may be found in Section 12.9).
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
15. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment.
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17. Has received prior therapy with an anti-PD-1 or anti-PD-L1 agent, or with an agent 
directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).
18. Has received prior chemotherapy for urothelial cancer with all available study 
therapies in the control arm (i.e. both prior paclitaxel and docetaxel in regions where 
vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in 
regions where vinflunine is an approved therapy). 
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
21. Has received a live virus vaccine within 30 days of planned start of trial treatment.
22. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial, 
unless prospective IRB approval (by chair or designee) is given allowing exception to 
this criterion for a specific subject.
Trial Treatment(s)
The treatment(s) to be used in this trial are outlined below in Table 2.
Table 2
Trial Treatment
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/ Treatment 
Period/Vaccination 
Regimen
Use
pembrolizumab 
(MK-3475)
200 mg
Q3W
IV infusion
Day 1 of each cycle
Experimental
Paclitaxel*
175 mg/m2
Q3W
IV infusion
Day 1 of each cycle 
Active
comparator
Docetaxel*
75 mg/m2
Q3W
IV infusion
Day 1 of each cycle
Active 
comparator
Vinflunine**
320 mg/m2
Q3W
IV infusion
Day 1 of each cycle
Active 
comparator
*
In case of mild hepatic impairment (total bilirubin ≥1.25 ULN), paclitaxel should be started at a dose of 135 mg/m2.  
Docetaxel will only be a comparator option for subjects with a total bilirubin ≤1x ULN, and an AST and/or ALT ≤ 1.5x 
ULN if alkaline phosphatase is also >2.5x ULN.
** In case of WHO/ECOG performance status (PS) of ≥1 or PS of 0 and prior pelvic irradiation, vinflunine should be 
started at the dose of 280 mg/m². In the absence of any hematological toxicity during the first cycle causing treatment 
delay or dose reduction, the dose will be increased to 320 mg/m² every 3 weeks for the subsequent cycles.  See Section 
5.2.1.2.1 for additional guidelines on dose modification for vinflunine, including starting doses in the setting of mild 
renal and hepatic impairment and in the elderly.
Note:  The overall proportion of subjects receiving vinflunine in the control arm is capped at approximately 35%.  
Vinflunine will only be a comparator option in countries where vinflunine is approved for the treatment of metastatic 
urothelial cancer.  
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Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
All supplies indicated in Table 2 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.
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 to record 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)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale. There are no specific calculations or evaluation required to be 
performed in order to administer the proper dose to each subject.
Treatment on the standard treatment arm will be prepared and administered as per the 
approved product label. The body surface area (BSA) in m2 should be calculated per local 
guidance.
Dose Modification for Pembrolizumab (MK-3475)
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 3. 
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Table 3
Dose Modification Guidelines for Drug-Related Adverse Events
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper 
over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.
Immune-
related AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper

Monitor participants for 
signs and symptoms of 
pneumonitis

Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment

Add prophylactic 
antibiotics for 
opportunistic infections
Grade 3 or 4, 
or recurrent 
Grade 2
Permanently 
discontinue
Diarrhea / 
Colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper

Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation 
(ie, peritoneal signs and 
ileus).

Participants with ≥ Grade 
2 diarrhea suspecting 
colitis should consider GI 
consultation and 
performing endoscopy to 
rule out colitis. 

Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  
If sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted via 
IV infusion.
Grade 4
Permanently 
discontinue
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Immune-
related AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer 
corticosteroids 
(initial dose of 0.5-
1 mg/kg 
prednisone or 
equivalent) 
followed by taper

Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned to 
baseline or is stable
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper
Type 1 diabetes 
mellitus 
(T1DM) or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure
Withhold

Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 

Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated.  

Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 

Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care

Monitor for signs and 
symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by taper.

Monitor changes of renal 
function
Grade 3 or 4 
Permanently 
discontinue
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Immune-
related AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity 
of AE administer 
corticosteroids

Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent 
Grade 2
Withhold

Based on type and 
severity of AE 
administer 
corticosteroids 

Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Grade 3
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM).  
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 4. 
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Table 4
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).
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
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Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.
5.2.1.2.1 Dose Modification for Standard Treatment with Paclitaxel, Docetaxel or 
Vinflunine
In general, treatment with paclitaxel, docetaxel or vinflunine will be withheld for drug-
related Grade 4 hematologic toxicities and for non-hematologic toxicity Grade 3 and 
subsequent doses modified as per Table 5 below.  Dose modifications will be applied for all 
subsequent doses.  Specific dose modification guidance for paclitaxel, docetaxel and 
vinflunine is found below in Sections 5.2.1.2.2.1, 5.2.1.2.2.2 and 5.2.1.2.2.3.  Dose 
modifications for intolerable Grade 2 drug-related adverse events may be considered after 
consultation with the Sponsor.  Dose modifications for paclitaxel, docetaxel or vinflunine
should also be considered according to local product labels.
Table 5
Dose Modification Guidelines for Drug-Related Adverse Events on the Active 
Comparator Arm
Toxicity*
Grade
Occurrence
Hold 
Treatment
Dose Modification
Treatment 
Discontinuation
Neutropenia
Grade 
1, 
2, 
3 
or 
Grade 
4 
lasting ≤7 
days
All
Hold treatment 
until neutrophils 
recover 
to 
>1500 
cells/mm3
N/A
N/A
Grade 
4 
lasting > 7 
days
1st
occurrence
Hold treatment 
until neutrophils 
recover 
to 
>1500 
cells/mm3
Restart treatment at:
Paclitaxel: 
135
mg/m2
Docetaxel: 60 mg/m2
Vinflunine: 
280 
mg/m2
Treatment 
discontinuation 
should 
be
considered
2nd
occurrence
Hold treatment 
until neutrophils 
recover 
to 
>1500 
cells/mm3
Restart treatment at:
Paclitaxel: 
100 
mg/m2
Docetaxel: 50 mg/m2
Vinflunine: 
250
mg/m2
Treatment 
discontinuation 
should 
be
considered
3rd
occurrence
Yes
N/A
Yes
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Toxicity*
Grade
Occurrence
Hold 
Treatment
Dose Modification
Treatment 
Discontinuation
Thrombocytopenia
Grade 
1, 
2, 3
All
Hold treatment 
until platelets 
recover to 
>100,000 
cells/mm3
N/A
N/A
Grade 4
1st
occurrence
Hold treatment 
until platelets 
recover to > 
100,000 
cells/mm3
Restart treatment at:
Paclitaxel: 
135
mg/m2
Docetaxel: 60 mg/m2
Vinflunine: 
280 
mg/m2
Treatment 
discontinuation 
should 
be
considered
2nd
occurrence
Hold treatment 
until platelets 
recover to 
>100,000 
cells/mm3
Restart treatment at:
Paclitaxel: 
100
mg/m2
Docetaxel: 50 mg/m2
Vinflunine: 
250 
mg/m2
Treatment 
discontinuation 
should 
be
considered
3rd
occurrence
Yes
N/A
Yes
Anemia
Grade 
1, 
2, 3
All
Until anemia 
resolves to 
Grade 1 or 
baseline
N/A
N/A
Grade 4
1st
occurrence
Until anemia 
resolves to 
Grade 1 or 
baseline
Restart treatment at:
Paclitaxel: 
135 
mg/m2
Docetaxel: 60 mg/m2
Vinflunine: 
280 
mg/m2
Treatment 
discontinuation 
should 
be
considered
2nd
occurrence
Until anemia 
resolves to 
Grade 1 or 
baseline
Restart treatment at:
Paclitaxel: 
100
mg/m2
Docetaxel: 50 mg/m2
Vinflunine: 
250 
mg/m2
Treatment 
discontinuation 
should 
be
considered
3rd
occurrence
Yes
N/A
Yes
Non-
hematological 
toxicity and other 
hematological 
toxicity not 
described above**
Grade 1, 2
All
No
None
N/A
Grade 3, 4
1st
occurrence
Yes, 
until 
toxicity resolves 
to Grade 0-1 or 
baseline
Restart treatment at:
Paclitaxel: 
135
mg/m2
Docetaxel: 60 mg/m2
Vinflunine: 
280 
mg/m2
Treatment 
discontinuation 
should 
be
considered
2nd
occurrence
Yes, 
until 
toxicity resolves 
to Grade 0-1 or 
baseline
Restart treatment at:
Paclitaxel: 
100
mg/m2
Docetaxel: 50 mg/m2
Vinflunine: 
250 
mg/m2
Treatment 
discontinuation 
should 
be
considered
3rd
occurrence
Yes
N/A
Yes
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Toxicity*
Grade
Occurrence
Hold 
Treatment
Dose Modification
Treatment 
Discontinuation
*See Table 6, Table 7 and Table 8 for additional dose modifications for drug-related adverse events specific to vinflunine,
paclitaxel and docetaxel, respectively.
**Subjects who experience suspected severe hypersensitivity reaction to paclitaxel, docetaxel or vinflunine (e.g. generalized 
rash/erythema, hypotension and/or bronchospasm, angioedema or anaphylaxis) should be discontinued from trial treatment.  
See Table 5 for guidelines on management of peripheral neuropathy.
In cases where the toxicity does not resolve to Grade 0-1 within 4 weeks after the last 
infusion (2 weeks for vinflunine), trial treatment should be discontinued after consultation 
with the Sponsor. With investigator and Sponsor agreement, subjects with a laboratory 
adverse event still at Grade 2 after 4 weeks may continue in the trial only if asymptomatic 
and controlled.  For information on the management of adverse events, see Section 5.6.1.
Specific Dose Modifications for Vinflunine
In case of WHO/ECOG performance status (PS) of ≥1 or PS of 0 and prior pelvic irradiation, 
vinflunine treatment should be started at the dose of 280 mg/m². In the absence of any 
hematological toxicity during the first cycle causing treatment delay or dose reduction, the 
dose will be increased to 320 mg/m² every 3 weeks for the subsequent cycles.
In subjects with moderate renal impairment (40 ml/min≤CrCl≤60 ml/min), the recommended 
dose is 280 mg/m² given once every 3 weeks.  In subjects with renal impairment (30 
ml/min≤CrCl<40 ml/min), the recommended dose is 250 mg/m² given once every 3 weeks.
The recommended dose of vinflunine is 250 mg/m² given once every 3 weeks in subjects
with mild liver impairment (Child-Pugh grade A) or in subjects with a Prothrombin time 
≥60% NV and 1.5xULN < Bilirubin ≤xULN and presenting at least one of the following 
criteria: transaminases > ULN and/or GGT > 5xULN .
The doses recommended in subjects ≥75 years old are as follows:
- in subjects at least 75 years old but less than 80 years, the dose of vinflunine to be given is 
280 mg/m² every 3 weeks.
- in subjects 80 years old and beyond, the dose of vinflunine to be given is 250 mg/m² every 
3 weeks.
In subjects who initiate vinflunine at 280 mg/m2 and who experience an AE requiring dose 
modification, the dose should be reduced to 250 mg/m2 following the 1st occurrence and 
resolution, and discontinued following a 2nd occurrence.  In subjects who initiate vinflunine 
at 250 mg/m2 and who experience an AE requiring dose modification, vinflunine should be 
discontinued.
Cases of Posterior Reversible Encephalopathy Syndrome (PRES) have been observed after 
administration of vinflunine. The typical clinical symptoms are, with various degrees: 
neurological (headache, confusion, seizure, visual disorders), systemic (hypertension), and 
gastrointestinal (nausea, vomiting). Radiological signs are white matter abnormalities in the 
posterior regions of the brain. 
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Vinflunine should be discontinued in subjects who develop neurological signs of PRES.
Specific dose modifications for subjects receiving vinflunine are detailed below in Table 6.
Table 6
Vinflunine Dose Modification for Drug-Related Adverse Events
Toxicity
Dose Adjustment
Initial Dose: Vinflunine 320 mg/m2
Initial Dose:  Vinflunine 280 
mg/m2
1st Event
2nd
Consecutive 
Event
3rd Consecutive 
Event
1st Event
2nd
Consecutive 
Event
Neutropenic 
fever  (defined as 
T ≥100.5°F and 
ANC ≤ 1,000//L)
Vinflunine 
280 mg/m2
Vinflunine 250 
mg/m2
Discontinue 
treatment 
Vinflunine 250 
mg/m2
Discontinue 
treatment
Mucositis or 
Constipation 
Grade 2  ≥5 days 
or Grade ≥3 any 
duration1
Cardiac ischemia 
in patients with 
prior history of 
myocardial 
infarction or 
angina pectoris
Discontinue 
treatment
N/A
N/A
Discontinue 
treatment
N/A
1NCI CTC Grade 2 constipation is defined as requiring laxatives, Grade 3 as an obstipation requiring manual evacuation or 
enema, Grade 4 as an obstruction or toxic megacolon. Mucositis Grade 2 is defined as “moderate”, Grade 3 as “severe” 
and Grade 4 as “life-threatening”
Specific Dose Modifications for Paclitaxel
Paclitaxel should not be administered to subjects with baseline neutrophil counts of less than 
1500 cells/mm3. Subjects should not be re-treated with subsequent cycles of paclitaxel until 
neutrophils recover to a level >1500 cells/mm3.  Severe conduction abnormalities have been 
documented in <1% of subjects during paclitaxel therapy and in some cases requiring 
pacemaker placement. If subjects develop significant conduction abnormalities during 
paclitaxel infusion, appropriate therapy should be administered and continuous cardiac 
monitoring should be performed during subsequent therapy with paclitaxel.
In case of mild hepatic impairment (total bilirubin ≥1.25 ULN), paclitaxel should be started 
at a dose of 135 mg/m2.
Dose modifications for subjects receiving paclitaxel are detailed below in Table 7.
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Table 7
Paclitaxel Dose Modification for Drug-Related Adverse Events
Toxicity
Grade
Occurrence
Hold 
Treatment
Dose 
Modification
Treatment 
Discontinuation
Peripheral 
Neuropathy
Grade 1, 2
No
135 mg/m2
N/A
Grade 3, 4
Yes
N/A
Discontinue 
upon onset
Neutropenic 
fever  (defined as 
T ≥100.5°F and 
ANC ≤ 1,000//L)
1
Hold until 
ANC ≥1,500/L
135 mg/m2
2
Hold until 
ANC ≥1,500/L
100 mg/m2
3
Yes
N/A
Yes
Specific Dose Modifications for Docetaxel
Docetaxel should not be given to subjects with bilirubin > 1x ULN, or to subjects with AST 
and/or ALT > 1.5 x ULN with concomitant alkaline phosphatase >2.5 x ULN. Subjects with 
elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are 
at increased risk for the development of Grade 4 neutropenia, febrile neutropenia, infections, 
severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Docetaxel 
should also not be given to subjects with a neutrophil count of < 1500 cells/mm3.  
Severe fluid retention has been reported following docetaxel therapy. Subjects should be 
premedicated with oral corticosteroids prior to each docetaxel Injection administration to reduce 
the incidence and severity of fluid retention (See Section 5.2.2.3). Subjects with pre-existing 
effusions should be closely monitored from the first dose for the possible exacerbation of the 
effusions. Subjects developing peripheral edema may be treated with standard measures, e.g., salt 
restriction, oral diuretic(s).
Dose modifications for subjects receiving docetaxel are detailed below in Table 8.
Table 8
Docetaxel Dose Modification for Drug-Related Adverse Events
Toxicity
Grade
Occurrence
Hold 
Treatment
Dose 
modification
Treatment 
Discontinuation
Peripheral 
Neuropathy
Grade 1, 2
No
60 mg/m2
N/A
Grade 3, 4
Yes
N/A
Discontinue upon 
onset
Neutropenic 
fever  (defined as 
T ≥100.5°F and 
ANC ≤ 1,000//L)
1
Hold until ANC 
≥1,500/L
60 mg/m2
2
Hold until ANC 
≥1,500/L
50 mg/m2
3
Yes
N/A
Yes
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Timing of Dose Administration
Trial treatment of pembrolizumab (MK-3475) may be administered up to 3 days before or 
after the scheduled Day 1 of each cycle due to administrative reasons.
Trial treatment of paclitaxel, docetaxel or vinflunine may be administered up to 3 days before 
or after scheduled dosing date for administrative reasons per investigator’s judgment.
All trial treatments will be administered on an outpatient basis.
Pembrolizumab (MK-3475)
Trial treatment of pembrolizumab (MK-3475) should be administered on Day 1 of each 3 
week cycle after all procedures/assessments have been completed as detailed on the Trial 
Flow Chart (Section 6.0).  
Pembrolizumab (MK-3475) 200 mg will be administered as a 30 minute IV infusion every 3 
weeks (treatment cycle intervals may be increased due to toxicity as described in Section 
5.2.1.2).  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 the preparation of the 
pembrolizumab (MK-3475) infusion fluid and administration of infusion solution.
Paclitaxel
Trial treatment of paclitaxel should be administered on Day 1 of each 3 week cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  
Paclitaxel 175 mg/m2 will be administered as an IV infusion administered over 3 hours. See 
Section 5.2.1.2.1.2 for guidelines on adjustment of initial dose.
All subjects should be premedicated prior to paclitaxel administration in order to prevent
severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg 
PO administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its 
equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or 
ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel. The appropriate premedication 
regimen may be determined by the investigator.
Docetaxel
Trial treatment of docetaxel should be administered on Day 1 of each 3 week cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  
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Docetaxel 75 mg/m2 will be administered as an IV infusion administered over 1 hour.  
All subjects should be premedicated with oral corticosteroids, such as dexamethasone 16 mg 
per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to docetaxel administration in 
order to reduce the incidence and severity of fluid retention as well as the severity of 
hypersensitivity reactions.  The appropriate premedication regimen may be determined by the 
investigator.
Vinflunine
Trial treatment of vinflunine should be administered on Day 1 of each 3 week cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  
Vinflunine 320 mg/m2 will be administered as an IV infusion administered over 20 minutes.  
See Section 5.2.1.2.1.1 for guidelines on adjustment of initial dose.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Imaging data for the primary analysis will be centrally reviewed by independent 
radiologist(s) without knowledge of subject treatment assignment. The study team at the 
Sponsor consisting of clinical, statistical, statistical programming and data management 
personnel, will be blinded to subject-level PD-L1 biomarker results until the time that the 
cutoff value of PD-L1 expression level for PD-L1 strongly positive is established and 
formally documented exclusively based on data outside of this study. 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 analysis, who will have no 
other responsibilities associated with the study.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS).
There are two treatment arms.  Subjects will be 
assigned randomly in a 1:1 ratio to pembrolizumab (MK-3475) OR investigator’s choice of 
paclitaxel, docetaxel or vinflunine. Within the control arm, the overall proportion of subjects 
receiving vinflunine will be capped at approximately 35%. Investigators must select one 
treatment among the control arm options before randomization occurs, to use in the event 
that the subject is randomized to the control arm.
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Stratification
Randomization will be stratified according to the following factors:
1. Eastern Cooperative Oncology Group (ECOG) Performance Scale (0/1vs. 2)
2. Presence or absence of liver metastases 
3. Hemoglobin (≥ 10 g/dL vs. <10 g/dL)
4. Time from completion of most recent chemotherapy (<3 months or ≥3 months)*.
Note: Subjects with ECOG 2 may only be enrolled if liver metastases are absent, 
hemoglobin is ≥10 g/dL, and time from completion (last dose) of most recent 
chemotherapy is ≥ 3 months (90 days).
* 90 days.
Concomitant Medications/Vaccinations (Allowed & 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.
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.  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 30 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2.
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Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response 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 (MK-3475)

Radiation therapy 
o
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 
Sponsor.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, intranasal 
influenza, rabies, BCG, and typhoid vaccine.
o
Note:  It is acceptable for subjects receiving paclitaxel, docetaxel or vinflunine
to receive live vaccines while participating in the trial.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor.
o
Note:  For subjects randomized to the paclitaxel, docetaxel or vinflunine arm,
the use of glucocorticoids on trial treatment is acceptable and is required for 
premedication.
o
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g. IV 
contrast dye or transfusions) is permitted.
o
Note: Use of intermittent inhaled steroids or local injection of corticosteroids 
is permitted upon consultation with the sponsor.

Strong inhibitors or inducers of the CYP3A4 enzymes (a common list of such agents 
may be found in Section 12.8).  Subjects in the Crossover Phase are allowed to 
receive strong inhibitors of the CY3A4 enzymes.

QT/QTc-prolonging drugs for subjects receiving vinflunine (a common list of such 
agents may be found in Section 12.9).
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
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The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines for Pembrolizumab (MK-3475)
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.1.2, Table 3.  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to Table 3 in Section 
5.2.1.2 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Supportive Care Guidelines for Paclitaxel, Docetaxel and Vinflunine
Pre-medication(s) for paclitaxel and docetaxel will be given as per standard of care (See 
Sections 5.2.2.2 and 5.2.2.3).  Corticosteroid pre-treatment or post-treatment of paclitaxel
and docetaxel is acceptable in concordance with the local label or standard of care.
Injection site reactions, including reactions secondary to extravasation, have been reported 
with paclitaxel.  These reactions were usually mild and consisted of erythema, tenderness, 
skin discoloration, or swelling at the injection site. More severe events such as phlebitis, 
cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. A specific 
treatment for extravasation reactions is unknown at this time. Given the possibility of 
extravasation, it is advisable to closely monitor the infusion site for possible infiltration 
during drug administration.
Severe conduction abnormalities have been documented in <1% of subjects during paclitaxel 
therapy and in some cases requiring pacemaker placement. If subjects develop significant 
conduction abnormalities during paclitaxel infusion, appropriate therapy should be 
administered and continuous cardiac monitoring should be performed during subsequent 
therapy with paclitaxel.
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Severe fluid retention has been reported following docetaxel therapy. Subjects should be 
premedicated with oral corticosteroids prior to each docetaxel Injection administration to 
reduce the incidence and severity of fluid retention (See Section 5.2.2.3). Subjects with pre-
existing effusions should be closely monitored from the first dose for the possible 
exacerbation of the effusions.  Subjects developing peripheral edema may be treated with 
standard measures, e.g., salt restriction, oral diuretic(s).
In order to prevent constipation, laxatives and dietary measures including oral hydration are 
recommended from day 1 to day 5 or 7 after each vinflunine administration.  Subjects at high 
risk of constipation (concomitant treatment with opiates, peritoneal carcinomas, abdominal 
masses, prior major abdominal surgery) should be medicated with an osmotic laxative from 
day 1 to day 7 administered once a day in the morning before breakfast.
Refer to the approved product label for additional supportive care guidance.
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
MK 3475, paclitaxel, docetaxel and vinflunine may also have adverse effects on a fetus in 
utero.  Furthermore, it is not known if these agents have transient adverse effects on the 
composition of sperm.  Therefore, non-pregnant, non-breast-feeding women may only be
enrolled if they are willing to use 2 methods of birth control or are considered highly unlikely 
to conceive.  Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 
year will be considered postmenopausal), or 3) not heterosexually active for the duration of 
the study.  The two birth control methods can be either two barrier methods or a barrier 
method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of 
pembrolizumab (MK-3475) or up to 180 days after the last dose of paclitaxel, docetaxel or 
vinflunine. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject.
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Male subjects randomized to receive paclitaxel, docetaxel or vinflunine should seek medical
advice regarding cryopreservation of sperm prior to receiving treatment, due to the 
possibility of infertility.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with MK-3475 or paclitaxel, 
docetaxel or vinflunine, the subject will immediately be removed from the study.  The site 
will contact the subject at least monthly and document the subject’s status until the 
pregnancy has been completed or terminated.  The outcome of the pregnancy will be reported 
to the Sponsor without delay and within 24 hours if the outcome is a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).  The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor.   If a male subject impregnates his female partner the study 
personnel at the site must be informed immediately and the pregnancy reported to the 
Sponsor and followed as described above and in Section 7.2.2.
Use in Nursing Women
It is unknown whether MK-3475, paclitaxel, docetaxel or vinflunine are excreted in human 
milk.  Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.  Once a 
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subject has discontinued treatment, even though he/she continues to be monitored in the trial, 
he/she may be allowed to begin treatment again if deemed medically appropriate.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment

Radiographic disease progression as determined by local/site assessment
o
Note: For unconfirmed radiographic disease progression, or confirmed 
progression with reduction in disease burden from baseline please see Section 
5.8.1

Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

Investigator's decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Completed 24 months of treatment with pembrolizumab (MK-3475)
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab (MK-3475) after 24 months may be eligible for up to one year 
of additional study treatment if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 7.1.5.2.1.   

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol 
Flow Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each 
subject will be followed for 30 days for adverse event monitoring (serious adverse events 
will be collected for 90 days after the end of treatment as described in Section 7.2.3.1).  
Subjects who discontinue for reasons other than progressive disease will have post-
treatment follow-up for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent or becoming lost to follow-up.  After documented 
disease progression each subject will be followed by telephone for overall survival until 
death, withdrawal of consent, or the end of the study, whichever occurs first.
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Treatment after Initial Radiologic Progression
Immunotherapeutic agents such as pembrolizumab (MK-3475) may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses.  The response patterns 
seen with such an approach may extend beyond the typical time course of responses seen 
with cytotoxic agents, and can manifest as a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions.  
If radiologic imaging by local/site assessment shows PD, tumor assessment may be repeated 
by the site 4 weeks later in order to confirm PD with the option of continuing treatment per 
below while awaiting radiologic confirmation of progression.  If repeat imaging shows SD, 
PR or CR, treatment may be continued as per treatment calendar.  If repeat imaging still 
meets the threshold for PD (≥ 20% increase in tumor burden compared to nadir) but shows a 
reduction in tumor burden compared to the previous time point, treatment may be continued 
as per treatment calendar after consultation with Sponsor. If repeat imaging confirms 
progressive disease without reduction in tumor burden compared to the previous time point, 
subjects will be discontinued from study therapy.  In determining whether or not the tumor 
burden has increased or decreased, investigators should consider all target lesions as well as
non-target lesions (please refer to the Procedures Manual).
The decision to continue study treatment after the 1st evidence of disease progression is at the 
Investigator’s discretion based on the clinical status of the subject as described in Table 9
below. Confirmatory imaging maybe performed as early as 28 days later; alternatively, the 
scan performed at the next scheduled time point (every 42 days ±7 days) may be used as 
confirmation. Subjects may receive study treatment while waiting for confirmation of PD if
they are clinically stable as defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

No decline in ECOG performance status

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention

Subjects exhibiting toxicity from trial therapy as outlined in Sections 5.2.1.2 and 7.2 
may NOT continue to receive trial therapy.
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Table 9
Imaging and Treatment After 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st
radiologic 
evidence of PD 
Repeat imaging at >
4 weeks at site to 
confirm PD
May continue study 
treatment 
at 
the 
Investigator’s 
discretion 
while 
awaiting 
confirmatory 
scan 
by site
Repeat imaging at >
4 weeks to confirm 
PD per physician 
discretion only
Discontinue 
treatment
Repeat 
scan 
confirms PD
(no 
reduction in tumor 
burden from prior 
scan)
No 
additional 
imaging required
Discontinue 
treatment
No 
additional 
imaging required
N/A
Repeat 
scan 
confirms 
PD 
(reduction in tumor 
burden from prior 
scan)
Continue regularly 
scheduled imaging 
assessments
Continue 
study 
treatment 
after 
consultation 
with 
Sponsor
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment 
if 
condition 
has 
improved 
and/or 
clinically stable per 
Investigator 
and 
Sponsor’s 
discretion
Repeat scan shows 
SD, PR or CR
Continue regularly 
scheduled imaging 
assessments 
Continue 
study 
treatment 
at 
the 
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment 
if 
condition 
has 
improved 
and/or 
clinically stable per 
Investigator’s 
discretion
NOTE: If a subject with confirmed radiographic progression (i.e. 2 scans at least 28 days 
apart demonstrating progressive disease) is clinically stable or clinically improved, and there 
is no further increase in the tumor dimensions at the confirmatory scan (as assessed by the 
investigator and site radiologist), an exception may be considered to continue treatment upon 
consultation with the Sponsor.
Discontinuation of Study Therapy after CR
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab (MK-3475) and had at 
least two treatments with pembrolizumab (MK-3475) beyond the date when the initial CR 
was declared.  Subjects who then experience radiographic disease progression may be 
eligible for up to one year of additional treatment with pembrolizumab (MK-3475) at the 
discretion of the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab (MK-3475), the subject meets the safety parameters listed in the 
Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume therapy at the same 
dose and schedule at the time of initial discontinuation.  Additional details are provided in 
Section 7.1.5.2.1.  Response or progression in this Second Course Phase will not count 
towards the ORR and PFS of the primary endpoint in this trial.
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Crossover Phase 
Subjects who were randomized to the control arm and experienced investigator-defined 
disease progression per RECIST 1.1 while receiving study treatment or who, after  stopping 
treatment on study, started subsequent anti-cancer therapy and then experienced progression 
are eligible for the Crossover Phase (provided they meet the eligibility criteria outlined in 
Section 7.1.5.2.2 and the trial is open). Subjects may be eligible for up to two years of 
treatment with pembrolizumab. A Second Course Phase will not be made available for 
subjects in the Crossover Phase. Additional details are provided in Sections 7.1.2.9 and 
7.1.5.2.2.  Response or progression in the Crossover Phase will not count towards the ORR 
and PFS of the primary endpoint in this trial.
Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days (± 3 
days) after the last dose of study medication or before the initiation of a new antineoplastic
treatment. Procedures and assessments performed at the Safety Follow-Up Visit and beyond 
should follow guidelines described in the Trial Flow Chart (Section 6.0). All AEs that occur 
within the 30-day safety follow-up visit should be recorded. Subjects with an AE >Grade 1 
will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new 
antineoplastic therapy, whichever occurs first. SAEs that occur within 90 days of the end of 
treatment or before initiation of a new antineoplastic treatment should also be followed and 
recorded. In subjects who start another cancer therapy before 30 days after discontinuation of 
study therapy, the Safety Follow-Up Visit should occur prior to the subject receiving another 
cancer therapy.
Duration of Follow-up
All subjects will be followed for at least 30 days after their last dose of trial treatment or until
initiation of a new anti-cancer treatment, whichever occurs first. Subjects who are 
discontinued from the trial due to an unacceptable drug-related AE will be followed until the 
resolution of the AE to Grade 0-1 or stabilization or until initiation of a new therapy for their 
cancer, whichever occurs first.
Subjects,
who discontinued study therapy without 
documented disease progression, should continue to be monitored for disease status by 
radiologic imaging according to the guidelines described in the Trial Flow Chart (Section 
6.0) for post-treatment follow-up. Disease monitoring should continue to be assessed every 6 
weeks (±7 days) (every 12 weeks following the 1st 12 months of trial treatment) until, 1) for
approximately two years after the last dose of trial treatment, 2) start of a new antineoplastic
therapy, 3) documented disease progression, or 4) until death, whichever occurs first.
Survival Follow-up
Once a subject stops receiving trial treatment, they will be followed for survival. Initially 
these data will be collected at the Safety Follow-up visit and the 3-month Follow-up visits, 
and any subsequent visits for imaging that may occur until PD is confirmed or starting a new 
anti-cancer therapy. Once the subject stops the imaging assessments for this protocol every 6 
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weeks (±7 days) or every 12 weeks (±7 days) after year 1 (e.g. for PD or starting a new anti-
cancer therapy) the subject moves into the survival follow-up phase and should be contacted 
by telephone every 12 weeks (± 7 days) to assess for survival status, until death, withdrawal 
of consent, or end of the study, whichever occurs first.
The Sponsor may request survival status data more frequently than every 12 weeks at 
specific time points during the study. Refer to section 7.1.5.3.3 Survival Follow-up and 
section 7.1.5.4 Survival Status for additional information.
Post-study treatments and the subject’s response to them will also be collected.
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.
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 Data 
Monitoring Committee (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 studies indicates a potential 
health hazard to subjects
5. Plans to modify or discontinue the development of the study drug
In the event of Sponsor decision to no longer supply study 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
Trial Period:
Screening
Phase
Screening 
Phase 
Screening 
Phase 
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d
-42 to -1
-28 to -1
-10 to -1
+3d
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days post 
Last dose
± 3
Every 6 
weeks post 
discon
±7
Every 12 
weeks
±7
Administrative Procedures
Informed Consent
Xe
Informed Consent for Future Biomedical 
Research
Xf
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication 
Reviewg
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X d
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Statusc
X
Clinical Procedures/Assessments
Review Adverse Eventsh, i
X
X
X
X
X
X
X
X
Xi
Xi
12-Lead Electrocardiogram (Locally 
performed)
X
Full Physical Examinationj
X
Directed Physical Examinationj
X
X
X
X
X
X
X
Vital Signs Weight and Heightk
X
X
X
X
X
X
X
X
X
X
ECOG Performance Statusl
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  
analysis performed by LOCAL 
laboratory
Pregnancy Test – Urine or Serum -HCGm
Xm
PT/INR and aPTTn
Xo
CBC with Differentialp
Xo
X
X
X
X
X
X
Xq
Chemistry Panelp
Xo
X
X
X
X
X
X
Xq
Urinalysisp
Xo
X
X
X
Xq
(T3, FT4 and TSH)p
Xo
X
X
X
Xq
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Trial Period:
Screening
Phase
Screening 
Phase 
Screening 
Phase 
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d
-42 to -1
-28 to -1
-10 to -1
+3d
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days post 
Last dose
± 3
Every 6 
weeks post 
discon
±7
Every 12 
weeks
±7
Laboratory Procedures/Assessments: 
analysis performed by CENTRAL 
laboratory
Blood for serum and plasma for 
Correlative Studies r
X
Blood samples for RNA and DNA for 
Correlative Studiess
X
X
X
X
Blood for Geneticst
X
Efficacy Measurements
Tumor Imaging
Xu,x
Xv
Xv
Xw
Xb
Tumor Tissue Collection
Archival or Newly Obtained Tissue 
Collection for biomarker analysisy
X
Patient Reported Outcomes
EuroQol EQ-5D
Xz
Xz
Xz
Xz
Xz
Xz
Xz
EORTC QLQ-C30
Xz
Xz
Xz
Xz
Xz
Xz
Xz
Health Economic Assessment (HEA)
Xz
Xz
Xz
Xz
Xz
Xz
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; however the 
treatment cycle interval may be increased due to toxicity (for pembrolizumab (MK-3475) arm only) according to the dose modification guidelines provided in Section 5.2.1.2.  If the interval is 
increased, all procedures except imaging should be performed based on the new dosing schedule.  Imaging should be performed at 9 weeks (63 days ± 7) from randomization and every 6 weeks 
thereafter (42 days ± 7 days) regardless of any treatment delays.  
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imaging every 6 weeks (42 ± 
7 days) in the first year and every 12 weeks (84 ± 7days) after year 1 until (1) the start of new anti-cancer treatment, (2) disease progression as assessed by investigator/site radiologist (3) death, or (4) 
the end of the study, whichever occurs first.
c.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. 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).
d.
In general, the window for each visit is ± 3 days unless otherwise noted.  Cycle 1 treatment must be given within 3 days of randomization.
e.
Written consent must be obtained prior to performing any protocol specified 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.g., within 42 days prior to the first dose of trial treatment).  Screening number will be assigned when the trial 
informed consent is signed.
f.
Signing the informed consent for future biomedical research (FBR) sample is optional.  Detailed instructions for the collection and management of specimens for FBR are provided in the Procedures 
Manual and Section 12.2.  
g.
Prior medications – Record all medications taken within 30 days of the first dose of trial treatment. Concomitant medications – Enter new medications started during the trial through the Safety 
Follow-up visit.  Record all medications taken for AEs as defined in Section 7.2.
h.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.  
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i.
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days after the last dose of trial 
treatment or the start of new anti-cancer treatment, whichever comes first.  Afterwards, report only SAEs and ECIs that are related to trial treatment.
j.
Full PE at Screening Visit; Directed PE for all other visits.
k.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at Visit 1 only.
l.
ECOG PS at Screening to be performed ≤ 10 days prior to Day 1 of trial treatment visit.
m. 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 study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
n.
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.
o.
Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.  See Section 7.1.3 for details regarding laboratory tests.
p.
For the paclitaxel/docetaxel/vinflunine arm, CBC and Chemistry tests should be collected on Day 1 of each 3 week cycle. For Cycles 1 and 2, CBC and Chemistry tests should also be collected on 
Days 8 and 15 of each cycle.  In subsequent cycles, CBC and Chemistry tests on Day 8 and Day 15 may be performed at the Investigator’s discretion. Thyroid Function Tests should be collected 
every 6 weeks. For the pembrolizumab (MK-3475) arm, CBC and Chemistry tests should be collected on Day 1 of each 3 week cycle. Thyroid Function Tests should be collected every 6 weeks. After 
Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests. For Cycle 1, the Screening samples are sufficient if 
performed within 10 days.  For subjects with a baseline estimated creatinine clearance below the normal institutional laboratory range, a baseline measured creatinine clearance should be performed.
q.
Unresolved abnormal labs that are drug related AEs should be followed until resolution. Labs do not need to be repeated after the end of treatment if labs are within normal range.
r.   Blood for serum and blood for plasma correlative studies is to be collected only predose at Cycle 1. See Procedures Manual. Any leftover samples from the correlative blood studies will be stored for 
future biomedical research if the subject signs the FBR consent
s.
Blood samples for RNA/DNA correlative studies should be collected Predose at Cycles 1, 2, and 3, and again at treatment discontinuation. See Procedures Manual. Any leftover samples from the 
correlative blood studies will be stored for future biomedical research if the subject signs the FBR consent.
t.
This sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or unless the IRB/IEC does not 
approve of the collection of the sample for these purposes. If the sample is collected, any leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent.
u.
The initial tumor imaging will be performed within 28 days prior to randomization.  Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of 
diagnostic quality and performed within 28 days prior to randomization. Measureable disease based on RECIST 1.1 must be confirmed by investigator/site radiologist before enrollment. All subjects 
will have a baseline bone scan performed at screening. Subjects with positive bone scans at baseline will be followed with additional scans performed at 9 weeks (± 7 days) from randomization and 
then every 6 weeks (± 7 days) thereafter or more frequently if clinically indicated.   For subjects with new symptoms suggestive of osseous metastasis, a bone scan should be obtained. Additionally, 
plain X-ray evaluation should be obtained for symptomatic sites with negative bone scan evaluations.  Refer to Section 7.1.2.6.3 of the protocol and site imaging manual.
v.
The first on-study imaging time point will be performed at 9 weeks (±7 days) from randomization and then every 6 weeks (± 7 days) thereafter or more frequently if clinically indicated.  After 12 
months, imaging frequency should be reduced to every 12 weeks (±7 days).  Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts or extension of 
pembrolizumab (MK-3475) cycle frequencies.  The same imaging technique should be used in a subject throughout the trial.  
w.
In subjects who discontinue study therapy without confirmed disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation (i.e., date of discontinue ± 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.
x.
All subjects will have a baseline bone scan performed at screening. Subjects with positive bone scans at baseline will be followed with additional scans performed at 9 weeks (±7 days) from
randomization and then every 6 weeks (±7 days) thereafter or more frequently if clinically indicated. Subjects with new symptoms concerning osseous metastasis will be evaluated with a bone scan. 
Refer to Section 7.1.2.6.3 of the protocol.
y.
Baseline tumor tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy (FNA not adequate) must be provided to the central vendor prior to randomization. 
Adequacy of the biopsy specimen for biomarker analysis must be confirmed by the central laboratory before enrollment. Detailed instructions for tissue collection, process and shipment are provided in the 
Procedures Manual.  If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue that would ordinarily be discarded at the end of the main study will be retained for FBR.  
z.
It is most relevant and strongly recommended that Electronic patient outcomes (ePROs) are administered prior to drug administration, adverse event evaluation and disease status notification starting
with EQ-5D, followed by EORTC QLQ-C30, and HEA.  Health economic assessment (HEA) to be completed by trained personnel prior to all other study procedures.  All ePROs are to be performed 
prior to Cycle 1, Cycle 2, Cycle 3, Cycle 4  and every 2 cycles thereafter (e.g., Cycle 6, Cycle 8, Cycle 10) up to a year or  End of Treatment, whichever comes first, and the 30-day post-treatment 
discontinuation follow-up visit.  If the subject does not completed the ePROs the MISS_MODE form must be completed to capture the reason the assessment was not performed. 
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Second Course Phase (Retreatment) for Pembrolizumab (MK-3475) Arm Only
Trial Period:
Treatment Cyclesa
End of Treatment
Post-Treatment
Treatment Cycle/Title:
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d:
+3d
± 3
± 3
± 3
± 3
± 3
At time of discon
30 days post 
last dose
±3
Every 6 weeks
post discon
±7
Every 12 
weeks
±7
Administrative Procedures
Eligibility Criteriae
X
Concomitant Medication Reviewf
X
X
X
X
X
X
X
X
Pembrolizumab (MK-3475) Administrationg
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Statusc
X
Clinical Procedures/Assessments
Review Adverse Eventsh
X
X
X
X
X
X
X
Xi
Xi
Full Physical Examinationj
Xj
Directed Physical Examinationj
X
X
X
X
X
X
Vital Signs, Weight and Heightk
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
Laboratory 
Procedures/Assessments:  
analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCGl
X
PT/INR and aPTTm
Xn
CBC with Differentialo
Xn
X
X
X
X
X
X
Xr
Chemistry Panelo
Xn
X
X
X
X
X
X
Xr
Urinalysis
X
T3, FT4 and TSHo
Xn
X
X
Xr
Efficacy Measurements
Tumor Imagingp
X
X
X
Xq
X
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; however the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided in Section 5.2.1.2.  If the interval 
is increased, all procedures except imaging should be performed based on the new dosing schedule.  Imaging should always be performed every 6 weeks (42 days ±7 
days) regardless of any treatment delays.  
b.
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 6 weeks (±7 days) until (1) the start of new anti-cancer treatment, (2) disease progression, (3) death, or (4) the end of the study, whichever 
occurs first.
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Trial Period:
Treatment Cyclesa
End of Treatment
Post-Treatment
Treatment Cycle/Title:
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d:
+3d
± 3
± 3
± 3
± 3
± 3
At time of discon
30 days post 
last dose
±3
Every 6 weeks
post discon
±7
Every 12 
weeks
±7
c.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. 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).
d.
In general, the window for each visit is ± 3 days unless otherwise noted.
e.
Subjects who either a) attain a CR and discontinue treatment or b) discontinue treatment after 24 months on pembrolizumab (MK-3475) 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.  
f.
Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit.  Record all medications taken for AEs as defined in 
Section 7.2.
g.
Subjects who restart treatment should resume at the same dose and cycle interval which they were receiving prior to discontinuation.
h.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness.  
i.
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 
days after the last dose of trial treatment or the start of new anti-cancer treatment, whichever comes first.  Afterwards, report only SAEs and ECIs that are related to trial 
treatment.
j.
Full PE at Screening Visit; Directed PE for all other visits. 
k.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at Visit 1 only.
l.
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of the retreatment phase.  If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should 
be repeated if required by local guidelines.
m. Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
n.
Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of pembrolizumab (MK-3475).  See 
Section 7.1.3 for details regarding laboratory tests.
o.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.
p.
A scan must be performed within 28 days prior to restarting treatment with pembrolizumab (MK-3475).  Imaging should continue to be performed every 6 weeks (42 ±7
days) from the first dose of trial treatment or more frequently if clinically indicated.  Imaging timing should follow calendar days and should not be adjusted for delays 
in cycle starts or extension of pembrolizumab (MK-3475) cycle frequencies.  The same imaging technique should be used in a subject throughout the trial.  Local 
reading (investigator assessment with site radiology reading) will be used to determine eligibility and for subject management.  The Sponsor will collect radiological 
assessments for analysis by a central imaging vendor.  The processes for image collection and transmission to the central vendor are in the Site Imaging Manual.
q.
In subjects who discontinue study therapy without confirmed disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation 
(i.e., date of discontinue ± 4 week window).  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation 
isn’t mandatory.
r.
Unresolved labs that are drug-related AEs should be followed until resolution.  Labs do not need to be repeated after the end of trial treatment if labs are within normal 
range.
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Crossover Phase for Control Arm Only
Trial Period:
Treatment Cyclesa
End of Treatment
Post-Treatment
Treatment Cycle/Title:
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d:
+3d
± 3
± 3
± 3
± 3
± 3
At time of discon
30 days post 
last dose
±3
Every 6 weeks
post discon
±7
Every 12 
weeks
±7
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Reviewe
X
X
X
X
X
X
X
X
Pembrolizumab (MK-3475) Administration
X
X
X
X
X
X
Post-study crossover Anticancer Therapy Status
X
X
Survival Status c
X
Clinical Procedures/Assessments
Review Adverse Eventsf
X
X
X
X
X
X
X
Xg
Xg
Full Physical Examinationh
Xh
Directed Physical Examinationh
X
X
X
X
X
X
Vital Signs and Weight i
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  analysis 
performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCGj
X
PT/INR and aPTTk
X
CBC with Differentiall
X
X
X
X
X
X
X
Xm
Chemistry Panell
X
X
X
X
X
X
X
Xm
Urinalysis
X
T3, FT4 and TSHl
X
X
X
Xm
Efficacy Measurements
Tumor Imagingn
X
X
Xo
X
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 in the Crossover Phase should always be performed every 12 weeks (84 days ±7 days) from Crossover Phase Cycle 1 Day 1, regardless of any treatment 
delays.  
b.
In subjects who discontinue treatment with pembrolizumab in the Crossover Phase without documented disease progression, every effort should be made to continue 
monitoring their disease status by radiologic imaging every 12 weeks (±7 days) until (1) the start of post-crossover new anti-cancer treatment, (2) disease progression, (3) 
death, or (4) the end of the study, whichever occurs first.
c.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. 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).
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Trial Period:
Treatment Cyclesa
End of Treatment
Post-Treatment
Treatment Cycle/Title:
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d:
+3d
± 3
± 3
± 3
± 3
± 3
At time of discon
30 days post 
last dose
±3
Every 6 weeks
post discon
±7
Every 12 
weeks
±7
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
e.
Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit.  Record all medications taken for AEs as defined in Section 
7.2.
f.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.  
g.
Record all AEs occurring within 30 days after the last dose of treatment in Crossover Phase.  Report all SAEs (related and unrelated to crossover treatment) and ECIs 
occurring up until 90 days after the last dose of Crossover treatment or the start of new anti-cancer treatment, whichever comes first.  Afterwards, report only SAEs and ECIs 
that are related to Crossover treatment.
h.
Full PE at Cycle 1; Directed PE for all other visits. 
i.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  .
j.
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of the Crossover phase.  If urine pregnancy results cannot 
be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated 
if required by local guidelines.
k.
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
l.
After Cycle 1 in the Crossover Phase, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests. 
m. Unresolved labs that are drug-related AEs should be followed until resolution.  Labs do not need to be repeated after the end of trial treatment if labs are within normal range.
n.
A scan must be performed within 30 days prior to treatment with pembrolizumab (MK-3475) in Crossover Phase.  Imaging should continue to be performed every 12 weeks 
(84 ±7 days) from the first dose of Crossover treatment or more frequently if clinically indicated.  Imaging timing should follow calendar days and should not be adjusted for 
delays in cycle starts or extension of pembrolizumab (MK-3475) cycle frequencies.  The same imaging technique should be used in a subject throughout the trial.  Local 
reading (investigator assessment with site radiology reading) will be used to determine eligibility and for subject management.  The Sponsor will collect radiological 
assessments for analysis by a central imaging vendor.  The processes for image collection and transmission to the central vendor are in the Site Imaging Manual.
o.
In subjects who discontinue study therapy without confirmed disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation (i.e., 
date of discontinue ± 4 week window).  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t 
mandatory.
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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.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
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.
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 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 
within 30 days before starting the trial.  Prior treatment for urothelial cancer will be recorded 
separately and not listed as a prior medication.
Prior Treatment Details for Urothelial Cancer
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries and record in the trial database.
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7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2.
Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject 
will move into survival follow-up.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
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.  
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
Investigators must choose a standard treatment (paclitaxel, docetaxel or vinflunine) prior to 
randomization and document the selection in the trial database (See Data Entry Guidelines).
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment for greater than 12 weeks between 
pembrolizumab (MK-3475) doses on the pembrolizumab (MK-3475) treatment arm require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on subject management.
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Administration of trial medication will be witnessed by the investigator and/or trial staff.  
The total volume of pembrolizumab (MK-3475) or comparator infused will be compared to 
the total volume prepared to determine compliance with each dose of pembrolizumab (MK-
3475) or comparator administered.  
The instructions for preparing and administering pembrolizumab (MK-3475) will be 
provided in the Pharmacy Manual.  Treatment with paclitaxel, docetaxel or vinflunine will be 
prepared and administered as per the approved product label.
Clinical Procedures/Assessments
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinical 
indicated.  Adverse events will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE Version 4.0 (see Section 12.6).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab (MK-3475) all AEs of unknown 
etiology associated with pembrolizumab (MK-3475) exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (termed immune-related adverse events, or irAEs).  Refer to the separate guidance 
document in the administrative binder regarding the identification, evaluation and 
management of potential irAEs.  
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
12-Lead Electrocardiogram
A standard 12-lead ECG will be performed using local standard procedures once at screening
visit as described in Section 6 – Trial Flow Chart. Clinically significant abnormal findings 
should be recorded as medical history.
Physical Exam
7.1.2.3.1 Full Physical Exam
The investigator or clinical designee will perform a complete physical exam during the 
screening period (See Trial Flow Chart Section 6.0).  Clinically significant abnormal findings 
should be recorded as medical history.  After the first dose of trial treatment new clinically 
significant abnormal findings should be recorded as AEs.
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7.1.2.3.2 Directed Physical Exam
The investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to Day 1 of each treatment cycle starting with Cycle 2.  New clinically 
significant abnormal findings should be recorded as AEs.
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart.  Vital signs should include temperature, pulse, respiratory rate, weight 
and blood pressure.  Height will be measured at screening only.  
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.5) at 
screening (within ≤10 days prior the dosing on Day 1 Cycle 1) and prior to the dosing on Day 
1 of each treatment cycle and discontinuation of trial treatment as specified in the Trial Flow 
Chart.  
Tumor Imaging and Assessment of Disease
Process for image collection and transmission to the central vendor can be found in the Site 
Imaging Manual.  CT scan is the preferred imaging modality for this study. Tumor imaging 
may be performed by computed tomography (CT) or magnetic resonance imaging (MRI), but 
the same imaging technique should be used in a subject throughout the trial. . Bone scans will 
also be utilized to assess osseous metastases. Additionally, plain X-ray evaluation will be 
obtained for symptomatic sites with negative bone scan evaluations.
Local site investigator/radiology assessment based on RECIST 1.1 will be used to determine 
subject eligibility.  All scheduled images for all study subjects from the sites will be 
submitted to the central imaging vendor. In addition, additional 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 central imaging vendor as well.
7.1.2.6.1 Initial Tumor Imaging
Initial tumor imaging must be performed within 28 days prior to the first dose of trial 
treatment.  The investigator/site radiologist must review pre-trial images to confirm the 
subject has measurable disease per RECIST 1.1.  The baseline imaging scan should also be 
submitted to the central imaging vendor.  Bone scans will be performed at baseline for all 
subjects.
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Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 28 days prior to the first 
dose of trial treatment. The same imaging technique should be used in a subject throughout 
the trial.  Subjects who enter the study with stable brain metastases should continue to have 
brain imaging as clinically indicated. 
7.1.2.6.2 Tumor Imaging During Trial
The first imaging assessment should be performed at 9 weeks (63 days ±7 days) from 
randomization.  Subsequent imaging should be performed every 6 weeks (42 days ±7 days)
or more frequently if clinically indicated.  After the first 12 months on trial therapy, the 
imaging interval should be decreased to every 12 weeks (±7 days).  Imaging should not be 
delayed for delays in cycle starts or extension of pembrolizumab (MK-3475) cycle intervals.  
Per RECIST 1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date the response was first documented.  The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response, or at 
the next scheduled scan, whichever is clinically indicated.  
Imaging should continue to be performed until disease progression is assessed by the 
investigator, the start of new anti-cancer treatment, withdrawal of consent, death, or the end 
of the study, whichever occurs first.  Disease progression may be confirmed at least 4 weeks 
after the first scan indicating progressive disease in clinically stable subjects.  Subjects who 
have unconfirmed disease progression may continue on treatment until progression is 
confirmed provided they have met the conditions detailed in Section 5.8.1.
7.1.2.6.3 Bone Scans
Bone scans will be performed at baseline for all subjects. Subjects with positive bone scans at 
baseline will be followed with additional scans performed at 9 weeks (Day 63 ±7 days) from 
randomization. Subsequent scans should be performed every 6 weeks (42 days ±7 days) or 
more frequently if clinically indicated. After the first 12 months on trial therapy, the scanning
interval should be decreased to every 12 weeks (±7 days). Subjects with new symptoms 
concerning osseous metastasis (e.g., new persistently elevated alkaline phosphatase) will be 
evaluated with a bone scan. Additionally, plain X-ray evaluation should be obtained for 
symptomatic sites with negative bone scan evaluations. 
New osseous uptake, upon 
confirmation with CT, will be assessed for progression per RECIST 1.1. Lytic/mixed lesions 
with soft tissue component may be included in the evaluation of disease burden if it meets 
measurability criteria while blastic lesions are considered non-measurable, in accordance 
with RECIST 1.1.
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7.1.2.6.4 Assessment of Disease
For the purposes of the primary study endpoints, RECIST 1.1 (Appendix 12.7) will be 
applied by the central imaging vendor as the primary measure for assessment of tumor 
response and date of disease progression. Subjects in the pembrolizumab (MK-3475) arm
who have unconfirmed progressive disease will be managed as detailed in Section 5.8.1, and 
these criteria may be applied at the discretion of the investigator to subjects in the control 
arm as well.  All scans, including confirmatory scans, should be submitted to the central 
imaging vendor for retrospective evaluation.  
Imaging during the follow-up period is to be repeated every 6 weeks (42 ±7 days), or every 
12 weeks after the first year following the initiation of trial therapy, for subjects who 
discontinue trial treatment for reasons other than disease progression until the subject 
experiences confirmed disease progression or starts a new anti-neoplastic therapy.  
Local reading (investigator assessment with site radiology reading) based on RECIST 1.1 
will be used to determine subject eligibility.  Confirmatory scans performed per modified 
RECIST will be evaluated by local reading for the purpose clinical decision-making.  The 
central imaging vendor will receive all images from the sites, and a retrospective analysis of 
subject eligibility and treatment response by modified RECIST, will also be performed by a 
central vendor.
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 lab 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 that indicate 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.
If a tumor biopsy is to be obtained from an intended target lesion during eligibility 
assessment, the biopsy should be performed prior to obtaining the baseline scan. Otherwise, 
a new baseline scan should be obtained.
Blood for correlative biomarker studies should be collected prior to Cycle 1, Cycle 2, Cycle 
3, and at treatment discontinuation.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
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Patient Reported Outcomes (PROs)
The EuroQol EQ-5D and EORTC QLQ-C30 questionnaires will be administered by trained 
site personnel and completed electronically by subjects. It is most relevant and strongly 
recommended that ePROs are administered prior to drug administration, adverse event 
evaluation and disease status notification.in the following order: EuroQol EQ-5D first then 
EORTC QLQ-C30 at the time points specified in the Trial Flow Chart.
The Health Economic Assessment (HEA) form will be completed via an interview with the 
patient by qualified site personnel after the subject completes all other questionnaires.  The 
form captures all non-study related health care contacts made throughout the study.
Crossover Phase Assessments and Procedures
Crossover subjects can initiate treatment with pembrolizumab 200 mg Q3W once 
investigators confirm that subjects meets the eligibility criteria as listed in Section 7.1.5.2.2.  
The subject will then start the Crossover Phase as outlined in the Crossover Flow Chart in 
Section 6.3.  Subjects must have baseline imaging scans performed within 30 days prior to 
the first dose of pembrolizumab in the Crossover Phase.  On study imaging will be performed 
every 12 weeks (84 ±7 days) after the first dose of Crossover trial treatment or more 
frequently, if clinically indicated.  Local reading of imaging (investigator assessment with 
site radiology reading) will be used for subject management.  All scans performed during the 
study should be submitted to the central imaging vendor.
Subjects may continue on pembrolizumab until investigator confirmed progressive disease as 
assessed by RECIST 1.1 (as described in Section 5.8.1) or up to two years from starting 
crossover treatment with pembrolizumab 200 mg Q3W, whichever comes first.  Subjects 
who discontinue study treatment in the Crossover Phase will follow the post-treatment phase 
procedures as outlined in Section 6.3.  
As described in Section 5.8.2, subjects who attain a confirmed CR per RECIST 1.1 will have 
the option to hold pembrolizumab while continuing in the trial.  Please note the following
exception: crossover subjects will not be eligible for Second Course Phase as outlined in 
Section 7.1.5.2.1.
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 pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
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Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 10.
Table 10
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine aminotransferase (ALT)
Protein
aPTT
WBC (total and 
differential) e
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Total triiodothyronine (T3)
(or Free T3)b
Red 
Blood 
Cell 
Count
Carbon 
dioxide 
(CO2
or 
bicarbonate)b
Microscopic 
exam, 
if 
abnormal 
results 
are 
noted
Free thyroxine (free T4)
Absolute 
Neutrophil Count
Calcium
Urine pregnancy testa
Thyroid 
Stimulating 
Hormone (TSH)
Absolute 
Lymphocyte Count
Chloride
PK [for subjects on the 
pembrolizumab (MK-3475)
arm only]
Creatininec
(GFR can also be used in place 
of creatinine or CrCl)
[Anti- pembrolizumab (MK-
3475)
Antibodies 
(for 
subjects 
on 
the 
pembrolizumab (MK-3475)
arm only]
Glucose
Blood 
for 
correlative 
studies
Phosphorus
Blood for FBR
Potassium
Blood for Genetics
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen d
Uric acid
a Perform on women of childbearing potential only.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required.
b Carbon dioxide and/or bicarbonate do not need to be performed if these tests are not done as part the of 
standard of care in the region 
c. For subjects with a baseline calculated creatinine clearance below the normal institutional laboratory range, a 
baseline measured creatinine clearance should be performed.
d Blood Urea Nitrogen is preferred; if not available urea may be tested
e Absolute or % acceptable per institutional standard.
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Laboratory tests for screening should be performed within 10 days prior to the first dose of 
trial treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 
hours prior to dosing.  Results must be reviewed by the investigator or qualified designee and 
found to be acceptable prior to each dose of trial treatment. The results from thyroid function 
tests are not required to be available nor reviewed prior to each dose of trial treatment. 
Pharmacokinetic/Pharmacodynamic Evaluations
The accumulation of robust PK and ADA data has allowed for the adequate characterization 
the clinical pharmacology of pembrolizumab across indications. Therefore, upon approval of 
Amendment 17, each site is to stop the collection of PK and ADA samples for all subjects. 
Blood samples for PK and ADA collected prior to Amendment 17 may be stored only at this 
time. Analysis will be performed if required.
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future use

Leftover tumor tissue

Leftover RNA

Leftover biomarker samples (serum and plasma)
Other Procedures
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial 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 on the pembrolizumab (MK-3475) arm who a) attain a 
CR or b) complete 24 months of treatment with pembrolizumab (MK-3475) may discontinue 
treatment with the option of restarting treatment if they meet the criteria specified in Section 
7.1.5.2.1.  After discontinuing treatment following assessment of CR or 24 months of 
treatment, these subjects should return to the site for a Safety Follow-up Visit (described in 
Section 7.1.5.3.1) and then proceed to the Follow-up Period of the study (described in 
Section 7.1.5.3.2).
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7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
This is an open label trial; there is no blinding for this 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 labs and trial assessments

Imaging equipment – as required for trial objectives
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Pharmacy 
Manual and Site Imaging Manual.
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 randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1.  Screening 
procedures may be repeated after consultation with the Sponsor.
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 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.

Informed Consent Form 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. 

Initial Tumor Imaging should be performed within 28 day of randomization.

Laboratory tests and evaluation of ECOG status are to be performed within 10 days 
prior to the first dose of trial treatment

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 study 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.
Treatment Period
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.  
7.1.5.2.1 Second Course Phase (Retreatment Period)
Subjects on the pembrolizumab (MK-3475) arm who stop pembrolizumab (MK-3475) with 
SD or better may be eligible for up to one year of additional pembrolizumab (MK-3475)
therapy if they progress after stopping MK-3745.  This retreatment is termed the Second 
Course Phase of this study and is only available if the study remains open and the subject 
meets the following conditions:
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
Either 
o
Stopped initial treatment with pembrolizumab (MK-3475) after attaining an 
investigator-determined confirmed CR according to RECIST 1.1

Was treated for at least 24 weeks with pembrolizumab (MK-3475) before 
discontinuing therapy

Received at least two treatments with pembrolizumab (MK-3475) beyond the 
date when the initial CR was declared
OR
o
Subject had SD, PR or CR and stopped pembrolizumab (MK-3475) treatment 
after 24 months of trial treatment for reasons other than disease progression or 
intolerability
AND

Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab (MK-3475)

Did not receive any anti-cancer treatment since the last dose of pembrolizumab (MK-
3475)

Have a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrate adequate organ function as detailed in Section 5.1.2

Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  

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 study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  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.

Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.

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 subject to participate, in the opinion of 
the treating investigator.
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Subjects who restart treatment will be retreated at the same dose frequency as when they last 
received pembrolizumab (MK-3475). Treatment will be administered for up to one additional 
year.
Note:  Subjects who receive pembrolizumab in the Crossover Phase are not eligible for the 
Second Course Phase.  
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
7.1.5.2.2 Crossover Phase
Subjects on the control arm who stop receiving the investigator’s choice of paclitaxel, 
docetaxel or vinflunine, and develop investigator-determined disease progression per 
RECIST 1.1 may enter the Crossover Phase to receive pembrolizumab, if the eligibility 
criteria below are met. Subjects who permanently discontinued from the study are not 
eligible for crossover. 
There are no laboratory requirements or limitations to enter the Crossover Phase. Subjects 
will have laboratory assessments while receiving study treatment as outlined in the Crossover 
Flow Chart in Section 6.3. 
The Crossover Phase of the study is only available if the study remains open and the subject
meets the criteria listed below.
Inclusion Criteria for Crossover from Control Arm to Pembrolizumab
In order to be eligible for participation in the Crossover Phase, the subject must:

Have been randomized to the control arm, taken at least one dose and subsequently 
discontinued treatment with paclitaxel, docetaxel or vinflunine.

Experienced an investigator-determined confirmed radiographic disease progression 
per RECIST 1.1 after stopping their initial treatment.

A scan must be performed within 30 days prior to starting treatment with 
pembrolizumab (MK-3475).

Did not receive any anti-PD1/PD-L1, anti-CTLA4 or other checkpoint inhibitor since 
the last dose of chemotherapy.

Have a performance status of 0 to 2 on the ECOG Performance Scale.

Subjects with known and treated brain metastasis are eligible provided they are 
clinically stable, and brain metastases have been treated. Steroid use for symptom 
control is allowed but the total daily dose should be ≤10 mg of prednisone or its
equivalent.

Have adequately recovered from adverse events of previous anti-cancer therapy.
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
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  

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 study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  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.

Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.

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 subject to participate, in the opinion of 
the treating investigator.
Exclusion Criteria for Crossover from Control Arm to Pembrolizumab
The subject must be excluded from participating in the Crossover Phase if the subject:

Has discontinued from study (MK-3475 KN045).

Has active pneumonitis of Grade 2 or greater or history of pneumonitis requiring 
systemic steroid therapy.

Has received thoracic radiation therapy of > 30 Gy within 6 months and have active 
and untreated brain metastasis.
Visit requirements are outlined in Section 6.3 – Trial Flow Chart.
Post-Treatment Visits
7.1.5.3.1 Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days (±3)
after the last dose of trial treatment or before the initiation of a new anti-cancer 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 0-1 or until the beginning of a new anti-cancer therapy, whichever occurs first.  
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-
cancer treatment should also be followed and recorded.  
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Subjects who are eligible for retreatment with pembrolizumab (MK-3475) (as described in 
Section 7.1.5.2.1) may have up to two safety follow-up visits, one after the Treatment Period 
and one after the Second Course Phase.
Subjects who are eligible for treatment with pembrolizumab in the Crossover Phase (as 
described in Section 7.1.5.2.2) may have up to two safety follow-up visits, one after the 
initial Treatment Period and one after the Crossover Phase.
7.1.5.3.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 6 weeks (42 ±7 days) by 
radiologic imaging to monitor disease status. After 1 year, the imaging time point will occur 
every 12 weeks (±7 days).  Every effort should be made to collect information regarding 
disease status until the start of new anti-cancer therapy, disease progression determined by 
the investigator/site radiologist, death, end of study or if the subject begins retreatment with 
pembrolizumab (MK-3475) as detailed in Section 7.1.5.2.1.  Information regarding post-
study anti-cancer treatment will be collected if new treatment is initiated.
Subjects who are eligible to receive retreatment with pembrolizumab (MK-3475) according 
to the criteria in Section 7.1.5.2.1 will move from the follow-up phase to the Second Course 
Phase when they experience disease progression.  Details are provided in Section 6.2 – Trial 
Flow Chart for Retreatment with pembrolizumab (MK-3475).
Subjects in the control arm who discontinued study treatment and are eligible to receive 
treatment with pembrolizumab in the Crossover Phase (according to the criteria in Section 
7.1.5.2.2) will move from the Follow-up Phase to the Crossover Phase if they experience 
investigator-confirmed disease progression per RECIST 1.1.  Details are provided in Section 
6.3 –Crossover Phase for Control Arm Only.
7.1.5.3.3 Survival Follow-up
Once a subject stops receiving trial treatment, they will be followed for survival. Initially 
these data will be collected at the Safety Follow-up visit and at the 3-month Follow-up visits, 
and any subsequent visits for imaging that may occur until PD is confirmed. Once the subject 
stops the imaging assessments for this protocol every 6 weeks or every 12 weeks after year 1 
(e.g. for PD or starting a new antineoplastic therapy), the subject moves into the Survival 
Follow-up Phase and should be contacted by telephone every 12 weeks (± 7 days) to assess 
for survival status. Post-study treatments and the subject’s response to them will also be 
collected.
Subjects in the control arm who discontinued study treatment and are eligible to receive 
treatment with pembrolizumab in the Crossover Phase (according to the criteria in Section 
7.1.5.2.2) will move from the Survival Follow-up Phase to the Crossover Phase if they 
experience investigator-determined disease progression by RECIST 1.1.  Details are provided 
in Section 6.3 –Crossover Phase for Control Arm Only.
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Survival Status
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.  For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim, and/or final analysis.  Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the sponsor defined time period will be contacted for their survival status (excluding 
participants that have a previously recorded 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 
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 
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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 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
For purposes of this trial, an overdose of pembrolizumab (MK-3475) will be defined as any 
dose of 1,000 mg or greater (≥5x the indicated dose). No specific information is available on 
the treatment of overdose of pembrolizumab (MK-3475). In the event of overdose, the 
subject should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated. 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.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported 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 
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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 adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 11 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 serious adverse event, or follow up to a serious adverse event, 
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 serious adverse event, or follow up 
to a serious adverse event, 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 
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guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
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 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, 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).
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).
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3. Additional adverse events:
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document.”  This document can be found in the administrative binder and 
provides guidance regarding identification, evaluation and management of ECIs and 
irAEs.  
ECIs identified in this guidance document from the date of first dose through 90 days 
following cessation of treatment, or 30 days after the initiation of a new anticancer 
therapy, whichever is earlier need to be reported to the SPONSOR within 24 hours of the 
event consistent with standard SAE reporting guidelines and either by electronic media or 
paper.  Sponsor Contact information can be found in the administrative binder.
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event.  Subjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes.  If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes.  If no other cause is found, then it is 
assumed to be immune-related.
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 study.  
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 study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
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.
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Table 11
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (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.
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.
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
Data Monitoring Committee (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 8.1.4 - Interim 
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.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
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8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes 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 Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding, will be documented in a supplemental SAP (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in 
the CSR.
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Eastern Cooperative Oncology Group (ECOG) Performance Scale (0/1 vs. 2), presence or 
absence of liver metastases, hemoglobin (≥ 10 g/dL vs. <10 g/dL), and time from completion 
of most recent chemotherapy (<3 months or ≥3 months) will be the stratification variables in 
all stratified analyses.
Efficacy Analyses
The intention-to-treat (ITT) population will serve as the primary analysis population in this 
study. The primary efficacy endpoints are progression-free-survival (PFS) (i.e., time from 
randomization to documented progressive disease or death due to any cause, whichever 
occurs first) and overall survival (OS) (i.e., time from randomization to death due to any 
cause) in PD-L1 strongly positive, PD-L1 positive, and all subjects. The primary analyses of 
PFS will be based on blinded independent radiologists’ review using RECIST 1.1. 
Supportive analyses based on investigator’s assessments using RECIST 1.1 will also be 
performed. The secondary endpoints include PFS per modified RECIST (see Section 8.2.3.1
for definition) and objective response rate (ORR) per RECIST 1.1 and modified RECIST 
based on blinded independent radiologists’ review. All the stratified analyses will be based 
on the stratification factors implemented for enrollment. In addition, a supportive stratified 
analyses will also be conducted for the primary efficacy endpoints based on the four strata 
defined by the number of risk factors (0, 1, 2 or 3 to 4) of the following [67]:  Eastern 
Cooperative Oncology Group (ECOG) Performance Scale >0, presence of liver metastases, 
hemoglobin <10 g/dL), and time from completion of most recent chemotherapy <3 months.
An outline of the efficacy analysis strategy is presented in Table 13 in Section 8.2.5.1. The 
strategy to address multiplicity issues with regard to multiple efficacy endpoints, multiple 
comparisons, multiple populations and interim analyses is described in Section 8.2.9 Interim 
Analyses and in Section 8.2.6 Multiplicity.
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Safety Analyses
The All-Patients-as-Treated (APaT) population will be employed for safety analyses. The 
analysis of safety results will follow a tiered approach. Please see Section 8.2.5.2 for details. 
Power and Sample Size
The study will randomize approximately 470 patients with a 1:1 ratio between the 
pembrolizumab (MK-3475) arm and the standard treatment arm. The study is event-driven 
and the sample size calculation is driven by survival events. Assuming the prevalence rates 
of PD-L1 positive subjects and PD-L1 strongly positive subjects among the overall 
population are 55% and 33%, respectively, a sample size of 470 all subjects will provide 
approximately 260 PD-L1 positive subjects and 156 PD-L1 strongly positive subjects. 
The sample size and power calculation of PFS is based on the following assumptions: 1) 
progression-free survival follows an exponential distribution with a median of 4 months in 
the standard treatment arm, 2) true hazard ratios between pembrolizumab (MK-3475) and 
standard therapy of 0.45, 0.5 and 0.5 for PD-L1 strongly positive, PD-L1 positive and all 
subjects, respectively, 3) an enrollment period of 12 months, and 4) a yearly dropout rate of 
5%. The estimated numbers of PFS events in PD-L1 strongly positive subjects and all 
subjects at the final PFS evaluation are estimated to be 137 and 420, respectively. The study 
provides 97% power for the PFS hypothesis in PD-L1 strongly positive subjects and >99% 
power for the PFS hypothesis in all subjects. 
The final OS analysis will be carried out after approximately 370 deaths in all subjects and 
110 deaths in PD-L1 strongly positive subjects have occurred between the pembrolizumab 
(MK-3475) arm and the paclitaxel, docetaxel or vinflunine arm for all subjects, barring early 
stopping for futility or efficacy. With the above numbers of events and before any alpha roll-
over, the study provides 88% and 86% power to demonstrate superiority of OS of 
pembrolizumab (MK-3475) relative to standard therapy at the pre-specified initial alpha 
(one-sided) levels in PD-L1 strongly positive and all subjects, respectively. The sample size
and power calculation of OS are based on the following assumptions: 1) overall survival 
follows an exponential distribution with a median of 8 months in the control arm; 2) the 
hazard ratio for OS between pembrolizumab (MK-3475) and control is 0.5, 0.6 and 0.7 for 
PD-L1 strongly positive, PD-L1 positive and all subjects, respectively. (deemed to be 
clinically meaningful in this population); 3) an enrollment period of 12 months and a 
minimum of 18 months follow-up after enrollment completion; and 4) a yearly drop-out rate 
of 2%.
The family-wise type I error rate for the primary hypotheses on PFS and OS as well as the 
secondary hypotheses on ORR is strongly controlled at 2.5% (one-sided) using the graphical 
method of Maurer and Bretz [68]. Additional details are provided in Section 8.2.6 
Multiplicity.
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Interim Analysis
There will be two interim analyses of PFS and OS for PD-L1 strongly positive (CPS>10%)
subjects and all subjects, respectively. For PD-L1 positive subjects, only the PFS and OS 
analyses at IA1 are included in the multiplicity controlled testing strategy. The timing of 
these interim analyses will be triggered by the pre-specified number of OS events. Results of 
the interim analyses will be reviewed by an external data monitoring committee (DMC).  
Further details of interim analyses are provided in Section 8.2.9 Interim Analysis as well as 
in the DMC Charter.
Statistical Analysis Plan
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
Although the trial is open label, analyses or summaries generated by randomized treatment 
assignment, actual treatment received, and/or PD-L1 biomarker status will be limited and 
documented. In addition, the independent radiologist(s) will perform the central imaging 
review without knowledge of treatment group assignment. The study team at the Sponsor 
consisting of clinical, statistical, statistical programming and data management personnel, 
will be blinded to subject-level PD-L1 biomarker results until the time that the cutoff value 
of PD-L1 expression level for PD-L1 strongly positive is established and formally 
documented exclusively based on data outside of this study.  
The SPONSOR will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS. 
Access to the allocation schedule for this study will be restricted to an external unblinded 
statistician and, as needed, an external scientific programmer performing the analysis, who 
will have no other responsibilities associated with the study. 
Treatment-level results at interim analyses of PFS and OS will be provided by an external 
unblinded statistician to the eDMC. Key enrollment metrics and study data will also be 
monitored by the external unblinded statistician to inform the timing of the interim PFS and 
OS analyses as needed. Limited additional SPONSOR personnel may be unblinded to the 
treatment level results of the interim analyses, if required, in order to act on the 
recommendations of the eDMC or facilitate regulatory filing after the interim analyses. The 
extent to which individuals are unblinded with respect to results of interim analyses will be 
documented by the unblinded statistician.
The eDMC will serve as the primary reviewer of the unblinded results of the interim analyses 
and will make recommendations for discontinuation of the study or modification to an 
executive oversight committee of the SPONSOR. Depending on the recommendation of the 
eDMC, the Sponsor may prepare a regulatory submission. If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
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oversight committee may be unblinded to results at the treatment level in order to act 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 study are stated in Section 3. The study is considered to 
have met its primary objective if pembrolizumab (MK-3475) is superior to the paclitaxel, 
docetaxel or vinflunine arm either in PFS or in OS at an interim analysis or final analysis in 
the overall population, the PD-L1 positive population or the PD-L1strongly positive 
population.
Analysis Endpoints
Efficacy Endpoints
Primary 
Progression-free survival - RECIST 1.1 by blinded independent radiologists’ review
Progression-free-survival (PFS) is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 based on blinded independent radiologists’ 
review or death due to any cause, whichever occurs first. See Section 8.2.5.1.1 for the 
definition of censoring.
A supportive analysis of PFS will be conducted using site radiology review as defined in the 
Imaging Review Charter.
Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Patients without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.
Secondary
Objective Response Rate (ORR) – RECIST 1.1 by blinded independent radiologists’ 
review
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR). Responses are based upon 
blinded central radiologists’ review per RECIST 1.1.
A supportive analysis of ORR will be conducted using site radiology review as defined in the 
Imaging Review Charter.
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PFS/ORR – modified RECIST by blinded independent radiologists’ review
PFS and ORR per modified RECIST are defined as specified for the respective endpoints 
using RECIST 1.1 above, with the exception that a confirmation assessment of PD (at least 4 
weeks after the initial PD assessment) is required for subjects who remain on treatment 
following a documented PD per RECIST 1.1. Subjects who discontinue treatment following 
a documented PD assessment per RECIST 1.1 will be counted as having disease progression 
on the date of the documented PD assessment. See Section 8.2.5.1.1 for the definition of 
censoring.
Supportive analyses will be conducted using site radiology review as defined in the Imaging 
Review Charter.
Response Duration - – RECIST 1.1 by blinded independent radiologists’ review
For subjects who demonstrated CR or PR, response duration is defined as the time from first 
documented evidence of CR or PR until disease progression or death. Response duration for 
subjects who have not progressed or died at the time of analysis will be censored at the date 
of their last tumor assessment.  Response duration will be calculated for RECIST 1.1 based 
on blinded independent radiologists’ review and site review.
Exploratory 
Exploratory endpoints of this study include but are not limited to PFS2, disease control rate, 
and response to treatment by biomarker subgroups. Patient-reported outcomes (PROs) while 
on treatment and post-discontinuation will be examined. The detailed PRO analysis plan will 
be included in a separate document.
An exploratory analysis of PFS2, defined as the time from randomization to subsequent 
disease progression after initiation of new anti-cancer therapy, or death from any cause, 
whichever first, will be carried out. If progression after next-line therapy cannot be measured, 
a PFS event is defined as the end or discontinuation of next-line treatment or death from any 
cause, whichever occurs first. Patients alive and for whom a PFS event has not been observed 
will be censored at the last time known to be alive and without second disease progression.
Safety Endpoints
Safety measurements are described in Section 7.
Analysis Population
Efficacy Analysis Population
The analysis of primary efficacy endpoints are based on the intention-to-treat (ITT) 
population, i.e., subjects will be included in the treatment group to which they are 
randomized. Details on the approach to handling missing data are provided in Section 8.2.5 
Statistical Methods.
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Safety Analysis Populations
The All Patients as Treated (APaT) population will be used for the analysis of safety data in 
this study. The APaT population consists of all randomized subjects who received at least 1 
dose of study treatment. Subjects will be included in the treatment group corresponding to 
the trial treatment they actually received for the analysis of safety data. 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. The baseline measurement and at least 
one laboratory or vital sign measurement obtained subsequent to at least one dose of trial 
treatment is required for inclusion in the analysis of each specific parameter. 
Details on the approach to handling missing data for safety analyses are provided in Section 
8.2.5 Statistical Methods.
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 8.2.5.2. Efficacy 
results that will be considered to be statistically significant after consideration of the strategy 
for controlling the Type I error are described in Section 8.2.6, Multiplicity. Nominal p-values 
may be computed for other efficacy analyses as a measure of strength of association between 
the endpoint and the treatment effect rather than for formal tests of hypotheses.
Statistical Methods for Efficacy Analyses
The family-wise type I error rate for this study is strictly controlled at 2.5% (one -sided) that 
allows the trial to declare positive in PFS or OS in the ITT population.  
The strategy to address multiplicity issues with regard to multiple efficacy endpoints and 
multiple analyses is described in Section 8.2.6 and Section 8.2.9.
8.2.5.1.1 Progression-Free Survival (PFS)
The non-parametric 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 hazard ratio and its 95% confidence interval from the stratified Cox 
model with Efron's method of tie handling and with a single treatment covariate will be 
reported. The same stratification factors used for randomization (see Section 5.4) will be 
applied to both the stratified log-rank test and the stratified Cox model. A sensitivity analysis 
based on a multivariate Cox PH model with treatment, stratification factors and other factors
as covariates will also be provided.
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the primary analysis, for the subjects who have PD, 
the true date of disease progression will be approximated by the date of the first assessment 
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at which PD is objectively documented per RECIST 1.1, regardless of discontinuation of 
study drug. Death is always considered as a confirmed PD event. Sensitivity analyses will be 
performed for comparison of PFS based on investigator's assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by central imaging 
vendor, two sensitivity analyses with different sets of censoring rules will be performed. The 
first sensitivity analysis is the same as the primary analysis except that the data for any 
subject who misses two or more consecutive disease assessments (with or without a 
subsequent death or progression) are censored at the last disease assessment prior to missing 
visits. The second sensitivity analysis is the same as the primary analysis except that it 
considers discontinuation of treatment or initiation of new anticancer treatment subsequent to 
discontinuation of study-specified treatments, whichever occurs later, to be a PD event for 
subjects without documented PD or death. If a subject meets multiple criteria for censoring, 
the censoring criterion that occurs earliest will be applied. The censoring rules for primary 
and sensitivity analyses are summarized in Table 12. In addition to the primary analysis and 
two sensitivity analyses listed in Table 12, another analysis, sensitivity analysis 3, will be 
conducted with special censorings rules for specific clinical scenarios. Sensitivity analysis 3 
is the same as the primary analysis except that it censors subjects with any of the following 
two clinical scenarios before PD or death at the time of last disease assessment prior to the 
clinical scenarios: (1) use of radiotherapy before study treatment discontinuation; (2) 
occurrence of a skeletal-related event (e.g., fracture) in patients with bone metastases at study 
entry. In case there is an imbalance between the treatment groups on disease assessment 
schedules or censoring patterns, we will also perform the following two additional PFS 
sensitivity analyses: (1) a PFS analysis using time to scheduled tumor assessment visit from 
randomization as opposed to actual tumor assessment time; (2) Finkelstein (1986)’s 
likelihood-based score test for  interval-censored data, which modifies the Cox proportional 
hazard model for interval censored data, will be used as a supportive analysis for the PFS 
endpoint [41]. The interval will be constructed so that the left endpoint is the date of the last 
disease assessment without documented PD and the right endpoint is the date of documented 
PD or death, whichever occurs earlier.
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Table 12
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Analysis Approach
Event Status
Study 
Therapy 
Discontinued
New Anti-
Cancer 
Therapy 
Initiated
# Missed 
Disease 
Assessments 
Before Event
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and No Death
No
No
N/A
Censored at last disease 
assessment 
Censored 
at 
last 
disease assessment 
Censored at last 
disease assessment 
No PD and No Death
Yes
No
N/A
Censored at last disease 
assessment 
Censored 
at 
last 
disease assessment 
progressed 
at 
treatment 
discontinuation
No PD and No Death
Yes or No
Yes
N/A
Censored at last disease 
assessment 
before 
new 
anticancer treatment
Censored 
at 
last 
disease assessment 
before 
new 
anticancer treatment
Progressed at date 
of new anticancer 
treatment
No PD and No Death
Yes or No
No
≥2 consecutive 
assessments
Censored at last disease 
assessment
Censored 
at 
last 
disease assessment 
prior to the  ≥ 2 
missed 
disease 
assessments
Censored at last 
disease assessment
PD or Death 
Yes or No
No
≤ 1
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 
Yes or No
No
≥ 2 consecutive 
assessments
Progressed 
at 
date 
of 
documented PD or death
Censored 
at 
last 
disease assessment 
prior to the  ≥ 2 
missed 
disease 
assessment
Progressed at date 
of documented PD 
or death
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The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[-log] of the survival function vs. time for PFS will 
be plotted for the comparison between pembrolizumab (MK-3475) and the paclitaxel, 
docetaxel or vinflunine arm. If the curves are not parallel, indicating that hazards are not 
proportional, a supportive analysis will be conducted to further account for the possible 
nonproportional hazards effect associated with immunotherapies using Fleming and 
Harrington's weighted log-rank test with the class of weights (G ρ, γ) [66]. The weights will be 
assigned under the assumption of a delayed clinical benefit so that later event times are 
weighted more heavily than early event times. Using this class of weights assuming 
parameters ρ =0 and γ=1, the weight at a given event time is 1 minus the estimated survival
function.
8.2.5.1.2 Overall Survival (OS)
The 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 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 (see Section 5.4) will be 
applied to both the stratified log-rank test and the stratified Cox model. A sensitivity analysis 
based on a multivariate Cox PH model with treatment, stratification factors and other factors
as covariates will also be provided.  
Subjects in the standard treatment arm may switch to another anti PD-1 treatment following 
confirmation of progressive disease. Exploratory analyses to adjust for the effect of crossover 
(to other PD-1therapies) on OS may be performed based on recognized methods, e.g. the 
Rank Preserving Structural Failure Time (RPSFT) model proposed by Robins and Tsiatis 
(1989), two stage model, etc. The choice of the method will be based on an examination of 
the appropriateness of the data to the assumptions required by the method. The RPSFT model 
provides a randomization-based estimate of treatment effect (RBEE) corrected for the bias 
induced by crossover. The 95% confidence intervals of the hazard ratio for OS after 
adjustment of the cross-over effect will be provided. The Kaplan-Meier estimates of the OS 
rate at 3 months, 6 months (when most cross-overs are likely to occur) and other time points 
of interest will also be compared between the two treatment groups to explore the 
confounding effect of subsequent treatments. To further account for the possible confounding 
effect, a sensitivity analysis of OS that censors subjects at the time of initiation of new 
therapy will be performed and an OS analysis that treats initiation of new therapy as a time-
dependent binary covariate will also be conducted. In the case where the proportional hazards 
assumption doesn’t hold, Fleming and Harrington’s weighted log-rank test or other methods, 
as appropriate, will be conducted. Further details of sensitivity analyses will be described in 
supplemental SAP.
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8.2.5.1.3 Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method with strata weighted by sample size will be used 
for comparison of the objective response rates between the treatment groups. The p-value and
95% confidence interval for the difference in response rates between the pembrolizumab 
(MK-3475) arm and the standard therapy arm will be provided. The same stratification 
factors used for randomization (see Section 5.4) will be applied to the analysis. Sensitivity 
analyses will be performed for comparison of ORR based on investigator's assessment. The 
ORR in overall population has also been included in the multiplicity scheme; see Section 
8.2.6.
8.2.5.1.4 Response Duration
If sample size permits, response duration will be summarized descriptively using Kaplan-
Meier medians and quartiles.  Only the subset of subjects who show a complete response or 
partial response will be included in this analysis. Response duration will be assessed using 
RECIST 1.1 separately by independent radiologists’ review and by site radiology review.
A summary of the primary analysis strategy for the primary and secondary efficacy endpoints 
is provided in Table 13.
8.2.5.1.5 Exploratory Analyses
Details of the statistical methods on exploratory analyses can be found in the sSAP.   
Table 13
Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints
Endpoint/Variable
(Description, Time 
Point)
Primary 
or 
Supportive 
Approach
Statistical Method
Analysis 
Population†
Missing Data 
Approach
Primary Endpoints:
PFS (RECIST 1.1) 
by independent 
radiologists’ review
P
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method
ITT
Censored 
according to rules 
in Table 12
PFS (RECIST 1.1) 
by independent 
radiologists’ review 
– Sensitivity 
Analyses 1& 2
S
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method
ITT
Censored 
according to rules 
in Table 12
OS
P
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method
ITT
Model based 
(censored at last 
contact date)
OS
S
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method
ITT
Censored at time 
of initiation of 
new therapy or 
last assessment 
date
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Endpoint/Variable
(Description, Time 
Point)
Primary 
or 
Supportive 
Approach
Statistical Method
Analysis 
Population†
Missing Data 
Approach
OS
S
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method
using initiation of new 
therapy as time-
dependent covariate
ITT
Censored at last 
contact date
Secondary Endpoints :
Objective response 
rate (RECIST 1.1) 
by independent 
radiologists’ review
P
Stratified Miettinen and 
Nurminen method
ITT
Patients with 
missing data are 
considered non-
responders
PFS (modified 
RECIST) by 
independent 
radiologists’ review
P
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method
ITT
Censored 
according to rules 
in Table 12
Objective response 
rate (modified 
RECIST) by 
independent 
radiologists’ review
P
Stratified Miettinen and 
Nurminen method
ITT
Patients with 
missing data are 
considered non-
responders
Response duration 
(RECIST 1.1) by 
independent 
radiologists’ review
P
Summary statistics 
using Kaplan-Meier 
method
All responders 
in ITT
Non-responders 
are excluded from
analysis
† The analysis populations for H3 and H4 are ITT in PDL1 positive subjects, and for H5 and H6 are ITT in PDL1 
strongly positive subjects.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.
Time to Grade 3-5 AE
Time to first Grade 3-5 AE is defined as the time from the first day of study drug to the first 
event of Grade 3-5 AE. For patients without a Grade 3-5 AE, the time to first Grade 3-5 AE 
is censored at 30 days post last study dose. The Kaplan-Meier method will be used to 
estimate the curve of time to first Grade 3-5 AE.  The treatment difference in time to first 
Grade 3-5 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.  
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Tiered Approach for Other Safety Analyses
The analysis of safety results will follow a tiered approach (Table 14). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons. Other safety parameters will be 
considered Tier 2 or Tier 3. Tier 2 parameters will be assessed via point estimates with 95% 
confidence intervals provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, vital signs, and ECG parameters that are not pre-specified as 
Tier-1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number 
of events observed. Membership in Tier 2 requires that at least 4 subjects in any treatment 
group exhibit the event; all other adverse experiences and predefined limits of change will 
belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety 
parameters. Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format. 
For this protocol, there are no Tier 1 events. In addition, the broad clinical and laboratory AE 
categories consisting of the percentage of subjects with any AE, any drug related AE, any 
serious AE, any Grade 3-5 AE, an AE which is both Grade 3-5 and drug-related, an AE 
which is both drug-related and serious, dose modification due to AE, and who discontinued 
due to an AE, and death will be considered Tier 2 endpoints. 95% confidence intervals (Tier 
2) will be provided for between-treatment differences in the percentage of subjects with 
events; these analyses will be performed using the stratified Miettinen and Nurminen 
method.
To properly account for the potential difference in follow-up time between the study arms, 
which is expected to be longer in the pembrolizumab (MK-3475) arm, AE incidence density 
adjusted for treatment exposure analyses may be performed as appropriate. Based on 
emerging external data, the supportive analysis strategy for safety parameters may be 
modified to improve the integrity and efficiency of the design. Should this happen, the 
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change will be documented in the sSAP, if not in a protocol amendment, at the earliest time 
before any unblinding of the data.
Table 14
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-
Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Grade 3-5 AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade3-5 and Drug-Related AE
X
X
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs (including ≥4 of subjects in 
one of the treatment groups)
X
X
Specific AEs, SOCs (incidence <4 of subjects in 
all of the treatment groups)
X
Tier 3
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
Summaries of Baseline Characteristics, Demographics, and Other Analyses
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 randomized, and the primary reason 
for discontinuation will be displayed. Demographic variables (such as age) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables. The reasons for exclusion from the ITT population (if any) will be summarized.
Multiplicity
Based on emerging biomarker data external to this study, the initial alpha allocation among 
the primary hypotheses is revised in Amendment 13 onward to reflect the change in 
biomarker strategy (Section 4.2.3.1.1). The reallocation of alpha occurs after the conduct of 
IA1, and proper adjustment is made to maintain the control of family-wise type I error rate
(FWER) with the implementation of this change. The type I error actually spent at IA1 will 
be kept intact and the re-allocation will only be applied to the remaining unspent alpha. The
family-wise type I error rate for this study is strongly controlled at 2.5% (one-sided) across 
all six primary hypotheses on PFS and OS and the secondary hypothesis on ORR, with the 
following alpha allocation before any alpha roll-over or adjustment for actual information 
fraction:
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
0.1% allocated to the PFS hypothesis in all subjects (H1), with 0.02% planned at IA1; 

1.0% allocated to the OS hypothesis in all subjects (H2), with 0.02% planned at IA1;

0.02% allocated to the PFS hypothesis in PD-L1 positive subjects (H3) at IA1 only;

0.18% allocated to the OS hypothesis in PD-L1 positive subjects (H4) at IA1 only;

0.38% allocated to the PFS hypothesis in PD-L1 strongly positive subjects (H5), with 
0.07% planned at IA1;

0.82% allocated to the OS hypothesis in PD-L1 strongly positive subjects (H6), with 
0.04% planned at IA1;
where the alpha spent at IA1 is based on the assumption of the planned information fractions 
along with the original pre-specified alpha allocation prior to Amendment 13 by the pre-
specified alpha spending function of  Hwang-Shih-DeCani (HSD) with gamma parameter (-
4). 
Under the revised alpha allocation, the alpha spending at IA2 and final analysis are 
determined by first applying the same HSD gamma (-4) spending function to distribute 
unspent alpha to IA2 and final analysis, respectively, and then incorporating them with the 
alpha that has already been spent at IA1 to form an interpolated alpha spending among the 
three analyses. For example, if the information fraction of OS at IA2 for all subjects (H2) is 
75%, then the alpha spending function of HSD gamma (-4) will distribute the total of 0.98%  
un-spent alpha for this hypothesis under the revised strategy with cumulative alpha spending 
of 0.35% and 0.98% at IA2 and FA, respectively. Incorporating the planned alpha spend of 
0.02% at IA1, the new cumulative alpha spending for the three analyses for all subjects 
becomes 0.02%, 0.37% (0.35%+0.02%) and 1.00% ( 0.98% + 0.02%). The corresponding 
stopping bounds in p-values at IA2 and FA can then be calculated. Please note the alpha 
spent at IA1, IA2 and final analysis will all be updated for the final report based on the actual 
numbers of events at each analysis and the corresponding boundaries will be adjusted
accordingly.
Table 15 summarizes cumulative alpha spending at each analysis under the 
current alpha allocation and planned events for each analysis.  
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Table 15
Cumulative Alpha Spending
Hypothesis
Analysis (Planned # of events; 
Information Fraction)
Cumulative Alpha Spending Based on 
Alpha Allocation†
PFS
H1 All Subjects 
IA1 (273; 65%)
0.000233
IA2 (357; 85%) 
0.000540
FA (420; 100%)
0.001000
H3 PD-L1 Positive
IA1 (151; 65%)
0.000233
IA2 (197; 85%)
n/a
FA (232; 100%)
n/a
H5 PD-L1 Strongly 
Positive
IA1 (89; 65%)
0.000698
IA2 (116; 85%)
0.002356
FA (137; 100%)
0.003767
OS
H2 All Subjects
IA1 (185; 50%)
0.000238
IA2 (277; 75%) 
0.003714
FA (370; 100%)
0.010000
H4 PD-L1 Positive
IA1 (99; 50%)
0.001788
IA2 (149; 75%)
n/a
FA (198; 100%)
n/a
H6 PD-L1 Strongly 
Positive
IA1 (55; 50%)
0.000358
IA2 (82; 75%)
0.003155
FA (110; 100%)
0.008212
†Before any alpha roll-over according to the method of Maurer and Bretz (2013).
If the pembrolizumab (MK-3475) arm is demonstrated to have a superior PFS or OS to the 
control arm at any analysis, then the initially allocated alpha will be rolled from that specific 
hypothesis into another hypothesis following the pre-specified rules in Figure 2 using the 
graphical approach of Maurer and Bretz (2013) [68].  Actual alpha allocation after the roll-
over will be updated based on the spending function used.
The ORR hypothesis (RECIST 1.1 per independent radiologist’s review) in all subjects will 
be tested following a group sequential approach. The ORR hypothesis is initially assigned a 
type I error rate of 0% and thus, cannot be tested unless the null hypothesis of H2 (OS in all 
subjects) is successfully rejected. 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 that will allow tight control of the 
overall type I error will be distributed by an alpha spending function of Hwang-Shih-DeCani 
based 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 4 scheduled scans if not discontinued.
Only subjects with “mature ORR information” will be included into the ORR analysis.  
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† Initially assigned alpha before any alpha rollover; final alpha level is subject to change with respect to actual alpha 
rollover. 
‡ Based on assumed information fractions for demonstration purpose only and will be updated accordingly with respect to 
actual information.
Figure 2
Type I Error Reallocation Strategy Following Closed Testing Principle
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Sample Size and Power Calculation
The study is event-driven and plans to randomize approximately 470 subjects with 1:1 ratio 
into the pembrolizumab (MK-3475) arm and the paclitaxel, docetaxel or vinflunine arm.
PFS analysis: The first PFS analysis will be conducted at the time of the first interim 
analysis for OS when the enrollment is completed and approximately 185 total OS events are 
observed for all subjects. All subjects enrolled at the time of the database lock will be 
included. Assuming the prevalence rates of PD-L1 positive and PD-L1 strongly positive 
subjects among the overall population are 55% and 33%, respectively, a sample size of 470 
all subjects may provide approximately 260 PD-L1 positive subjects and 156 PD-L1 strongly 
positive subjects. At the time of the first PFS analysis for PD-L1 positive and all subjects, 
approximately 151 and 273 PFS events (per primary censoring rules), respectively, may have 
occurred. At this analysis the study has approximately 77% and 99% powers to demonstrate 
superiority in PFS of pembrolizumab (MK-3475) relative to the paclitaxel, docetaxel or 
vinflunine arm for PD-L1 positive and all subjects, respectively, at the pre-specified initial 
alpha (one-sided) level as specified in Section 8.2.6. With the assumed sample size of ~156 
PD-L1 strongly positive subjects and the projected ~89 PFS events available at this time, this 
analysis would have ~72% power to reject the null hypothesis of PFS in PD-L1 strongly 
positive subjects (H5). The sample size and power calculation is based on the following 
assumptions: 1) progression-free survival follows an exponential distribution with a median 
of 4 months in the standard therapy arm, 2) the true hazard ratio between pembrolizumab 
(MK-3475) and standard therapy are 0.45, 0.5 and 0.5 for PD-L1 strongly positive, PD-L1 
positive and all subjects, respectively, 3) an enrollment period of 12 months, and 4) a yearly 
dropout rate of 5%.  Any change to the timing, along with its rationale, will be documented 
in a memo to the study file before the database lock.
The second analysis of PFS per RECIST 1.1 by independent radiology review will be 
performed for PD-L1 strongly positive and all subjects at the time of the second interim OS 
analysis when approximately 277 OS events are observed for all subjects and 82 OS events 
are observed for PD-L1 strongly positive subjects. The final PFS analysis will be conducted 
at the time of the final OS analysis when approximately 370 OS events are observed for all 
subjects and 110 OS events are observed for PD-L1 strongly positive subjects. It is expected 
that at this time approximately 137 and 420 PFS events would have been observed between 
the two arms for PD-L1 strongly positive and all subjects, respectively. With the above 
assumed PFS events, overall power of the PFS analyses for the two populations are 
approximately 97% and >99%, respectively. On the other hand, these numbers of events can 
also test the following hazard ratios with 90% power: 0.50, 0.56 and 0.65 for strongly 
positive, positive and all subjects, respectively. 
OS analyses:  The first interim analysis for OS will be conducted after the full enrollment 
and approximately 185 OS events are observed for all subjects. The purpose of the OS 
interim analysis is to determine if the risk/benefit ratio to the trial population as a whole is 
unacceptable and subsequently whether the trial may be stopped early at the recommendation 
of the DMC.  Further details of the interim analysis strategy, including efficacy and futility 
rules, are given in Section 8.2.9. 
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The final OS analysis will be conducted after approximately 370 deaths in all subjects and 
110 deaths in PD-L1 strongly positive subjects have occurred between the pembrolizumab 
(MK-3475) arm and the paclitaxel, docetaxel or vinflunine arm, if the trial is not stopped 
early for efficacy or futility. The timing of the final OS analysis is expected to be about 18
months after enrollment completion. With 370 events at the final analysis, the study provides 
88%and 86% powers to demonstrate superiority in OS of pembrolizumab (MK-3475)
relative to standard therapy at the initially allocated alpha levels before any alpha roll-over in 
PD-L1 strongly positive and all subjects, respectively. Conditional on different scenarios of 
alpha roll-overs, the overall power of OS in all subjects can be up to 92%.
The sample size and power calculation is based on the following assumptions: 1) OS follows 
an exponential distribution with a median of 8 months in the standard therapy arm, 2) hazard 
ratio between pembrolizumab (MK-3475) and standard therapy is 0.5, 0.6 and 0.7 for PD-L1 
strongly positive, PD-L1 positive and all subjects, respectively, 3) an enrollment period of 12
months and a minimum of 18 months follow-up after enrollment completion; and 4) a yearly 
drop-out rate of 2%.
ORR analysis: As described in Section 8.2.6, the ORR hypothesis in all subjects is initially 
assigned a type I error rate of 0%. Conditional on the success of OS hypothesis in all subjects 
(H2), the ORR analysis can be tested following a group sequential approach with overall 
alpha rolled over from H2. The information fraction of ORR analysis will be calculated at the 
time of the interim analyses of OS and used by the pre-specified alpha spending function to 
determine nominal type I error rates at interim analyses that will allow tight control of the 
overall type I error rate. It is projected that the information fractions of the ORR analysis is 
about 60% at the time of the first OS interim analysis and 100% at the time of the second OS 
interim analysis. Depending on the results from the primary hypotheses on OS and PFS, the 
possible overall type I error rate available for the ORR analysis is ranged from 0% to 2.3%
under the revised alpha allocation in this amendment. Under one specific scenario with type
I error rates of 1.8%, this study can rule out a between-group ORR difference of 11.6% with 
~90% power and a group sequential design of two analyses (information fractions of 60% 
and 100%), assuming the underlying ORR for the control group is 11.6%. If the type I error 
rate is only 1.0% in the above example, then the between-group ORR difference of 11.6% 
can be ruled out with 84% power.
The assumptions for the median PFS of 4 months, the median OS of 8 months and the ORR 
of 11.6% in the standard therapy arm are based on a weighted average of median PFS,
median OS and ORR estimates from 2L trials of single agents [29, 30, 32, 33, 34, 42, 43, 44, 
45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62]. 
The sample size and power calculations were performed using the software EAST and R 
(package “gsDesign”).
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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 
endpoint will be estimated and plotted within each category of the following classification 
variables:

Age category (≤65 vs. >65 years)

PD-L1 subgroup (strongly positive vs. not strongly positive )

Sex (female vs. male)

Race (white vs. non-white)

ECOG status (0 / 1 vs. 2 and 0 vs 1 / 2)

Geographic region of enrolling site (East Asia vs. non-East Asia and EU vs. non-EU)

Prior platinum therapy (carboplatin vs. cisplatin)

Setting of most recent prior therapy (neoadjuvant vs. adjuvant vs. 1L metastatic vs. 2L 
metastatic)

Presence or absence of liver metastases at baseline

Baseline hemoglobin (≥ 10 g/dL vs. <10 g/dL)

Time from completion/discontinuation of most recent prior therapy to baseline
(<3months vs. ≥3 months)

Histology (transitional cell vs. mixed transitional/non-transitional histology)

Smoking status (never vs. former vs. current)

Brain metastasis status (prior brain metastasis vs. no prior brain metastasis)

Investigators’ choice of paclitaxel, docetaxel or vinflunine

Burden of disease in terms of baseline tumor volume 
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.
Interim Analysis
There are two planned interim analyses for PD-L1 strongly positive and all subjects, 
respectively. For PD-L1 positive subjects, the hypotheses of PFS and OS will only be tested
at IA1.  The futility bounds of this study are non-binding and the bounds are considered 
guidance rather than strict bounds. Results of the interim analysis will be reviewed by an 
eDMC. Depending on the recommendation of the eDMC, the Sponsor may prepare a 
regulatory submission if any of the six primary objectives are met at interim analysis. Further 
details of interim analyses are provided below and will be incorporated into the DMC 
Charter.
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PFS and Interim OS Analysis
The first PFS and OS analysis will take place when enrollment is complete and
approximately 185 OS events have been observed between the pembrolizumab (MK-3475)
and standard therapy for all subjects. The first interim analysis is expected to occur ~15
months after study start.
As specified in Section 8.2.6, an interpolated alpha spending function based on HSD gamma 
(-4) and the revised alpha allocation is constructed to implement group sequential boundaries 
that control the type I error rates for PFS hypotheses H1 and H5. The pembrolizumab (MK-
3475) arm will be compared to the paclitaxel, docetaxel or vinflunine arm. At the first 
interim analysis, an approximate observed HR of ~0.655 or less would demonstrate PFS 
superiority for all subjects at α = 0.02% (one-sided). This hazard ratio corresponds to 
approximately 2.1-month improvement over the median PFS of 4 months in the paclitaxel, 
docetaxel or vinflunine arm. However, because immunotherapies have been shown to impact 
PFS curves at later time points (i.e., the tail of the curve), the observed difference in medians 
may be an underrepresentation of the treatment effect. If there are fewer than or more than 
the projected number of PFS events at the time of the first interim analysis, the alpha 
functions will be adjusted to accommodate the revised interim analysis timing using the 
fraction of the estimated total PFS events.
Similarly, for both OS hypotheses (H2 and H6), an interpolated alpha spending function 
based on HSD gamma (-4) and the revised alpha allocation is constructed to implement 
group sequential boundaries that control the type I error rate. Please see Section 8.2.6 for 
details. The non-binding futility analyses are also planned with a beta spending function of 
HSD gamma (-20). Table 16 and Table 17 summarize the efficacy and futility rules for the 
OS analyses.
Approximately 185 OS events will be observed for all subjects at the time of the first interim 
analysis and an interim OS analysis will be conducted at the level determined by the 
spending function boundaries and the actual number of OS events. As shown in Table 16 an 
approximate observed hazard ratio < ~0.598, i.e., at least 5.4-month improvement in median 
OS, would demonstrate OS superiority at the interim analysis for all subjects (H2). A futility 
analysis will be conducted at the same time and an observed hazard ratio > 1.30 will 
approximately meet the criterion for futility. The boundaries for OS hypothesis testing will 
be re-calculated if the actual monitoring schedule is altered. If there are more than 185 OS 
events for all subjects at the time of the first interim analysis, the alpha and beta spending 
functions will be adjusted to accommodate the revised interim analysis timing using the 
fraction of planned total OS events in the overall population that drives timing of analyses.
Table 16 summarizes the timing, sample size and decision guidance for the planned PFS and 
OS analyses (IA1, IA2 and Final Analysis) for PD-L1 strongly positive, positive and all 
subjects under one hypothetical scenario with initially assigned type I rates only. Table 17
summarizes the futility boundaries of the OS hypotheses at the interim analysis. The actual 
boundaries will be determined from the actual number of PFS or OS events at the time of the 
specified IA using the alpha- and beta-spending functions.
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Table 16
Summary of Timing, Sample Size and Decision Guidance at the Planned PFS and 
OS Analyses
Analysis
Criteria for 
Conduct of 
Analysis
(Projected 
timing)
Value
Approx. 
Number 
of 
Events
Efficacy Boundary†
Z Statistic
p-value (1-
sided) at 
Boundary
Approx. 
Observed 
HR at 
Boundary
IA 1:
PFS (H1, H3, 
H5) 
OS (H2, H4, 
H6)
Full enrollment 
~ 185 OS events
(50% 
information)  
for all subjects
H1 PFS 
All Subjects
273
3.500
0.0002
0.655
H2 OS 
All Subjects
185
3.494
0.0002
0.598
H3 PFS 
PDL1 Positive
151
3.500
0.0002
0.566
H4 OS 
PDL1 Positive
99
2.913
0.0018
0.557
H5 PFS PDL1 
Strongly Positive 
89
3.196
0.0007
0.508
H6 OS PDL1 
Strongly Positive
55
3.384
0.0004
0.402
IA 2: 
PFS (H1 and  
H5) 
OS (H2 and 
H6)
~277 OS events  
(75% 
information) for 
all subjects and 
~ 82 OS events 
(75% 
information) for 
PDL1 Strongly 
Positive 
Subjects
H1 PFS 
All Subjects
357
3.345
0.0004
0.702
H2 OS 
All Subjects
277
2.683
0.0036
0.725
H5 PFS PDL1 
Strongly Positive 
116
2.865
0.0021
0.588
H6 OS PDL1 
Strongly Positive
82
2.745
0.0030
0.546
Final 
Analysis:
PFS (H1and 
H5)
OS (H2 and 
H6)
~ 370 OS events 
for all subjects 
and ~110 OS 
events for PDL1 
Strongly 
Positive 
Subjects
H1 PFS 
All Subjects
420
3.182
0.0007
0.733
H2 OS 
All Subjects
370
2.381
0.0086
0.781
H5 PFS PDL1 
Strongly Positive 
137
2.782
0.0027
0.622
H6 OS PDL1 
Strongly Positive
110
2.459
0.0070
0.625
† Based on initially assigned type I error rate before any alpha roll-over and projected number of events at study mile stones. Actual 
efficacy boundaries will be based on actual numbers of events available at study milestones. 
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Table 17
Summary of Futility Boundary at the Planned Interim Analyses on OS
Analysis
Value
Approx. 
Number 
of Events
Non-binding Futility Boundary
Z Statistic
p-value (1-
sided) at 
Boundary
Approx. 
Observed 
HR at 
Boundary
IA 1
H2 OS 
All Subjects
185
-1.767
0.961
1.297
H4 OS 
PDL1 
Positive
99
-1.938
0.974
1.476
H6 OS PDL1 
Strongly 
Positive
55
-1.715
0.957
1.587
IA 2
H2 OS 
All Subjects
277
0.100
0.460
0.988
H6 OS PDL1 
Strongly 
Positive
82
0.148
0.441
0.968
For demonstration purpose, the beta in this table is based on initially assigned alpha only; actual futility bounds 
will be updated if overall beta is changed with respect to alpha roll-over.  
If a null hypothesis is rejected, the alpha can be rolled over to another hypothesis following 
the pre-specified rules in Section 8.2.6. The revised decision guidance for PFS and OS with 
respect to the rolled-over alpha from the rejection of other hypothesis(es) is summarized in 
Table 18 below. Please note that the actual boundaries for the alpha spending function will be 
adjusted based on the actual number of events and/or ORR information fractions observed at 
the time of the corresponding analysis. 
Table 18
Summary of Revised Efficacy Decision Guidance (Selected Scenarios)
Analysis
Value
Updated Efficacy Boundary (after alpha roll-
over†)
Z Statistic
p-value (1-
sided) at 
Boundary
Approx. 
Observed HR or 
ORR-Difference‡
at Boundary
If Null Hypotheses of H5 and H6 are Rejected
IA 1
H1 PFS All Subjects
3.060
0.0011
0.691
H2 OS All Subjects
3.331
0.0004
0.613
IA 2
H1 PFS All Subjects
2.870
0.0021
0.738
H2 OS All Subjects
2.475
0.0067
0.743
Final Analysis
H1 PFS All Subjects
2.677
0.0037
0.770
H2 OS All Subjects
2.143
0.0161
0.800
If Null Hypotheses of H1, H5 and H6 are Rejected
IA 1
H2 OS All Subjects
3.265
0.0005
0.619
IA 2
H2 OS All Subjects
2.390
0.0084
0.751
Final Analysis
H2 OS  All Subjects
2.045
0.0204
0.809
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Analysis
Value
Updated Efficacy Boundary (after alpha roll-
over†)
Z Statistic
p-value (1-
sided) at 
Boundary
Approx. 
Observed HR or 
ORR-Difference‡
at Boundary
If Null Hypothesis of H2 is Rejected
IA 1
ORR All Subjects
2.899
0.0019
12.9%
IA 2
ORR All Subjects
2.358
0.0092
8.2%
Final Analysis
ORR All Subjects
2.358
0.0092
8.2%
If Null Hypothesis of H2 and H6 are Rejected
IA 1
ORR All Subjects
2.254
0.0121
8.2%
IA 2
ORR All Subjects
2.164
0.0152
7.5%
Final Analysis
ORR All Subjects
2.164
0.0152
7.5%
†Only selective scenarios are demonstrated in this table. 
‡Assume the underlying ORRs in the control and pembrolizumab groups are 11.6% and 23.2%, respectively.
Final OS Analysis
The final analysis will take place when approximately 370 deaths in all subjects and 110 
deaths in PD-L1 strongly positive subjects have occurred between the pembrolizumab (MK-
3475) arm and the paclitaxel, docetaxel or vinflunine arm in all subjects which is expected to 
occur ~30 months after study start. If the timing of events occurs faster than anticipated, the 
test boundary at the final analysis will be adjusted to use the remaining Type I error not spent 
at earlier analyses. A 95% confidence interval will be provided for the hazard ratio to 
characterize the OS effect in case the superiority is not demonstrated.  
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Compliance 
with trial treatment administration will be measured by subjects: 1) receiving unscheduled 
study 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.
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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 19.  
Table 19
Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab (MK-3475) 100 mg/ 4 mL
Solution for Infusion
Vinflunine 250 mg/ 10 mL
Solution for Infusion
Docetaxel 80 mg/4 mL
Solution for Infusion
Paclitaxel 100 mg/ 16.7 mL
Solution for Infusion
The paclitaxel, vinflunine and docetaxel will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements. All other products will be provided locally 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 to record 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.
Subjects will receive open label pembrolizumab (MK-3475) vials, vinflunine kits, docetaxel 
kits and paclitaxel kits. Each kit of vinflunine, docetaxel and paclitaxel will contain one 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.  
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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.
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.
Standard Policies
Trial site personnel will have access to a central electronic 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 member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
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.  
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The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
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.
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The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
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 
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Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
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.
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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 
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 
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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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11.0 LIST OF REFERENCES
1.
Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8.
2.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 
Nat Med 2002;8(8):793-800.  
3.
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.
4.
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66.  
5.
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42.
6.
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.  
7.
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400.
8.
Usubütün A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.  
9.
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7.
10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19.
11. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94.  
12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4.  
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.  
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14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30.  
15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.  
16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10:840-841.  
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106.  
18. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.  
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58:449-59.  
20. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.  
21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6.  
22. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value 
of tumour-infiltrating lynmphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-
24.  
23. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57.  
24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.  
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25. Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ 
cell infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 
2010;59:909-19.  
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71.
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
2005;23:515-48.  
28. Jemal A, Bray F, Center MM, Ferlay J, Ward E, and Forman D. Global Cancer 
Statistics. CA Cancer J Clin 2011;61:69-90.
29. Vaughn DJ, Broome CM, Hussain M, Gutheil JC and Markowitz AB. Phase II Trial of 
Weekly Paclitaxel in Patients With Previously Treated Advanced Urothelial Cancer. 
Journal of Clinical Oncology. 2002;20(4):937-940.
30. McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI and Bajorin DF. 
Phase II Trial of Docetaxel in Patients With Advanced or Metastatic Transitional-Cell 
Carcinoma. Journal of Clinical Oncology. 1997;15(5):1853-1857.
31. Witte RS, Elson P, Bono B, Knop R, Richardson RR, Dreicer R, and Loehrer Sr. PJ. 
Journal of Clinical Oncology. 1997;15(2):589-593.
32. Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, 
et al. Phase II Study of Pemetrexed for Second-Line Treatment of Transitional Cell 
Cancer of the Urothelium. Journal of Clinical Oncology. 2006;24:3451-3457.
33. Joly F, Houede N, Noal S, Chevreau C, Priou F, Chinet-Charrot P, Rolland F, Flechon 
A, et al. Clinical Genitourinary Cancer. 2009;7(2):E28-E33.
34. Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, 
Carles J, et al. Journal of Clinical Oncology. 2009;27(27):4454-4461.
35. Sonpavde G, Sternberg CN, Rosenberg JE, Hahn NM, Galsky MD, and Vogelzang NJ. 
Second-line systemic therapy and emerging drugs for metastatic transitional-cell 
carcinoma of the urothelium. Lancet Oncol. 2010;11(9):861-870.
36. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer.  Version 2.2014, 
NCCN.org
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37. Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, 
Boehle A, Chevreau C, et al. Randomized Phase III Study Comparing 
Paclitaxel/Cisplatin/Gemcitabine and Gemcitabine/Cisplatin in Patients With Locally 
Advanced or Metastatic Urothelial Cancer Without Prior Systemic Therapy: EORTC 
Intergroup Study 30987. Journal of Clinical Oncology. 2012;30:1107-1113.
38. Wong Y-N, Litwin S, Vaughn D, Cohen S, Plimack ER, Lee J, Song W, Dabrow M, et 
al. Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced 
Urothelial Tract Carcinoma. Journal of Clinical Oncology. 2012;30(28):3545-3551.
39. Rabin R and de Charro F. EQ-5D: a measure of health status from the EuroQol Group.
Ann Med 2001;33:337-343. 
40. Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985; 4: 213–226.
41. Finkelstein DM (1986). A proportional hazards model for interval-censored failure time 
data. Biometrics 42, 845-54.
42. Akaza H, Naito S, Usami M, Miki T, Miyanaga N, Taniai H and the Japanese 
Gemcitabine Study Group. Efficacy and Safety of Gemcitabine Monotherapy in Patients 
with Transitional Cell Carcinoma after Cisplatin-Containing Therapy: A Japanese 
Experience. Jpn J Clan Oncol 2007;37(3)201-206.
43. Albers P Onkologie 2002 Albers P, Siener R, Haertlein M, Fallahi M, Haeutle D, Perabo 
FGE, Steiner G, Blatter J and Mueller SC. Gemcitabine Monotherapy as Second-Line 
Treatment in Cisplatin-Refractory Transitional Cell Carcinoma – Prognostic Factors for 
Response and Improvement of Quality of Life. Onkologie 2002;25:47-52.
44. Bellmunt J Cancer Invest 2002 Bellmunt J, Cos J, Cleries R, Perez M, Ribas A, Eres N, 
Murio JE, Margarit C, and Baselga J. Feasibility trial of methotrexate-paclitaxel as a 
second line therapy in advance urothelial cancer. Cancer Invest 2002;20(5-6):673-685.
45. Culine S, Theodore C, De Santis M, Bui B, Demkow T, Lorenz J, Rolland F, Delgado F-
M, et al. A phase II study of vinflunine in bladder cancer patients progressing after first-
line platinum-containing regimen. British Journal of Cancer 2006;94:1395-1401.
46. Dreicer R, Li S, Manola J, Haas N, Roth B, and Wilding G. Phase 2 Trial of Epothilone 
B Analog BMS-247550 (Ixabepilone) in Advanced Carcinoma of the Urothelium 
(E3800): A Trial of the Eastern Cooperative Oncology Group. Cancer 2007; 100:759-
63.
47. Fechner G, Siener R, Reimann M, Kobalz L, Albers P, and Members of the German 
Association of Urologic Oncology (AUO) Bladder Cancer Study Group. Randomised 
phase II trial of gemcitabine and paclitaxel second-line chemotherapy in patients with 
transitional cell carcinoma (AUO Trial AB 20/99). J Clin Pract 2006;60(1):27-31.
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48. Gallagher DJ, Milowsky MI, Gerst SR, Ishill N, Riches J, Regazzi A, Boyle MG, Trout 
A, et al. Phase II Study of Sunitinib in Patients With Metastatic Urothelial Cancer. 
Journal of Clinical Oncology 2010;28(8):1373-1379.
49. Kanai K, Kikuchi E, Ohigashi T, Miyajima A, Nakagawa K, Nakashima J, and Oya M. 
Gemcitabine and paclitaxel chemotherapy for advanced urothelial carcinoma in patients 
who have received prior cisplatin-based chemotherapy. Int J Clin Oncol 2008;(13):510-
514.
50. Ko Y-J, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang 
L, et al. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic 
urothelial carcinoma: a single group, multicenter, phase 2 study. Lancet Oncology 
2013;14(8):769-776.
51. Krege S, Rembrink V, Borgermann CH, Otto T, and Rubben H. Docetaxel and 
Ifosfamide as Second Line Treatment for Patients with Advanced or Metastatic 
Urothelial Cancer After Failure of Platinum Chemotherapy: A Phase 2 Study. The 
Journal of Urology 2001;165:67-71.
52. Lin C-C, Hsu C-H, Huang C-Y, Keng J-Y, Tsai Y-C, Huang K-H, Cheng A-L and Pu Y-
S. Gemcitabine and ifosfamide as a second-line treatment for cisplatin-refractory 
metastatic urothelial carcinoma: a phase II study. Anti-Cancer Drugs 2007;18:487-491.
53. Lorusso V, Pollera CF, Antimi M, Luporini G, Gridelli C, Frassineti GL, Oliva C, Pacini 
M, et al. A Phase II Study of Gemcitabine in Patients with Transitional Cell Carcinoma 
of the Urinary Tract Previously Treated with Platinum. Eu J Can 1998;34(8):1208-1212.
54. Milowsky MI, Iyer G, Regazzi AM, Al-Ahmade H, Gerst SR, Ostrovnaya I, Gellert LL, 
Kaplan R, et al. Phase II study of everolimus in metastatic urothelial cancer. BJU 
2013;112:462-470.
55. Prozanto P, Vigani A, Pensa F, Vanoli M, Tani F, and Vaira F. Second Line 
Chemotherapy with Ifosfamide as Outpatient Treatment for Advanced Bladder Cancer. 
Am J of Clin Oncol 1997; 20(5):519-521.
56. Sternberg CN, de Mulder PHM, Theodore C, Fossa SD, Van Oosterom AT, Witjes F, 
Spina M, van Groeningen CJ, et al. Randomized Phase III Trial of High-Dose-Intensity 
Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (MVAC) Chemotherapy and 
Recombinant Human Granulocyte Colony-Stimulating Factor Versus Classic MVAC in 
Advanced Urothelial Tract Tumors: European Organization for Research and Treatment 
of Cancer Protocol No. 30924. Journal of Clinical Oncology. 2001;19:2638-2646.
57. Suyama T, Ueda T, Fukasawa S, Imamura Y, Nakamura K, Miyasaka K, Sazuka T, 
Egoshi K-I, et al. Combination of Gemcitabine and Paclitaxel as Second-line 
Chemotherapy for Advanced Urothelial Carcinoma. Jpn J Clin Oncol 2009;39(4):244-
250.
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58. Sweeney CJ, Williams SD, Finch DE, Bihrle R, Foster RS, Collins M, Fox S, Roth BJ. 
A Phase II Study of Paclitaxel and Ifosfamide for Patients with Advanced Refractory 
Carcinoma of the Urothelium. Cancer 1999;86:514-518.
59. Takahashi T, Higashi S, Nishiyama H, Segawa T, Nakamura E, Kinoshita H, Itoh N, 
Yamamoto S, et al. Biweekly Paclitaxel and Gemcitabine for Patients with Advanced 
Urothelial Cancer Ineligible for Cisplatin-Based Regimen. Jpn J Clin Oncol 
2006;36(2):104-108.
60. Vaishampayan UN, Faulkner JR, Small EJ, Redman BG, Keiser WL, Petrylak DP, 
Crawford ED. Phase II Trial of Carboplatin and Paclitaxel in Cisplatin-Pretreated 
Advanced Transitional Cell Carcinoma. Cancer 2005;104:1627-1632.
61. Vaughn DJ, Srinivas S, Stadler WM, Pili R, Petrylak D, Sternberg CN, Smith, DC, 
Ringulette S, et al. Vinflunine in Platinum-Pretreated Patients With Locally Advanced 
or Metastatic Urothelial Carcinoma. Cancer 2009;115:4110-7.
62. Witte RS, Manola J, Burch PA, Kuzel T, Weinshel EL, and Loeher, Sr. PJ. Topotecan in 
previously treated advanced urothelial carcinoma: an ECOG phase II trial. 
Investigational New Drugs 1998;16:191-195.
63. Chen C, Beckman RA. Hypothesis testing in a confirmatory phase III trial with a 
possible subset effect. Stat Biopharm Res 2009;1(4):431-40. 
64. Wang S-J, O’Neil RT, Hung HMJ. Approaches to evaluation of treatment effect in 
randomized clinical trials with genomic subset. Pharmaceut Statist 2007;6:227-44.
65. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease 
among adults with previously diagnosed diabetes. JAMA 2004;291(3):335-42.
66. Harrington DP, Fleming TR. A class of rank test procedures for censored survival data. 
Biometrika, 1982; 69 (3): 553-566.
67. Sonpavde, G., Pond, G. R., Fougeray, R., Choueiri, T. K., Qu, A. Q., Vaughn, D. J., et 
al. Time from prior chemotherapy enhances prognostic risk grouping in the second-line 
setting of advanced urothelial carcinoma: a retrospective analysis of pooled, prospective 
phase 2 trials. European urology 2013; 63(4): 717-723.
68. Maurer, W., and  Bretz, F. Multiple testing in group sequential trials using graphical 
approaches. Statistics in Biopharmaceutical Research 2013; 5.4 :311-320.
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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 DNA, RNA, serum, plasma, and tumor specimen(s) collected in the current trial will 
be used to study various causes for how subjects may respond to a drug/vaccine.  The 
DNA, RNA, serum, plasma, and tumor specimen(s) will be stored to provide a resource 
for future trials conducted by Merck focused on the study of biomarkers responsible for 
how a drug/vaccine enters and is removed by the body, how a drug/vaccine works, other 
pathways a drug/vaccine may interact with, or other aspects of disease.  The specimen(s) 
may be used for future assay development and/or drug/vaccine development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
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Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
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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, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
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5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
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this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
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public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
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14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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Abbreviations
Abbreviation/Term
Definition
2L
Second Line
AE
Adverse Event
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ß-HCG
Beta Human Chorionic Gonadotropin
BSA
Body Surface Area
CBC
Complete Blood Count
CNS
Central Nervous System
CR
Complete Response
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
DNA
Deoxyribonucleic acid
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eDMC
External Data Monitoring Committee
EOC
Executive Oversight Committee
ePRO
Electronic Patient Reported Outcomes
ERC
Ethics Review Committee
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FWER
Family-wise type I error rate 
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HCV
Hepatitis C
HIV
Human Immunodeficiency Virus
HSD
Hwang-Shih-DeCani 
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
INR
International Normalized Ratio
irAEs
Immune-related Adverse Events
IRB
Institutional Review Board
ISS
International Staging System
ITIM
Immunoreceptor Tyrosine-based Switch Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intent-to-Treat
IV
Intravenous
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Abbreviation/Term
Definition
IVRS/IWRS
Interactive 
Voice 
Response 
System/Interactive 
Web 
Response System
Kg
kilogram
mAb
Monoclonal Antibody
mcL
Millimeters
MEL
Melanoma 
mg
Milligram
mg/kg
Milligram per Kilogram
mL
milliliter
MRI
Magnetic Resonance Imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 
Inc.
NA or N/A
Not Applicable
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
ORR
Overall Response Rate
OS
Overall Survival
OTC
Over-the-counter
PBPK
Physiologically based pharmaokinetic
PD
Progressive Disease
PFS
Progression Free Survival
PGt
Pharmacogenetic
PK
Pharmacokinetic
PK/PD
Pharmacokinetic-Pharmacodynamic
PO
Oral Administration
PR
Partial Response
PSA
Prostate Specific Antigen
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOC
Standard of Care
TIL
Tumor-Infiltrating Lymphocytes
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
WHO
World Health Organization
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ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, 
S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. 
New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009 Jan;45(2):228-47.
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Strong Inhibitors and Strong Inducer of CYP3A4
Strong inhibitors of CYP3A4 include:

Clarithromycin

Indinavir

Itraconazole

Ketoconazole

Nefazodone

Nelfinavir

Ritonavir

Saquinavir
This appendix is not intended to be a comprehensive list of strong CYP3A4 inhibitors, but to 
provide a practical list of commonly prescribed medications that should be avoided in 
subjects participating in this study.  Additional guidance for investigators on potential strong 
CYP3A4 
inhibitors 
of 
clinical 
significance 
may 
be 
found 
at 
http://medicine.iupui.edu/flockhart/.
The web-based resources are intended as guidance for the investigators and not necessarily as 
a list of prohibited medications.
Strong inducers of CYP3A4 include:

Carbamazepine

Phenytoin

Phenobarbital

Rifampin

Hypericum perforatum (St John’s Wort)
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QT Prolongation Medications
FDA DRUG PRODUCT LABELS
QT PROLONGATION
Boxed 
Warnings
Warnings & 
Precautions
Adverse 
Reactions
Clinical 
Pharmacology
Clinical
Studies
Arsenic Trioxide
Amiodarone
Citalopram
Ambrisentan
Citalopram
Droperidol
Arsenic Trioxide
Clarithromycin
Azilsartan Medoxomil
Dofetilide
Ibutilide
Azithromycin
Dronedarone 
Azithromycin
Itraconazole
Bisacodyl
Droperidol
Citalopram
Ketoconazole
Ciprofloxacin
Erythromycin
Crizotinib
Nilotinib
Citalopram
Fesoterodine 
Darifenacin
Vandetanib
Clarithromycin
Fluoxetine
Desvenlafaxine
Clozapine
Granisetron 
Dexlansoprazole
Cyclophosphamide
Ketoconazole
Dolasetron 
Dasatinib
Mirtazapine
Eltrombopag Olamine
Dofetilide
Ondansetron
Etravirine
Dolasetron
Oxybutynin 
Everolimus
Droperidol
Risperidone
Ezogabine
Erythromycin
Sertraline 
Fexofenadine
Ezogabine
Sotalol 
Ibutilide 
Famotidine
Vandetanib
Ixabepilone
Fluconazole
Venlafaxine
Ketoconazole
Fluoxetine
Levetiracetam
Gemifloxacin
Mexiletine
Granisetron
Moxifloxacin 
Haloperidol
Nilotinib
Ibutilide
Olopatadine 
Iloperidone
Plerixafor
Itraconazole
Pseudoephedrine
Ketoconazole
Quinidine
Levofloxacin
Ranolazine
Lopinavir/Ritonavir
Telbivudine
Methadone
Teriflunomide
Nabilone
Tolterodine
Nilotinib
Vandetanib
Ofloxacin
Voriconazole
Ondansetron
Paroxetine
Pimozide
Posaconazole
Propafenone
Quinine Sulfate
Ranolazine
Romidepsin
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FDA DRUG PRODUCT LABELS
QT PROLONGATION
Boxed 
Warnings
Warnings & 
Precautions
Adverse 
Reactions
Clinical 
Pharmacology
Clinical
Studies
Sevoflurane
Solifenacin 
Sorafenib 
Sotalol 
Sunitinib 
Tacrolimus
Tolterodine 
Vandetanib
Vardenafil
Vemurafenib
Voriconazole
Ziprasidone 
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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 – 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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MK-3475 PROTOCOL 045 Amendment 13
Supplemental Statistical Analysis Plan (sSAP)
1.0 INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of confirmatory 
analyses for this trial, this supplemental SAP provides additional statistical analysis details/data 
derivations and documents modifications or additions to the analysis plan that are not “principal” 
in nature and result from information that was not available at the time of protocol finalization.
2.0 SUMMARY OF CHANGES
The sSAP was amended to align with the changes outlined in protocol amendment 13. In 
addition, statistical considerations on patient-reported outcomes (PRO) were included in Section 
3.2.12 of this sSAP.
3.0 ANALYTICAL AND METHODOLOGICAL DETAILS
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in
Section 3.2. Eastern Cooperative Oncology Group (ECOG) Performance Scale (0/1 vs. 2), 
presence or absence of liver metastases, hemoglobin (≥ 10 g/dL vs. <10 g/dL), and time from 
completion of most recent chemotherapy (<3 months or ≥3 months) will be the stratification
variables in all stratified analyses.
3.1.1
Efficacy Analyses
The intention-to-treat (ITT) population will serve as the primary analysis population in this 
study. The primary efficacy endpoints are progression-free-survival (PFS) (i.e., time from 
randomization to documented progressive disease or death due to any cause, whichever occurs 
first) and overall survival (OS) (i.e., time from randomization to death due to any cause) in PD-
L1 strongly positive, PD-L1 positive, and all subjects. The primary analyses of PFS will be based 
on blinded independent radiologists’ review using RECIST 1.1. Supportive analyses based on 
investigator’s assessments using RECIST 1.1 will also be performed. The secondary endpoints 
include PFS per modified RECIST (see Section 3.2.3.1 for definition) and objective response 
rate (ORR) per RECIST 1.1 and modified RECIST based on independent radiologists’ review. 
All the stratified analyses will be based on the stratification factors implemented for enrollment. 
In addition, a supportive stratified analysis will also be conducted for the primary efficacy 
endpoints based on the four strata defined by the number of risk factors (0, 1, 2 or 3 to 4) of the 
following [1]:  Eastern Cooperative Oncology Group (ECOG) Performance Scale >0, presence 
of liver metastases, hemoglobin <10 g/dL), and time from completion of most recent 
chemotherapy <3 months. An outline of the efficacy analysis strategy is presented in Table 2 in 
Section 3.2.5.1. The strategy to address multiplicity issues with regard to multiple efficacy 
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endpoints, multiple comparisons, multiple populations and interim analyses is described in 
Section 3.2.9 Interim Analyses and in Section 3.2.6 Multiplicity.
3.1.2
Safety Analyses
The All-Patients-as-Treated (APaT) population will be employed for safety analyses. The 
analysis of safety results will follow a tiered approach.
3.1.3
Power and Sample Size
The study will randomize approximately 470 patients with a 1:1 ratio between the 
pembrolizumab (MK-3475) arm and the standard treatment arm. The study is event-driven and 
the sample size calculation is driven by survival events. Assuming the prevalence rates of PD-L1 
positive and PD-L1 strongly positive subjects among the overall population are 55% and 33%, 
respectively, a sample size of 470 all subjects will provide approximately 260 PD-L1 positive 
subjects and 156 PD-L1 strongly positive subjects. 
The sample size and power calculation of PFS is based on the following assumptions: 1) 
progression-free survival follows an exponential distribution with a median of 4 months in the 
standard treatment arm, 2) the true hazard ratios between pembrolizumab (MK-3475) and 
standard therapy are 0.45, 0.5 and 0.5 for PD-L1 strongly positive, PD-L1 positive and all 
subjects, respectively, 3) an enrollment period of 12 months, and 4) a yearly dropout rate of 5%. 
The estimated number of PFS events in PD-L1 strongly positive subjects and all subjects at the 
final PFS evaluation are estimated to be 137 and 420, respectively. The study provides 97% 
power for the PFS hypothesis in PD-L1 strongly positive subjects and >99% power for the PFS 
hypothesis in all subjects. 
The final OS analysis will be carried out after approximately 370 deaths in all subjects and 110 
deaths in PD-L1 strongly positive subjects have occurred between the pembrolizumab (MK-
3475) arm and the paclitaxel, docetaxel or vinflunine arm for all subjects, barring early stopping 
for futility or efficacy. With the above numbers of events and before any alpha roll-over, the 
study provides 88% and 86% power to demonstrate superiority of OS of pembrolizumab (MK-
3475) relative to standard therapy at the pre-specified initial alpha (one-sided) levels in PD-L1 
strongly positive and all subjects, respectively. The sample size and power calculation of OS are
based on the following assumptions: 1) overall survival follows an exponential distribution with 
a median of 8 months in the control arm; 2) the hazard ratio for OS between pembrolizumab 
(MK-3475) and control is 0.5, 0.6 and 0.7 for PD-L1 strongly positive, PD-L1 positive and all 
subjects, respectively. (deemed to be clinically meaningful in this population); 3) an enrollment 
period of 12 months and a minimum of 18 months follow-up after enrollment completion; and 4) 
a yearly drop-out rate of 2%. 
The family-wise type I error rate  for the primary hypotheses on PFS and OS as well as the 
secondary hypothese on ORR is strongly controlled at 2.5% (one-sided) using the graphical 
method of Maurer and Bretz [2]. Additional details are provided in Section 3.2.6 Multiplicity.
3.1.4
Interim Analysis
There will be two interim analyses of PFS and OS for PD-L1 strongly positive (CPS>10%) 
subjects and all subjects, respectively. For PD-L1 positive subjects, only the PFS and OS 
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analyses at IA1 are included in the multiplicity controlled testing strategy.  The timing of these 
interim analyses will be triggered by the pre-specified number of OS events. Results of the 
interim analyses will be reviewed by an external data monitoring committee (DMC).  Further 
details of interim analyses are provided in Section 3.2.9 Interim Analysis as well as in the DMC 
Charter.
Statistical Analysis Plan
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
Although the trial is open label, analyses or summaries generated by randomized treatment 
assignment, actual treatment received, and/or PD-L1 biomarker status will be limited and 
documented. In addition, the independent radiologist(s) will perform the central imaging review 
without knowledge of treatment group assignment. The study team at the Sponsor consisting of 
clinical, statistical, statistical programming and data management personnel, will be blinded to 
subject-level PD-L1 biomarker results before the cutoff value of PD-L1 expression level for PD-
L1 strongly positive is established and formally documented exclusively based on data outside of 
this study.  
The SPONSOR will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS. 
Access to the allocation schedule for this study will be restricted to an external unblinded 
statistician and, as needed, an external scientific programmer performing the analysis, who will 
have no other responsibilities associated with the study. 
Treatment-level results at the first interim analysis of PFS and OS will be provided by an 
external unblinded statistician to the eDMC. Key enrollment metrics and study data will also be 
monitored by the external unblinded statistician to inform the timing of the first PFS and OS 
analyses as needed. Limited additional SPONSOR personnel may be unblinded to the treatment 
level results of the first PFS analyses, if required, in order to act on the recommendations of the 
eDMC or facilitate regulatory filing after the PFS analysis. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented by the unblinded 
statistician.
The eDMC will serve as the primary reviewer of the unblinded results of the interim analyses
and will make recommendations for discontinuation of the study or modification to an executive 
oversight committee of the SPONSOR. Depending on the recommendation of the eDMC, the 
Sponsor may prepare a regulatory submission. If the eDMC recommends modifications to the 
design of the protocol or discontinuation of the study, this executive oversight committee may be 
unblinded to results at the treatment level in order to act on these recommendations. Additional 
logistical details, revisions to the above plan and data monitoring guidance will be provided in 
the DMC Charter.
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Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3 of Amendment 13 of Protocol 045.
The study is considered to have met its primary objective if pembrolizumab (MK-3475) is 
superior to the paclitaxel, docetaxel or vinflunine arm either in PFS or in OS at an interim 
analysis or final analysis in the overall population, the PD-L1 positive population or the PD-
L1strongly positive population.
Analysis Endpoints
Efficacy Endpoints
Primary 
Progression-free survival - RECIST 1.1 by blinded independent radiologists’ review
Progression-free-survival (PFS) is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 based on blinded independent radiologists’ 
review or death due to any cause, whichever occurs first.  See Section 3.2.5.1.1 for definition of 
censoring.
A supportive analysis of PFS will be conducted using site radiology review as defined in the 
Imaging Review Charter .
Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Patients without documented death at the time of the final analysis will be censored at the date of 
the last follow-up.
Secondary
Objective Response Rate (ORR) – RECIST 1.1 by blinded independent radiologists’ review 
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR). Responses are based upon blinded 
central radiologists’ review per RECIST 1.1.  
A supportive analysis of ORR will be conducted using site radiology review as defined in the 
Imaging Review Charter.
PFS/ORR – modified RECIST 1.1 by blinded independent radiologists’ review 
PFS and ORR per modified RECIST 1.1 are defined as specified for the respective endpoints 
using RECIST 1.1 above, with the exception that a confirmation assessment of PD (at least 4 
weeks after the initial PD assessment) is required for subjects who remain on treatment following 
a documented PD per RECIST 1.1.  Subjects who discontinue treatment following a documented 
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PD assessment per RECIST 1.1 will be counted as having disease progression on the date of the 
documented PD assessment.  See Section 3.2.5.1.1 for definition of censoring.
Supportive analyses will be conducted using site radiology review as defined in the Imaging 
Review Charter.
Response Duration - – RECIST 1.1 by blinded independent radiologists’ review 
For subjects who demonstrated CR or PR, response duration is defined as the time from first 
documented evidence of CR or PR until disease progression or death. Response duration for 
subjects who have not progressed or died at the time of analysis will be censored at the date of 
their last tumor assessment.  Response duration will be calculated for RECIST 1.1 based on 
blinded independent radiologists’ review and site review.
Exploratory 
Exploratory endpoints of this study include but not limit to PFS2, disease control rate, and 
response to treatment by biomarker subgroups. Patient-reported outcomes (PROs) while on 
treatment and post-discontinuation will be examined. The detailed PRO analysis plan is included 
in Section 3.2.12. 
An exploratory analysis of PFS2, defined as the time from randomization to subsequent disease 
progression after initiation of new anti-cancer therapy, or death from any cause, whichever first, 
will be carried out. If progression after next-line therapy cannot be measured, a PFS event is 
defined as end or discontinuation of next-line treatment or death from any cause, whichever 
occurs first. Patients alive and for whom a PFS event has not been observed will be censored at 
the last time known to be alive and without second disease progression.
Safety Endpoints
Safety measurements are described in Section 7 of protocol.
Analysis Population
Efficacy Analysis Population
The analysis of primary efficacy endpoints are based on the intention-to-treat (ITT) population, 
i.e., subjects will be included in the treatment group to which they are randomized. Details on the 
approach to handling missing data are provided in Section 3.2.5 Statistical Methods.
Safety Analysis Populations
The All Patients as Treated (APaT) population will be used for the analysis of safety data in this 
study. The APaT population consists of all randomized subjects who received at least 1 dose of 
study treatment. Subjects will be included in the treatment group corresponding to the trial 
treatment they actually received for the analysis of safety data. 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. The baseline measurement and at least one laboratory or 
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vital sign measurement obtained subsequent to at least one dose of trial treatment is required for 
inclusion in the analysis of each specific parameter.
Details on the approach to handling missing data for safety analyses are provided in Section 
3.2.5 Statistical Methods.
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 3.2.5.2. Efficacy 
results that will be considered to be statistically significant after consideration of the strategy for 
controlling the Type I error are described in Section 3.2.6, Multiplicity. Nominal p-values may 
be computed for other efficacy analyses as a measure of strength of association between the 
endpoint and the treatment effect rather than formal tests of hypotheses.
Statistical Methods for Efficacy Analyses
The family-wise type I error rate for this study is strictly controlled at 2.5% (one -sided) that 
allows the trial to declare positive in PFS or OS in the ITT population.  
The strategy to address multiplicity issues with regard to multiple efficacy endpoints and 
multiple analyses is described in Section 3.2.6 and Section 3.2.9.
3.2.5.1.1 Progression-Free Survival (PFS)
The non-parametric 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 hazard ratio and its 95% confidence interval from the stratified Cox model with Efron's 
method of tie handling and with a single treatment covariate will be reported. The same 
stratification factors used for randomization (see protocol Section 5.4) will be applied to both the 
stratified log-rank test and the stratified Cox model. A sensitivity analysis based on multivariate 
Cox PH model with treatment, stratification factors and other factors as covariates will also be 
provided. 
Since disease progression is assessed periodically, progressive disease (PD) can occur any time 
in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the primary analysis, for the subjects who have PD, the 
true date of disease progression will be approximated by the date of the first assessment at which 
PD is objectively documented per RECIST 1.1, regardless of discontinuation of study drug.
Death is always considered as a confirmed PD event. Sensitivity analyses will be performed for 
comparison of PFS based on investigator's assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by central imaging 
vendor, two sensitivity analyses with different sets of censoring rules will be performed. The first 
sensitivity analysis is the same as the primary analysis except that the data for any subject who 
misses two or more consecutive disease assessments (with or without a subsequent death or 
progression) are censored at the last disease assessment prior to missing visits. The second 
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sensitivity analysis is the same as the primary analysis except that it considers discontinuation of 
treatment or initiation of new anticancer treatment subsequent to discontinuation of study-
specified treatments, whichever occurs later, to be a PD event for subjects without documented 
PD or death. If a subject meets multiple criteria for censoring, the censoring criterion that occurs 
earliest will be applied. The censoring rules for primary and sensitivity analyses are summarized 
in Table 1. In addition to the primary analysis and two sensitivity analyses listed in Table 1, 
another analysis, sensitivity analysis 3, will be conducted with special censorings rules for 
specific clinical scenarios. Sensitivity analysis 3 is the same as the primary analysis except that it 
censors subjects with any of the following two clinical scenarios before PD or death at the time 
of last disease assessment prior to the clinical scenarios: (1) use of radiotherapy before study 
treatment discontinuation; (2) occurrence of a skeletal-related event (e.g., fracture) in patients 
with bone metastases at study entry. In case there is an imbalance between the treatment groups 
on disease assessment schedules or censoring patterns, we will also perform the following two 
additional PFS sensitivity analyses: (1) a PFS analysis using time to scheduled tumor assessment 
visit from randomization as opposed to actual tumor assessment time; (2) Finkelstein (1986)’s 
likelihood-based score test for  interval-censored data, which modifies the Cox proportional 
hazard model for interval censored data, will be used as a supportive analysis for the PFS 
endpoint [3]. The interval will be constructed so that the left endpoint is the date of the last 
disease assessment without documented PD and the right endpoint is the date of documented PD 
or death, whichever occurs earlier.
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Table 1
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Analysis Approach
Event Status
Study 
Therapy 
Discontinued
New Anti-
Cancer 
Therapy 
Initiated
# Missed 
Disease 
Assessments 
Before Event
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and No Death
No
No
N/A
Censored at last disease 
assessment 
Censored at last 
disease assessment 
Censored at last 
disease assessment 
No PD and No Death
Yes
No
N/A
Censored at last disease 
assessment 
Censored at last 
disease assessment 
Progressed at 
treatment 
discontinuation
No PD and No Death
Yes or No
Yes
N/A
Censored at last disease 
assessment before new 
anticancer treatment
Censored at last 
disease assessment 
before new 
anticancer treatment
Progressed at date 
of new anticancer 
treatment
No PD and No Death
Yes or No
No
≥ 2 consecutive 
assessments
Censored at last disease 
assessment
Censored at last 
disease assessment 
prior to the  ≥ 2 
missed disease 
assessments
Censored at last 
disease assessment
PD or Death 
Yes or No
No
≤ 1
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 
Yes or No
No
≥ 2 consecutive 
assessments
Progressed at date of 
documented PD or death
Censored at last 
disease assessment 
prior to the  ≥ 2 
missed disease 
assessment
Progressed at date 
of documented PD 
or death
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The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[-log] of the survival function vs. time for PFS  will be 
plotted for the comparison between pembrolizumab (MK-3475) and the paclitaxel, docetaxel or 
vinflunine arm. If the curves are not parallel, indicating that hazards are not proportional, a 
supportive analysis will be conducted to further account for the possible nonproportional hazards 
effect associated with immunotherapies using Fleming and Harrington's weighted log-rank test 
with the class of weights (G ρ, γ) [4]. The weights will be assigned under the assumption of a 
delayed clinical benefit so that later event times are weighted more heavily than early event 
times. Using this class of weights assuming parameters ρ =0 and γ=1, the weight at a given event 
time is 1 minus the estimated survival function.
3.2.5.1.2 Overall Survival (OS)
The 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 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 (see Protocol Section 5.4) will be applied to both the stratified 
log-rank test and the stratified Cox model. A sensitivity analysis based on multivariate Cox PH 
model with treatment, stratification factors and other factors as covariates will also be provided.  
Subjects in the standard treatment arm may switch to another anti PD-1 treatment following 
confirmation of progressive disease. Exploratory analyses to adjust for the effect of crossover (to 
other PD-1therapies) on OS may be performed based on recognized methods, e.g. the Rank 
Preserving Structural Failure Time (RPSFT) model proposed by Robins and Tsiatis (1989), two 
stage model, etc. The choice of the method will be based on an examination of the 
appropriateness of the data to the assumptions required by the method. The RPSFT model 
provides a randomization-based estimate of treatment effect (RBEE) corrected for the bias 
induced by crossover. The 95% confidence intervals of the hazard ratio for OS after adjustment 
of the cross-over effect will be provided. The Kaplan-Meier estimates of the OS rate at 3 months, 
6 months (when most cross-overs are likely to occur) and other time points of interest will also 
be compared between the two treatment groups to explore the confounding effect of subsequent 
treatments. To further account for the possible confounding effect, a sensitivity analysis of OS 
that censors subjects at the time of initiation of new therapy will be performed and an OS 
analysis that treats initiation of new therapy as a time-dependent binary covariate will also be 
conducted. In the case where the proportional hazards assumption doesn’t hold, Fleming and 
Harrington’s weighted log-rank test or other methods, as appropriate, will be conducted.
3.2.5.1.3 Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method will be used for comparison of the objective 
response rates between the treatment groups. A 95% confidence interval for the difference in 
response rates between the pembrolizumab (MK-3475) arm and the standard therapy arm will be 
provided. The same stratification factors used for randomization (see Section 5.4) will be applied 
to the analysis. Sensitivity analyses will be performed for comparison of ORR based on 
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investigator's assessment. The ORR in overall population has also been included in the 
multiplicity scheme; see Section 3.2.6.
3.2.5.1.4 Response Duration
If sample size permits, response duration will be summarized descriptively using Kaplan-Meier 
medians and quartiles.  Only the subset of subjects who show a complete response or partial 
response will be included in this analysis.  Response duration will be assessed using RECIST 1.1 
separately by independent radiologists’ review and by site radiology review.
A summary of the primary analysis strategy for the primary and secondary efficacy endpoints is 
provided in Table 2.
3.2.5.1.5 Exploratory Analyses
An exploratory analysis of PFS2, defined as the time from randomization to subsequent disease 
progression after initiation of new anti-cancer therapy, or death from any cause, whichever first, 
will be carried out. If progression after next-line therapy cannot be measured, a PFS event is 
defined as end or discontinuation of next-line treatment or death from any cause, whichever 
occurs first. Patients alive and for whom a PFS event has not been observed should be censored 
at the last time known to be alive and without second disease progression.
EORTC QLQ-C30 and EQ-5D changes will be summarized as part of the exploratory analysis. 
Longitudinal and descriptive data analysis will be used to evaluate patient-reported outcomes. 
Several approaches will be considered to address the issue of informative missing data: (i) 
truncating the analysis observation period at the visit closest to median duration of treatment in 
the comparator arm, (ii) hierarchical pattern mixture models incorporating reason for 
missingness (a model that treats disease progression as a time-varying covariate) and (iii) 
multiple imputation methods. The difference in PRO score for progressed patients compared to 
patients with no radiographic evidence of tumor progression will be evaluated within each 
treatment arm. For HEA, descriptive statistics by treatment group will include total counts of 
each type of healthcare contact, as well as the total number of hospital days. Details will be 
provided in a separate PRO analysis plan.
An exploratory analysis of PFS and OS by PD-L1 score, either as a dichotomous or continuous 
variable, as well as PFS2 will be conducted using the same methods as the primary analysis.
Table 2
Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints
Endpoint/Variable
(Description, Time 
Point)
Primary 
or 
Supportive 
Approach
Statistical Method
Analysis 
Population†
Missing Data 
Approach
Primary Endpoints: 
PFS (RECIST 1.1) 
by independent 
radiologists’ review
P
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method 
ITT
Censored 
according to rules 
in Table 1
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PFS (RECIST 1.1) 
by independent 
radiologists’ review 
– Sensitivity 
Analyses 1& 2
S
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method 
ITT
Censored 
according to rules 
in Table 1
OS
P
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method
ITT
Model based 
(censored at last 
contact date)
OS
S
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method
ITT
Censored at time 
of initiation of 
new therapy or 
last assessment 
date
OS
S
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method 
using initiation of new 
therapy as time-
dependent covariate
ITT
Censored at last 
contact date
Secondary Endpoints :
Objective response 
rate  (RECIST 1.1) 
by independent 
radiologists’ review 
P
Stratified Miettinen and 
Nurminen method
ITT
Patients with 
missing data are 
considered non-
responders
PFS (modified 
RECIST)  by 
independent 
radiologists’ review 
P
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron's 
tie handling method 
ITT
Censored 
according to rules 
in Table 1
Objective response 
rate  (modified 
RECIST) by 
independent 
radiologists’ review 
P
Stratified Miettinen and 
Nurminen method
ITT
Patients with 
missing data are 
considered non-
responders
Response duration 
(RECIST 1.1) by 
independent 
radiologists’ review 
P
Summary statistics 
using Kaplan-Meier 
method
All responders 
in ITT 
Non-responders 
are excluded from 
analysis
† The analysis populations for H3 and H4 are ITT in PDL1 positive subjects, and for H5 and H6 are ITT in PDL1 
strongly positive subjects. 
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.
Time to Grade 3-5 AE
Time to first Grade 3-5 AE is defined as the time from the first day of study drug to the first 
event of Grade 3-5 AE. For patients without a Grade 3-5 AE, the time to first Grade 3-5 AE is 
censored at 30 days post last study dose. The Kaplan-Meier method will be used to estimate the 
curve of time to first Grade 3-5 AE.  The treatment difference in time to first Grade 3-5 AE will 
be assessed by the stratified log-rank test. A stratified Cox proportional hazard model with 
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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.  
Tiered Approach for Other Safety Analyses
The analysis of safety results will follow a tiered approach (Table 3). The tiers differ with respect 
to the analyses that will be performed. Safety parameters or adverse experiences of special 
interest that are identified a priori constitute “Tier 1” safety endpoints that will be subject to 
inferential testing for statistical significance with p-values and 95% confidence intervals 
provided for between-group comparisons. Other safety parameters will be considered Tier 2 or 
Tier 3. Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for between-group comparisons; only point estimates by treatment group are provided 
for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined limits of 
change in laboratory, vital signs, and ECG parameters that are not pre-specified as Tier-1 
endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number of events 
observed. Membership in Tier 2 requires that at least 4 subjects in any treatment group exhibit 
the event; all other adverse experiences and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment groups 
of equal size each have less than 4 events and thus would add little to the interpretation of 
potentially meaningful differences. Because many 95% confidence intervals may be provided 
without adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse experiences and predefined limits of 
change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety 
parameters. Summary statistics for baseline, on-treatment, and change from baseline values will 
be provided by treatment group in table format.
For this protocol, there are no Tier 1 events. In addition, the broad clinical and laboratory AE 
categories consisting of the percentage of subjects with any AE, any drug related AE, any serious 
AE, any Grade 3-5 AE, an AE which is both Grade 3-5 and drug-related, an AE which is both 
drug-related and serious, dose modification due to AE, and who discontinued due to an AE, and 
death will be considered Tier 2 endpoints. 95% confidence intervals (Tier 2) will be provided for 
between-treatment differences in the percentage of subjects with events; these analyses will be 
performed using the stratified Miettinen and Nurminen method.
To properly account for the potential difference in follow-up time between the study arms, which 
is expected to be longer in the pembrolizumab (MK-3475) arm, AE incidence density adjusted 
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for treatment exposure analyses may be performed as appropriate. Based on emerging external 
data, the supportive analysis strategy for safety parameters may be modified to improve the 
integrity and efficiency of the design. Should this happen, the change will be documented in the 
sSAP, if not in a protocol amendment, at the earliest time before any unblinding of the data.
Table 3
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
p-
Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Grade 3-5 AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade3-5 and Drug-Related AE
X
X
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs (including ≥4 of subjects in one of the 
treatment groups)
X
X
Tier 3
Specific AEs, SOCs (incidence <4 of subjects in all of 
the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital Signs)
X
Summaries of Baseline Characteristics, Demographics, and Other Analyses
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 randomized, and the primary reason for 
discontinuation will be displayed. Demographic variables (such as age) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables. The reasons for exclusion from the ITT population (if any) will be summarized.
Multiplicity
Based on emerging biomarker data external to this study, the initial alpha allocation among the 
primary hypotheses is revised in Amendment 13 onward to reflect the change in biomarker 
strategy (Section 4.2.3.1.1). The reallocation of alpha occurs after the conduct of IA1, and proper 
adjustment is made to maintain the control of family-wise type I error rate (FWER) with the 
implementation of this change. The type I error actually spent at IA1 will be kept intact and the 
re-allocation will only be applied to the remaining unspent alpha. The family-wise type I error 
rate for this study is strongly controlled at 2.5% (one-sided) across all six primary hypotheses on 
PFS and OS and the secondary hypothesis on ORR, with 

0.1% allocated to the PFS hypothesis in all subjects (H1), with 0.02% planned at IA1;
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
1.0% allocated to the OS hypothesis in all subjects (H2), with 0.02% planned at IA1;

0.02%  allocated to the PFS hypothesis in PD-L1 positive subjects (H3) at IA1 only;

0.18% allocated to the OS hypothesis in PD-L1 positive subjects (H4) at IA1 only;

0.38% initially allocated to the PFS hypothesis in PD-L1 strongly positive subjects (H5),
with 0.07% planned at IA1;

0.82% initially allocated to the OS hypothesis in PD-L1 strongly positive subjects (H6) ), 
with 0.04% planned at IA1;
where the alpha spent at IA1 is based on the assumption of the planned information fractions 
along with the original pre-specified alpha allocation prior to Amendment 13 by the pre-
specified alpha spending function of Hwang-Shih-DeCani (HSD) with gamma parameter (-4). 
Under the revised alpha allocation, the alpha spending at IA2 and final analysis are determined 
by first applying the same HSD gamma (-4) spending function to distribute unspent alpha to IA2 
and final analysis, respectively, and then incorporating them with the alpha that has already been 
spent at IA1 to form an interpolated alpha spending among the three analyses. For example, if 
the information fraction of OS at IA2 for all subjects (H2) is 75%, then the alpha spending 
function of HSD gamma (-4) will distribute the total of 0.98%  un-spent alpha for this hypothesis 
under the revised strategy with cumulative alpha spending of 0.35% and 0.98% at IA2 and FA, 
respectively. Incorporating the planned alpha spend of 0.02% at IA1, the new cumulative alpha 
spending for the three analyses for all subjects becomes 0.02%, 0.37% (0.35%+0.02%) and 
1.00% ( 0.98% + 0.02%). The corresponding stopping bounds in p-values at IA2 and FA can 
then be calculated. Please note the alpha spent at IA1, IA2 and final analysis will all be updated 
for the final report based on the actual numbers of events at each analysis and the corresponding 
boundaries will be adjusted accordingly. Table 4 summarizes cumulative alpha spending at each 
analysis under the current alpha allocation and planned events for each analysis.  
Table 4
Cumulative Alpha Spending
Hypothesis
Analysis (Planned # of events; 
Information Fraction)
Cumulative Alpha Spending Based on 
Alpha Allocation†
PFS
H1 All Subjects 
IA1 (273; 65%)
0.000233
IA2 (357; 85%) 
0.000540
FA (420; 100%)
0.001000
H3 PD-L1 Positive
IA1 (151; 65%)
0.000233
IA2 (197; 85%)
n/a
FA (232; 100%)
n/a
H5 PD-L1 Strongly 
Positive
IA1 (89; 65%)
0.000698
IA2 (116; 85%)
0.002356
FA (137; 100%)
0.003767
OS
H2 All Subjects
IA1 (185; 50%)
0.000238
IA2 (277; 75%) 
0.003714
FA (370; 100%)
0.010000
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H4 PD-L1 Positive
IA1 (99; 50%)
0.001788
IA2 (149; 75%)
n/a
FA (198; 100%)
n/a
H6 PD-L1 Strongly 
Positive
IA1 (55; 50%)
0.000358
IA2 (82; 75%)
0.003155
FA (110; 100%)
0.008212
†Before any alpha roll-over according to the method of Maurer and Bretz (2013).
If the pembrolizumab (MK-3475) arm is demonstrated to have a superior PFS or OS to the 
control arm at any analysis, then the initially allocated alpha will be rolled from that specific 
hypothesis into another hypothesis following the pre-specified rules in Figure 1 using the 
graphical approach of Maurer and Bretz (2013)  [2].   Actual alpha allocation after the roll-over 
will be updated based on the spending function used.  
The ORR hypothesis (RECIST 1.1 per independent radiologist’s review) in all subjects will be 
tested following a group sequential approach. The ORR hypothesis is initially assigned a type I 
error rate of 0% and thus, cannot be tested unless the null hypothesis of H2 (OS in all subjects) is 
successfully rejected. 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 that will allow strong control of the overall type I error will be 
distributed by an alpha spending function of Hwang-Shih-DeCani based 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 4 scheduled scans if not discontinued. Only subjects with “mature ORR 
information” will be included into the ORR analysis.   
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† Initially assigned alpha before any alpha rollover; final alpha level is subject to change with respect to 
actual alpha rollover.
‡ Based on assumed information fractions for demonstration purpose only and will be updated 
accordingly with respect to actual information.
Figure 1
Type I Error Reallocation Strategy Following Closed Testing Principle
Sample Size and Power Calculation
The study is event-driven and plans to randomize approximately 470 subjects with 1:1 ratio into 
the pembrolizumab (MK-3475) arm and the paclitaxel, docetaxel or vinflunine arm.
FWER α = 2.5% (one sided) 
H5: PD-L1++ 
PFS 
α5 = 0.38%
H6: PD-L1++ 
OS 
α6 = 0.82%
H1: All 
Subjects PFS 
α1 = 0.1%
†
H2:
All Subjects OS 
α2 = 1.0%
†
ORR in All 
Subjects
αorr = 0%
†
H4: PD-L1+ OS 
(IA1 Only)
α4 = 0.18%‡
H3: PD-L1+ PFS 
(IA1 Only)
α3 = 0.02%‡
If H5 rejected at 
any analysis, shift 
α5 to α1
If H1 rejected at 
any analysis, shift 
α1 to α2
If H6 rejected at 
any analysis, 
shift α6 to α2
If H2 rejected at 
any analysis, shift 
α2 to ORR in all 
subjects
If ORR rejected at 
any analysis, shift 
αorr to H1
No alpha rollover
No alpha rollover
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PFS analysis: The first PFS analysis will be conducted at the time of the first interim analysis 
for OS when the enrollment is completed and approximately 185 total OS events are observed 
for all subjects. All subjects enrolled at the time of the database lock will be included. Assuming 
the prevalence rates of PD-L1 positive and PD-L1 strongly positive subjects among the overall 
population are 55% and 33%, respectively, a sample size of 470 all subjects may provide 
approximately 260 PD-L1 positive subjects and 156 PD-L1 strongly positive subjects. At the 
time of the first PFS analysis for PD-L1 positive and all subjects, approximately 151 and 273 
PFS events (per primary censoring rules), respectively, may have occurred. At this analysis the 
study has approximately 77% and 99% powers to demonstrate superiority in PFS of 
pembrolizumab (MK-3475) relative to the paclitaxel, docetaxel or vinflunine arm for PD-L1 
positive and all subjects, respectively, at the pre-specified initial alpha (one-sided) level as 
specified in Section 3.2.6. With the assumed sample size of ~156 PD-L1 strongly positive 
subjects and the projected ~89 PFS events available at this time, this analysis would have ~72% 
power to reject the null hypothesis of PFS in PD-L1 strongly positive subjects (H5).  The sample 
size and power calculation is based on the following assumptions: 1) progression-free survival 
follows an exponential distribution with a median of 4 months in the standard therapy arm, 2) the 
true hazard ratio between pembrolizumab (MK-3475) and standard therapy are 0.45, 0.5 and 0.5 
for PD-L1 strongly positive, PD-L1 positive and all subjects, respectively, 3) an enrollment 
period of 12 months, and 4) a yearly dropout rate of 5%.  Any change to the timing, along with 
its rationale, will be documented in a memo to the study file before the database lock.
The second analysis of PFS per RECIST 1.1 by independent radiology review will be performed 
for PD-L1 strongly positive and all subjects at the time of the second interim OS analysis when 
approximately 277 OS events are observed for all subjects and 82 OS events are observed for 
PD-L1 strongly positive subjects. The final PFS analysis will be conducted at the time of the 
final OS analysis when approximately 370 OS events are observed for all subjects and 110 OS 
events are observed for PD-L1 strongly positive subjects. It is expected that at this time 
approximately 137 and 420 PFS events would have been observed between the two arms for PD-
L1 strongly positive and all subjects, respectively. With the above assumed PFS events, overall 
power of the PFS analyses for the two populations are approximately 97% and >99%, 
respectively. On the other hand, these numbers of events can also test the following hazard ratios 
with 90% power: 0.50and 0.65 for strongly positive and all subjects, respectively. 
OS analyses:  The first interim analysis for OS will be conducted after the full enrollment and 
approximately 185 OS events are observed for all subjects. The purpose of the OS interim 
analysis is to determine if the risk/benefit ratio to the trial population as a whole is unacceptable 
and subsequently whether the trial may be stopped early at the recommendation of the DMC.  
Further details of the interim analysis strategy, including efficacy and futility rules, are given in 
Section 3.2.9. 
The final OS analysis will be conducted after ~370 deaths in all subjects and 110 deaths in PD-
L1 strongly positive subjects have occurred between the pembrolizumab (MK-3475) arm and the 
paclitaxel, docetaxel or vinflunine arm, if the trial is not stopped early for efficacy or futility. The 
timing of the final OS analysis is expected to be about 18 months after enrollment completion. 
With 370 events at the final analysis, the study provides 88% and 86% powers to demonstrate 
superiority in OS of pembrolizumab (MK-3475) relative to standard therapy at the initially 
allocated alpha levels before any alpha roll-over in PD-L1 strongly positive and all subjects, 
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respectively. Conditional on different scenarios of alpha roll-overs, the overall power of OS in all 
subjects can be up to 92%.
The sample size and power calculation is based on the following assumptions: 1) OS follows an 
exponential distribution with a median of 8 months in the standard therapy arm, 2) hazard ratio 
between pembrolizumab (MK-3475) and standard therapy is 0.5, 0.6 and 0.7 for PD-L1 strongly 
positive, PD-L1 positive and all subjects, respectively, 3) an enrollment period of 12 months and 
a minimum of 18 months follow-up after enrollment completion; and 4) a yearly drop-out rate of 
2%.
ORR analysis:  As described in Section 3.2.6, the ORR hypothesis in all subjects is initially 
assigned a type I error rate of 0%. Conditional on the success of OS hypothesis in all subjects 
(H2), the ORR analysis can be tested following a group sequential approach with overall alpha 
rolled over from H2. The information fraction of ORR analysis will be calculated at the time of 
the interim analyses of OS and used by the pre-specified alpha spending function to determine 
nominal type I error rates at interim analyses that will allow strong control of the overall type I 
error rate. It is projected that the information fractions of the ORR analysis is about 60% at the 
time of the first OS interim analysis and 100% at the time of the second OS interim analysis. 
Depending on the results from the primary hypotheses on OS and PFS, the possible overall type I 
error rate available for the ORR analysis is ranged from 0% to 2.3% under the revised alpha 
allocation in this amendment. Under one specific scenario with type I error rates of 1.8%, this 
study can rule out a between-group ORR difference of 11.6% with 90% power and a group 
sequential design of two analyses (information fractions of 60% and 100%), assuming the 
underlying ORR for the control group is 11.6%. If the type I error rate is only 1.0% in the above 
example, then the between-group ORR difference of 11.6% can be ruled out with 84% power.
The assumptions for the median PFS of 4 months, the median OS of 8 months and the ORR of 
11.6% in the standard therapy arm are based on a weighted average of median PFS, median OS 
and ORR estimates from 2L trials of single agents [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 
19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30].  
The sample size and power calculations were performed using the software EAST and R 
(package “gsDesign”).
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 endpoint will be 
estimated and plotted within each category of the following classification variables:

Age category (≤65 vs. >65 years)

PD-L1 subgroup (strongly positive vs. not strongly positive)

Sex (female vs. male)

Race (white vs. non-white)

ECOG status (0 / 1 vs. 2)

Geographic region of enrolling site (East Asia vs. non-East Asia and EU vs. non-EU)

Prior platinum therapy (carboplatin vs. cisplatin)
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
Setting of most recent prior therapy (neoadjuvant vs. adjuvant vs. 1L metastatic vs. 2L 
metastatic)

Presence or absence of liver metastases at baseline

Baseline hemoglobin (≥ 10 g/dL vs. <10 g/dL)

Time from completion/discontinuation of most recent prior therapy to baseline (<3months 
vs. ≥3 months)

Histology (transitional cell vs. mixed transitional/non-transitional histology)

Smoking status (never vs. former vs. current)

Brain metastasis status (prior brain metastasis vs. no prior brain metastasis)

Investigators’ choice of paclitaxel, docetaxel or vinflunine

Burden of disease in terms of baseline tumor volume 
The consistency of the treatment effect will be assessed descriptively via summary statistics by 
category for the classification variables listed above.
Interim Analysis
There are two planned interim analyses for PD-L1 strongly positive and all subjects, 
respectively. For PD-L1 positive subjects, the hypotheses of PFS and OS will only be tested at 
IA1. The futility bounds of this study are non-binding and the bounds are considered guidance 
rather than strict bounds. Results of the interim analysis will be reviewed by an external data 
monitoring committee (eDMC). Depending on the recommendation of the eDMC, the Sponsor 
may prepare a regulatory submission if any of the six primary objectives are met at interim 
analysis. Further details of interim analyses are provided below and will be incorporated into the 
DMC Charter. 
PFS Analysis and Interim OS Analysis
The first PFS and OS analysis will take place when enrollment is complete and approximately 
185 OS events have been observed between the pembrolizumab (MK-3475) and standard therapy 
for all subjects. The first interim analysis is expected to occur ~15 months after study start. 
As specified in Section 3.2.6,  an interpolated alpha spending function based on HSD gamma (-
4)  is constructed to implement group sequential boundaries that control the type I error rates. 
The pembrolizumab (MK-3475) arm will be compared to the paclitaxel, docetaxel or vinflunine 
arm. At the first interim analysis, an approximate observed HR of ~0.655 or less would 
demonstrate PFS superiority for all subjects at α = 0.02% (one-sided). This hazard ratio 
corresponds to approximately 2.1-month improvement over the median PFS of 4 months in the 
paclitaxel, docetaxel or vinflunine arm. However, because immunotherapies have been shown to 
impact PFS curves at later time points (i.e., the tail of the curve), the observed difference in 
medians may be an underrepresentation of the treatment effect. If there are fewer than or more 
than the projected number of PFS events at the time of the first interim analysis, the alpha 
functions will be adjusted to accommodate the revised interim analysis timing using the fraction 
of the estimated total PFS events.
Similarly, for both OS hypotheses (H2 and H6), an interpolated alpha spending function based 
on HSD gamma (-4) and the revised alpha allocation is constructed to implement group 
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sequential boundaries that control the type I error rate. Please see Section 3.2.6 for details. The 
non-binding futility analyses are also planned with a beta spending function of HSD gamma (-
20). Table 5 and Table 6 summarize the efficacy and futility rules for the OS analyses.
Approximately 185 OS events will be observed for all subjects at the time of the first interim 
analysis and an interim OS analysis will be conducted at the level determined by the spending 
function boundaries and the actual number of OS events. As shown in Table 5 an approximate 
observed hazard ratio < ~0.598, i.e., at least 5.4-month improvement in median OS, would 
demonstrate OS superiority at the interim analysis for all subjects (H2). A futility analysis will be 
conducted at the same time and an observed hazard ratio > 1.30 will approximately meet the 
criterion for futility. The boundaries for OS hypothesis testing will be re-calculated if the actual 
monitoring schedule is altered. If there are more than 185 OS events for all subjects at the time 
of the first interim analysis, the alpha and beta spending functions will be adjusted to 
accommodate the revised interim analysis timing using the fraction of planned total OS events in 
the overall population that drives timing of analyses.
Table 5 summarizes the timing, sample size and decision guidance for the planned PFS and OS 
analyses for PD-L1 strongly positive, positive and all subjects under one hypothetical scenario 
with initially assigned type I rates only. Table 6 summarizes the futility boundaries of the OS 
hypotheses at the interim analysis. The actual boundaries will be determined from the actual 
number of PFS or OS events at the time of the specified IA using the alpha- and beta-spending 
functions.
The final OS analysis will be conducted after ~370 OS events for all subjects are observed at the 
alpha level determined by the spending function boundaries and actual number of OS events. 
Table 5
Summary of Timing, Sample Size and Decision Guidance at the Planned PFS and OS 
Analyses
Analysis
Criteria for 
Conduct of 
Analysis
(Projected 
timing)
Value
Approx. 
Number 
of 
Events
Efficacy Boundary†
Z Statistic
p-value (1-
sided) at 
Boundary
Approx. 
Observed 
HR at 
Boundary
IA 1:
PFS (H1, H3, 
H5) 
OS (H2, H4, 
H6)
Full enrollment 
~ 185 OS events
(50% 
information)  
for all subjects
H1 PFS 
All Subjects
273
3.500
0.0002
0.655
H2 OS 
All Subjects
185
3.494
0.0002
0.598
H3 PFS 
PDL1 Positive
151
3.500
0.0002
0.566
H4 OS 
PDL1 Positive
99
2.913
0.0018
0.557
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H5 PFS PDL1 
Strongly Positive 
89
3.196
0.0007
0.508
H6 OS PDL1 
Strongly Positive
55
3.384
0.0004
0.402
IA 2: 
PFS (H1 and  
H5) 
OS (H2 and 
H6)
~277 OS events  
(75% 
information) for 
all subjects and 
~ 82 OS events 
(75% 
information) for 
PDL1 Strongly 
Positive 
Subjects
H1 PFS 
All Subjects
357
3.345
0.0004
0.702
H2 OS 
All Subjects
277
2.683
0.0036
0.725
H5 PFS PDL1 
Strongly Positive 
116
2.865
0.0021
0.588
H6 OS PDL1 
Strongly Positive
82
2.745
0.0030
0.546
Final 
Analysis:
PFS (H1and 
H5)
OS (H2 and 
H6)
~ 370 OS events 
for all subjects 
and ~110 OS 
events for PDL1 
Strongly 
Positive 
Subjects
H1 PFS 
All Subjects
420
3.182
0.0007
0.733
H2 OS 
All Subjects
370
2.381
0.0086
0.781
H5 PFS PDL1 
Strongly Positive 
137
2.782
0.0027
0.622
H6 OS PDL1 
Strongly Positive
110
2.459
0.0070
0.625
† Based on initially assigned type I error rate before any alpha roll-over and projected number of events at study mile stones. Actual 
efficacy boundaries will be based on actual numbers of events available at study milestones. 
Table 6
Summary of Futility Boundary at the Planned Interim Analyses on OS
Analysis
Value
Approx. 
Number 
of Events
Non-binding Futility Boundary
Z Statistic
p-value (1-
sided) at 
Boundary
Approx. 
Observed 
HR at 
Boundary
IA 1
H2 OS 
All Subjects
185
-1.767
0.961
1.297
H4 OS 
PDL1 
Positive
99
-1.938
0.974
1.476
H6 OS PDL1 
Strongly 
Positive
55
-1.715
0.957
1.587
IA 2
H2 OS 
All Subjects
277
0.100
0.460
0.988
H6 OS PDL1 
Strongly 
Positive
82
0.148
0.441
0.968
For demonstration purpose, the beta in this table is based on initially assigned alpha only; actual futility bounds 
will be updated if overall beta is changed with respect to alpha roll-over.  
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If a null hypothesis is rejected, the alpha can be rolled over to another hypothesis following the 
pre-specified rules in Section 3.2.6. The revised decision guidance for PFS and OS with respect 
to the rolled-over alpha from the rejection of other hypothesis(es) is summarized in Table 7
below. Please note that the actual boundaries for the alpha spending function will be adjusted 
based on the actual number of events and/or ORR information fractions observed at the time of 
the corresponding analysis.
Table 7
Summary of Revised Decision Guidance for OS 
Analysis
Value
Updated Efficacy Boundary (after alpha roll-
over†)
Z Statistic
p-value (1-
sided) at 
Boundary
Approx. 
Observed HR or 
ORR-Difference‡
at Boundary
If Null Hypotheses of H5 and H6 are Rejected
IA 1
H1 PFS All Subjects
3.060
0.0011
0.691
H2 OS All Subjects
3.331
0.0004
0.613
IA 2
H1 PFS All Subjects
2.870
0.0021
0.738
H2 OS All Subjects
2.475
0.0067
0.743
Final Analysis
H1 PFS All Subjects
2.677
0.0037
0.770
H2 OS All Subjects
2.143
0.0161
0.800
If Null Hypotheses of H1, H5 and H6 are Rejected
IA 1
H2 OS All Subjects
3.265
0.0005
0.619
IA 2
H2 OS All Subjects
2.390
0.0084
0.751
Final Analysis
H2 OS  All Subjects
2.045
0.0204
0.809
If Null Hypothesis of H2 is Rejected
IA 1
ORR All Subjects
2.899
0.0019
12.9%
IA 2
ORR All Subjects
2.358
0.0092
8.2%
Final Analysis
ORR All Subjects
2.358
0.0092
8.2%
If Null Hypothesis of H2 and H6 are Rejected
IA 1
ORR All Subjects
2.254
0.0121
8.2%
IA 2
ORR All Subjects
2.164
0.0152
7.5%
Final Analysis
ORR All Subjects
2.164
0.0152
7.5%
†Only selective scenarios are demonstrated in this table. 
‡Assume the underlying ORRs in the control and pembrolizumab groups are 11.6% and 23.2%, respectively.
Final OS Analysis
The final analysis will take place when approximately 370 deaths in all subjects and 110 deaths 
in PD-L1 strongly positive subjects have occurred between the pembrolizumab (MK-3475) arm 
and the paclitaxel, docetaxel or vinflunine arm in all subjects which is expected to occur ~30 
months after study start. If the timing of events occurs faster than anticipated, the test boundary 
at the final analysis will be adjusted to use the remaining Type I error not spent at earlier 
analyses. A 95% confidence interval will be provided for the hazard ratio to characterize the OS 
effect in case the superiority is not demonstrated. 
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Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Compliance with 
trial treatment administration will be measured by subjects: 1) receiving unscheduled study 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.
Statistical Analysis on Patient-reported Outcomes (PRO)
The patient-reported outcomes are exploratory objectives in KEYNOTE 045. Therefore no 
formal hypotheses were formulated for PRO. The section will focus on PRO endpoints as 
measured by the EORTC QLQ-C30 and EuroQol-5D (EQ-5D).
The global health status/quality of life scale from EORTC QLQ-C30 will be the key PRO 
endpoint. Time to deterioration (TTD) of this endpoint has been used as the key PRO endpoint in 
advanced NSCLC clinical trials [31, 32, 33]. The TTD is measured as the time point when the 
score decreases by 10 or more (out of 100), with or without subsequent confirmation.
Supportive analyses will include all QLQ-C30 sub-scales/items. The QLQ-C30 includes five 
functional dimensions (physical, role, emotional, cognitive, and social), three symptom scales 
(fatigue, nausea/vomiting, and pain), and six single item measures (dyspnea, insomnia, appetite 
loss, constipation, diarrhea, and financial difficulties). Supportive analysis will also include 
alternative approaches such as estimating the effect of disease progression on HRQoL.
EQ-5D is another set of endpoints as a measure of health outcome. The EQ-5D will provide data 
for use in economic models and analyses including developing health utilities or QALYs.
Key PRO Endpoints:
1. The mean score changes from baseline to week 15 as measured by the EORTC QLQ-C30 
global health status/quality of life scale.
2. The time to deterioration (TTD) as measured by the EORTC QLQ-C30 global health 
status/quality of life scale.
Since there is no formal hypothesis for PRO analysis, P-values for treatment comparisons of 
pembrolizumab vs. control for key PRO endpoints will only be provided for reference without 
multiplicity adjustment. 
Supportive PRO Endpoints:
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The mean score changes, the number, and proportions of deterioration/stable/improvement, from 
baseline to week 15, of:
–
EORTC QLQ-C30 global health status/quality of life scale (the number and proportions 
of deterioration/stable/improvement from baseline to week 15).
–
Each EORTC QLQ-C30 functional subscale: physical functioning, role functioning, 
emotional functioning, cognitive functioning, and social functioning.
–
Each EORTC QLQ-C30 symptom subscale score: fatigue, nausea and vomiting, pain, 
dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties.
–
EQ-5D utility score
–
EQ-5D Health State Score
In addition, mean PRO scores over time willalso be summarized.
Scoring Algorithm:
QLQ-C30 Scoring: For each scale or item, a linear transformation will be applied to standardize 
the score as between 0 and 100, according to the corresponding scoring standard. For functioning 
and global health status/quality-of-life scales, a higher value indicates a better level of function; 
for symptom scales and items, a higher value indicates increased severity of symptoms.
According to the QLQ-C30 Manuals, if items I1, I2,…,In are included in a scale, the linear 
transformation procedure is as follows:
1. Compute the raw score:
2. Linear transformation to obtain the score S:
Function scales: 
Symptom scales/items: 
Global health status/QoL: 
100
1

Range
RS
S
Range is the difference between the maximum possible value of RS and the minimum possible 
value. If more than half of the items within one scale are missing, then the scale is considered 
missing. Otherwise, the score will be calculated as the average score of those available items 
[34].
n
I
I
I
RS
n /)
...
(
2
1




100
1
1










Range
RS
S
100
1 

Range
RS
S
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EQ-5D scoring: EQ-5D utility score will be calculated based on the European algorithm [35]. 
The schedule for PRO data collection:
Table 8 provides the schedule for PRO data collection.
Table 8  PRO Data Collection Schedule
Original Phase Treatment Week
Discontinuation
Safety 
Follow-up1
0
3
6
9
15
21
27 and Q6W 
beyond
Pembrolizumab
C1
C2
C3
C4
C6
C8
C10 and every 
2 
cycles 
beyond
X
X
Control
C1
C2
C3
C4
C6
C8
C10 and every 
2 
cycles 
beyond
X
X
C: Cycle.
1 If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at the time of the 
mandatory Safety Follow up Visit, PROs do not need to be repeated.
The general rule of mapping relative day to analysis visit is provided in table 2 (due to space 
limit, only up to Week 21 is displayed).
Table 9: Mapping Relative Day to Analysis Visit
Treatment Week
Week
0
3
6
9
15
21
Day
1
21
42
63
105
147
Range
-7 to 1
2 to 31
32 to 52
53 to 83
84 to 126
127 to 168
At each scheduled visit, two instruments, EQ5D and EORTC QLQ-C30, will be collected. If a 
patient does not complete the PRO instruments, the site staff will record the reason for the 
missing from the pre-defined choices. If there are multiple PRO collections within any of the 
stated time windows, we use the closest collection to the target day.
Analysis Populations
The primary analysis approach for the pre-specified exploratory PRO endpoints will be based on 
a quality of life related full analysis set (FAS) population. This population consists of all 
randomized patients who have received at least one dose of study medication, and have 
completed at least one PRO assessment.
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Analysis Approaches
This section describes the planned analyses for the PRO endpoints. Table 10 gives an overview 
of the analyses planned for all PRO endpoints. Compliance will be summarized by treatment 
group and visit.
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Table 10   Planned Statistical Analysis
Endpoint
Analysis
Primary Statistical Method
Report
Score change from baseline
Treatment effect 
estimation/comparison
Mixed effect model based on the 
missing at random (MAR) 
assumption
lsmean score (95% C.I.) by 
treatment group and visit,  
lsmean score change (95% C.I.) 
from baseline by treatment 
group and visit, pairwise 
between-group difference in 
score change from baseline 
(95% C.I., p-value).
Disease progression 
effect estimation
Mixed effect model based on the 
MAR assumption
p-value of the interaction effect 
between progression and 
treatment discontinuation, by 
treatment group.
Time to deterioration
Treatment effect 
estimation/comparison
Kaplan-Meier plot, stratified log 
rank test and Cox proportional 
hazards model with Efron’s tie 
handling method
Hazard Ratio (95% C.I., p-
value); Kaplan-Meier plot
Proportion of 
deterioration/stable/improvement
Treatment effect 
estimation/comparison
Summary with multiple imputation 
based on the MAR assumption
Proportion estimate (95% C.I.) 
by treatment group and visit
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Treatment effect on PRO
To assess the treatment effects of treatment on the PRO, for each continuous endpoint defined, a 
constrained longitudinal data analysis (cLDA) model will be used as the primary analysis 
method, with the PRO score as the response variable, and treatment by study visit interaction, 
and stratification factors (study protocol, Section 5.4) as covariates.
The cLDA model is specified as follows:
,...
3,2,1,0
    
,...,
3
,2
,1
    
,
)
0
(
)
(
0






t
j
X
t
I
Y
E
i
i
jt
ijt



, where Yijt is the PRO score for 
subject i, with treatment assignment j, at visit t, 
0

is the baseline mean for all treatment groups,
jt

is the mean change from baseline for treatment group j at time t, 
i
X is the stratification factor 
vector for this patient, and 
it
is the coefficient vector for stratification factor at time t.
Treatment effect on PRO score change from baseline will be evaluated at 15 weeks and 
potentially at 21 weeks, if the completion rate in the control arm is larger than 50%. Between-
group comparison will be performed and the differences in the lsmean change from baseline will 
be reported, together with 95% C.I. and nominal p-value at the primary analysis time points. In
addition, model-based lsmean score with 95% C.I. will be provided by treatment group and study 
visit.
Most of the patients without disease progression are expected to have complete data up to Week 
15. Patients with disease progression confirmed or feeling worse due to drug-related AE may 
have missing PRO assessments. The missing data must be handled accordingly to obtain valid 
statistical inference. The cLDA model implicitly treats missing data as missing at random 
(MAR). Sensitivity analyses may be conducted in case the robustness of MAR assumption is 
questionable.
Effect of disease progression on PRO
A supportive analysis will be performed to assess the effects of disease progression and 
treatment on global health status/quality of life. A constrained longitudinal data analysis (cLDA) 
model will be applied, with the PRO score as the response variable, and treatment by study visit 
interaction, stratification, and progression status (time-varying) as covariates.
The cLDA model is specified as follows:
,...
3,2,1,0
    
,
...
3,2
,1
    
,
)
0
(
)
(
0







t
j
Z
X
t
I
Y
E
t
j
i
jt
ijt




, where Yijt is the PRO score 
for subject i, with treatment assignment j, at visit t, 
0

is the baseline mean for all treatment 
groups,
jt

is the mean change from baseline for treatment group j at time t, 
i
X is the 
stratification factor vector for this patient, is the coefficient vector for stratification factors, 
j
is the disease progression effect for treatment j, and 
t
Z is the progression status at visit t.
The point estimate of the effect of disease progression on the lsmean PRO score change from 
baseline will be reported, together with 95% C.I., overall and by treatment groups.
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Analysis of the Proportions of Deterioration/Stable/Improvement
Patients’ post-baseline PRO score will be classified as “improved” “stable” or “deteriorated” 
according to a 10 points or greater change (out of 100) for each of the instrument/scale, as this 
magnitude of change is perceived by patients as being clinically significant [36]. The number 
and proportion of patients who “improved”, “stable”, or “deteriorated”, from baseline will be 
summarized by treatment group and at week 3, 6, 9, 15 and 21.
Since missing data cannot be ignored at week 15 or week 21, additional summaries of 
deterioration/stable/improvement will be provided based on multiply-imputed data sets to handle 
the issue of missing data at week 15 and potentially at 21 weeks (if the completion rate in the 
control arm is larger than 50%). Specifically, proportions will be calculated based on the 
multiply imputed data sets in the PRO score analysis, and then synthesized based on Rubin’s 
rule. Proportions based on MAR imputation will be the primary result for proportions of 
deterioration/stable/improvement.
Analysis of the Time to Deterioration
The time-to-deterioration is defined in as the time to first onset of 10 or more decrease from 
baseline under censoring rule shown in Table 11. The non-parametric Kaplan-Meier method will 
be used to estimate the TTD in each group. The treatment difference in time-to-deterioration 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. 
The hazard ratio, 95% confidence interval, and p-value will be reported. The same stratification 
factors used for randomization (as defined by study protocol, Section 5.4) will be used in the 
stratified Cox PH model.
Table 11 Censoring Rules for Time-to-Deterioration 
Scenario
Outcome
No baseline assessments
Right censored at treatment start date
Deterioration documented
Event observed at time of assessment (first 
deterioration)
Ongoing or discontinued from study without 
deterioration
Right censored at time of last assessment
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Compliance Summary
Completion and compliance of QLQ-C30 and EQ-5D by visit and by treatment will be described 
within the PRO FAS population. Numbers and percentages of complete and missing data at each 
visit will be summarized for each of the treatment groups.
Completion Rate in the FAS population is defined as the percentage of the number of subjects 
who complete at least one item over the number of subjects in the FAS population at each time 
points.
	
 
	 = 	  	
 ℎ 	
	 
 	
 	 
	
	  	
  
ℎ	  

The completion rate is expected to shrink in the later visit during study period due to the subjects 
who discontinued early. Therefore, another measurement, Compliance Rate, defined as the 
percentage of observed visit over number of eligible subjects who are expected to complete the 
PRO assessment (not including the subjects missing by design (such as death, discontinuation, 
translation not available) will be employed as the support for completion rate).
	 
	 = 
	  	
 ℎ 	
	 
 	
 	 
	
	  	 	
 ℎ 	  	
	! 
 	
	
The reasons of non-completion and non-compliance will be provided in supplementary table:
–
Completed as scheduled
–
Not completed as scheduled
–
Off-study: not scheduled to be completed.
In addition, reasons for non-completion as scheduled of these measures will be collected using 
“miss_mode” forms filled by site personnel, and will be summarized in table format. An 
instrument is considered complete as at least one valid score available according to the missing 
item rules outlined in the EORTC Manual.
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