A Phase II Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy for Metastatic Triple-Negative Breast Cancer (mTNBC) - (KEYNOTE-086)
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02447003
8-Dec-2017
Document Date: 
A Phase II Clinical Trial of Pembrolizumab (MK-3475) as 
Monotherapy for Metastatic Triple-Negative Breast Cancer 
(mTNBC) – (KEYNOTE-086)

Product:  MK-3475 
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Protocol/Amendment No.: 086-02
MK-3475-086-02 Final Protocol
8-Dec-2017
Confidential
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 II Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy for Metastatic 
Triple-Negative Breast Cancer (mTNBC) – (KEYNOTE-086)
IND NUMBER:  124,442
EudraCT NUMBER:  2015-000294-13
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
2.1
Trial Diagram........................................................................................................ 17
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 21
Primary Objective(s) & Hypothesis(es) .............................................................. 21
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 21
3.2
Exploratory Efficacy Objectives (*centrally confirmed) .................................. 21
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 22
Background ........................................................................................................... 22
4.1
Pharmaceutical and Therapeutic Background .................................................... 22
4.1.1
Rationale................................................................................................................ 26
4.2
Rationale for the Trial and Selected Subject Population .................................... 26
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 31
4.2.2
Rationale for Endpoints ...................................................................................... 32
4.2.3
4.2.3.1
Efficacy endpoints ....................................................................................... 32
4.2.3.2
Safety endpoints........................................................................................... 33
4.2.3.3
PD-L1 Biomarker Endpoint......................................................................... 34
4.2.3.4
Pharmacokinetic Endpoints ......................................................................... 34
4.2.3.5
Biomedical Exploratory Endpoints.............................................................. 34
4.2.3.6
Future Biomedical Research........................................................................ 36
Benefit/Risk ........................................................................................................... 36
4.3
5.0
METHODOLOGY ................................................................................................... 37
Entry Criteria........................................................................................................ 37
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 37
5.1.1
Subject Inclusion Criteria.................................................................................... 37
5.1.2
Subject Exclusion Criteria .................................................................................. 39
5.1.3
 
 
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Trial Treatment(s) ................................................................................................ 41
5.2
Dose Selection/Modification .............................................................................. 41
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 41
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 42
Timing of Dose Administration .......................................................................... 46
5.2.2
Trial Blinding/Masking....................................................................................... 46
5.2.3
Randomization or Treatment Allocation............................................................ 46
5.3
Stratification.......................................................................................................... 46
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 47
5.5
Acceptable Concomitant Medications ................................................................ 47
5.5.1
Prohibited Concomitant Medication ................................................................... 47
5.5.2
Rescue Medications & Supportive Care............................................................. 48
5.6
Diet/Activity/Other Considerations..................................................................... 49
5.7
Diet...................................................................................................................... 49
5.7.1
Contraception...................................................................................................... 50
5.7.2
Use in Pregnancy ................................................................................................ 50
5.7.3
Use in Nursing Women....................................................................................... 51
5.7.4
Subject Withdrawal/Discontinuation Criteria................................................... 51
5.8
Discontinuation of Study Therapy after CR ....................................................... 52
5.8.1
Subject Replacement Strategy............................................................................. 52
5.9
Beginning and End of the Trial ........................................................................... 53
5.10
Clinical Criteria for Early Trial Termination ................................................... 53
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 54
Initial Treatment Phase........................................................................................ 54
6.1
Second Course Phase (Retreatment)................................................................... 58
6.2
7.0
TRIAL PROCEDURES ........................................................................................... 60
Trial Procedures ................................................................................................... 60
7.1
Administrative Procedures.................................................................................. 60
7.1.1
7.1.1.1
Informed Consent......................................................................................... 60
General Informed Consent.................................................................... 60
7.1.1.1.1
Consent and Collection of Specimens for Future Biomedical 
7.1.1.1.2
Research................................................................................................ 61
 
 
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7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 61
7.1.1.3
Subject Identification Card .......................................................................... 61
7.1.1.4
Medical History ........................................................................................... 61
Disease Details...................................................................................... 61
7.1.1.4.1
Menopausal Status ................................................................................ 61
7.1.1.4.2
7.1.1.5
Prior and Concomitant Medications Review ............................................... 62
Prior Medications.................................................................................. 62
7.1.1.5.1
Prior Treatment Details for Breast Cancer..................................... 62
7.1.1.5.1.1
Concomitant Medications..................................................................... 62
7.1.1.5.2
Subsequent Anti-cancer Therapy Status ........................................ 62
7.1.1.5.2.1
7.1.1.6
Assignment of Screening Number............................................................... 62
7.1.1.7
Assignment of Randomization Number....................................................... 62
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 63
Clinical Procedures/Assessments........................................................................ 63
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 63
7.1.2.2
Physical Exam.............................................................................................. 63
Full Physical Exam ............................................................................... 63
7.1.2.2.1
Directed Physical Exam........................................................................ 64
7.1.2.2.2
7.1.2.3
Vital Signs.................................................................................................... 64
7.1.2.4
12-Lead Electrocardiogram ......................................................................... 64
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 64
7.1.2.6
Tumor Imaging and Assessment of Disease................................................ 64
Baseline Tumor Imaging ...................................................................... 65
7.1.2.6.1
On Study Tumor Imaging ..................................................................... 65
7.1.2.6.2
Bone Scans and X-Rays........................................................................ 66
7.1.2.6.3
RECIST 1.1........................................................................................... 66
7.1.2.6.4
irRECIST .............................................................................................. 66
7.1.2.6.5
Laboratory Procedures/Assessments .................................................................. 68
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 68
7.1.3.2
Blood for Menopausal Status....................................................................... 70
7.1.3.3
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 70
Blood Collection for Serum Pembrolizumab Pharmacokinetics -
7.1.3.3.1
PK ......................................................................................................... 71
 
 
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Blood Collection for Anti-Drug (Pembrolizumab) Antibodies -
7.1.3.3.2
ADA...................................................................................................... 71
7.1.3.4
Tumor Tissue Collection.............................................................................. 71
7.1.3.5
Correlative Blood Collections – Samples for Correlative, Genetic, and 
Circulating MDSC Analyses ....................................................................... 72
7.1.3.6
Future Biomedical Research........................................................................ 72
Other Procedures................................................................................................. 73
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 73
Withdrawal From Future Biomedical Research ................................... 73
7.1.4.1.1
7.1.4.2
Blinding/Unblinding .................................................................................... 73
7.1.4.3
Calibration of Critical Equipment................................................................ 74
Visit Requirements.............................................................................................. 74
7.1.5
7.1.5.1
Screening...................................................................................................... 74
7.1.5.2
Treatment Cycles ......................................................................................... 75
Second Course Phase (Retreatment Period) ......................................... 75
7.1.5.2.1
7.1.5.3
Post-Treatment............................................................................................. 76
Discontinuation Visit ............................................................................ 76
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 76
7.1.5.3.2
Follow-up Visits ................................................................................... 77
7.1.5.3.3
Survival Follow-up ............................................................................... 77
7.1.5.3.4
7.1.5.4
Survival Status ............................................................................................. 77
Assessing and Recording Adverse Events .......................................................... 77
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 78
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 79
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 79
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 79
7.2.3.2
Events of Clinical Interest............................................................................ 80
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 82
Evaluating Adverse Events ................................................................................. 82
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 85
7.2.5
Trial Governance and Oversight......................................................................... 85
7.3
Data Monitoring Committee ............................................................................... 85
7.3.1
 
 
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8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 85
Statistical Analysis Plan Summary ..................................................................... 85
8.1
Statistical Analysis Plan ....................................................................................... 86
8.2
Responsibility for Analyses/In-House Blinding ................................................. 86
8.2.1
Hypotheses/Estimation ....................................................................................... 87
8.2.2
Analysis Endpoints ............................................................................................. 87
8.2.3
8.2.3.1
Efficacy Endpoints....................................................................................... 87
8.2.3.2
Safety Endpoints .......................................................................................... 88
8.2.3.3
Biomarker Endpoints ................................................................................... 88
8.2.3.4
Pharmacokinetic Endpoints ......................................................................... 88
8.2.3.5
Other Endpoints ........................................................................................... 88
Analysis Populations........................................................................................... 89
8.2.4
8.2.4.1
Efficacy Analysis Populations ..................................................................... 89
8.2.4.2
Safety Analysis Populations ........................................................................ 89
Statistical Methods.............................................................................................. 89
8.2.5
8.2.5.1
Statistical Methods for Efficacy Analyses ................................................... 89
8.2.5.2
Statistical Methods for Safety Analyses ...................................................... 91
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses....................................................................................................... 92
Demographic and Baseline Characteristics .......................................... 92
8.2.5.3.1
Multiplicity ......................................................................................................... 92
8.2.6
Sample Size and Power Calculations.................................................................. 92
8.2.7
Subgroup Analyses and Effect of Baseline Factors ............................................ 97
8.2.8
Interim Analyses ................................................................................................. 97
8.2.9
Compliance (Medication Adherence) ............................................................... 100
8.2.10
Extent of Exposure............................................................................................ 101
8.2.11
Other Analyses.................................................................................................. 101
8.2.12
8.2.12.1 Biomarker Analyses................................................................................... 101
8.2.12.2 Other Exploratory Analysis ....................................................................... 101
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 101
Investigational Product ...................................................................................... 101
9.1
Packaging and Labeling Information ............................................................... 101
9.2
 
 
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Clinical Supplies Disclosure............................................................................... 102
9.3
Storage and Handling Requirements................................................................ 102
9.4
Discard/Destruction/Returns and Reconciliation ............................................ 102
9.5
Standard Policies................................................................................................. 102
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 102
Confidentiality..................................................................................................... 102
10.1
Confidentiality of Data ..................................................................................... 102
10.1.1
Confidentiality of Subject Records ................................................................... 103
10.1.2
Confidentiality of Investigator Information...................................................... 103
10.1.3
Confidentiality of IRB/IEC Information........................................................... 103
10.1.4
Compliance with Financial Disclosure Requirements..................................... 104
10.2
Compliance with Law, Audit and Debarment ................................................. 104
10.3
Compliance with Trial Registration and Results Posting Requirements ...... 106
10.4
Quality Management System............................................................................. 106
10.5
Data Management............................................................................................... 106
10.6
Publications ......................................................................................................... 107
10.7
11.0
LIST OF REFERENCES....................................................................................... 109
12.0
APPENDICES......................................................................................................... 116
Merck Code of Conduct for Clinical Trials...................................................... 116
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 118
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 124
ECOG Performance Status................................................................................ 135
12.4
Abbreviations ...................................................................................................... 136
12.5
13.0
SIGNATURES......................................................................................................... 140
Sponsor's Representative ................................................................................... 140
13.1
Investigator.......................................................................................................... 140
13.2
 
 
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LIST OF TABLES
Table 1
Efficacy of Currently Used Monotherapy Regimens in mTNBC......................... 30
Table 2
Adequate Organ Function Laboratory Values ...................................................... 39
Table 3
Trial Treatment ..................................................................................................... 41
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab....................................................... 43
Table 5
Infusion Reaction Treatment Guidelines .............................................................. 49
Table 6
irRECIST: Tumor Imaging and Treatment after 1st Radiologic 
Evidence of PD or SD, CR or PR......................................................................... 67
Table 7
Laboratory Tests ................................................................................................... 69
Table 8
Evaluating Adverse Events................................................................................... 83
Table 9
Censoring Rules for DOR..................................................................................... 90
Table 10
Analysis Strategy for Primary/Secondary Efficacy Endpoints in 
Cohorts A and C.................................................................................................... 91
Table 11
Summary of Sample Size Calculation .................................................................. 93
Table 12
Two-sided 95% A-C CI of ORR with Different Sample Size.............................. 94
Table 13
Two-sided 95% A-C CI of ORR with 55 Evaluable Subjects.............................. 95
Table 14
Two-sided 95% Exact CI of AE Incidence Rate with 55 Evaluable 
Subjects................................................................................................................. 95
Table 15
Two-sided 95% A-C CI of ORR with 80 or 100 Subjects.................................... 96
Table 16
Two-sided 95% Exact CI of AE Incidence Rate with 80 Evaluable 
Subjects................................................................................................................. 96
Table 17
Probability of Futility under Different True Response Rate§ in PD-L1 
(-)......................................................................................................................... 100
Table 18
Probability to Initiate Cohort C under Different True ORR in PD-L1 
Strong (+)............................................................................................................ 100
Table 19
Product Descriptions........................................................................................... 101
 
 
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LIST OF FIGURES
          
Figure 1
Cohort A: 2L+ Monotherapy for mTNBC - Study Schematic† .......................... 18
Figure 2
Cohort B: 1L Monotherapy for PD-L1 (+) mTNBC - Study 
Schematic†............................................................................................................. 19
Figure 3
Cohort C: Expansion of the PD-L1 strong (+) subpopulation from 
Cohort A - Study Schematic ................................................................................. 20
Figure 4
Decision Tree........................................................................................................ 99
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.2 and Table 4
Dose Modification 
(Escalation/Titration/Other)
Insertion of revised language and revised 
dose modification table that includes 
myocarditis specific guidelines.
To add/clarify language in alignment 
with pembrolizumab current label 
and core data sheet, including 
addition of myocarditis grade 
clarification and actions for dose 
modification evaluations.
2.1
Trial Design 
Clarification that subjects should be 
contacted approximately every 12 weeks.
To 
specify 
the 
timepoints 
for 
survival status assessment during the 
course of the study, during the study 
follow-up period, and after study 
discontinuation, as necessary. 
To introduce flexibility of survival 
status activities to ensure that current 
and complete survival data are 
available at the time of database 
locks.
6.0 
6.1
6.2
Trial Flow Chart
Initial Treatment Phase
Second Course Phase 
(Retreatment)
Amended rows for survival status to 
allow assessment throughout the trial.
Clarification of existing footnotes for 
survival status follow-up.
7.1.5.3.3
Follow-up Visits
Addition of text to enable survival follow-
up activities throughout the study.
7.1.5.3.4
Survival Follow-up (SFU)
Clarification that subjects should be 
contacted approximately every 12 weeks.
Deletion of redundant text that is now 
captured in a separate new section 
(Section 7.1.5.4).
7.1.5.4
New Section: Survival 
Status
Addition of text to enable survival follow-
up activities throughout the study.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number
(s)
Section Title (s)
Description of Change (s)
Rationale
1.0
Trial Summary
Addition of text referring to extension 
study.
To add information on the 
transfer of patients to the 
extension study. 
2.2
Trial Diagram (Figure 1, Figure 2)
Addition of information to trial 
diagrams for extension study.
4.2.2
Rationale for Dose 
Selection/Regimen/Modification
Rationale for dose selection replaced.
To provide the most current 
information supporting a 
pembrolizumab 200 mg fixed 
dose, based on recent data 
obtained in the pembrolizumab 
development program.
4.2.3.4
Pharmacokinetic Endpoints
Clarification that pharmacokinetics 
(PK) of pembrolizumab will be 
explored per existing modeling analysis 
plan.
To allow flexibility regarding PK 
analysis.
5.5.2
Prohibited Concomitant Medication
Clarification of allowed and prohibited 
vaccines.
To update prohibited concomitant 
medications, based on the current 
pembrolizumab label and core 
data sheet.
 
 
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Section Number
(s)
Section Title (s)
Description of Change (s)
Rationale
5.6
Rescue Medications & Supportive 
Care
Addition of cross-reference to Table 4.
Deletion of bulleted description of 
treatment guidance for management of 
adverse events. 
Clarification of guidance in Table 5.
To add a cross-reference the 
section 
containing 
treatment 
guidance 
for 
infusion-related 
AEs, and to reduce repetition. 
To clarify timing of the use of 
epinephrine, and to provide the 
location where further guidance 
is available.
5.8
Subject Withdrawal/
Discontinuation Criteria
Addition of new discontinuation criteria 
in case of malignancy or pneumonitis.
To improve consistency with 
Dose Modification Guidelines
and include all conditions that 
should lead to discontinuation of 
pembrolizumab, based on the 
current pembrolizumab label and 
core data sheet.
5.10
Beginning and End of the Trial
Addition of text referring to the
extension study.
To add information on the 
transfer 
of 
patients 
to 
the 
extension study.
6.1
Initial Treatment Phase
Addition of ‘X’ at discontinuation visit 
to the rows for blood for plasma and 
serum for correlative studies
Correction 
of 
error, 
for 
consistency with Section 7.1.3.5.
 
 
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Section Number
(s)
Section Title (s)
Description of Change (s)
Rationale
7.1.3.3
Pharmacokinetic/Pharmacodynamic 
Evaluations
Clarification that collected PK and anti-
drug antibodies (ADA) samples may 
only be stored at this time.  Further 
analysis may be performed if required.  
Ongoing PK and/or ADA sampling may 
be reduced or discontinued.
The accumulation of robust PK 
and ADA data in the program has 
allowed 
for 
the 
adequate 
characterization 
the 
clinical 
pharmacology of pembrolizumab 
across indications.  Samples will 
be stored and may be analyzed at 
a later date.
7.1.5.2.1
Second Course Phase (Retreatment 
Period)
Treatment duration clarified from one 
year to 17 cycles.
Clarification of text and eligibility 
criteria for second course (retreatment)
in terms of previous pembrolizumab 
treatment cycles.
Addition of eligibility criteria for 
meeting safety criteria and status of the 
study.
Clarification that an objective response 
or disease progression that occurs 
during the Second Course Phase will 
not be counted as an event for the 
primary analysis.
To 
clarify 
the 
number 
of 
treatment 
cycles 
for 
second 
course treatment, and to clarify 
the eligibility requirements for 
second course treatment. 
12.2
Collection and Management of 
Specimens for Future Biomedical 
Research
Reference 2 source corrected for ICH 
E15 guideline.
Correction of
current website 
link.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
A Phase II Study of Pembrolizumab as Monotherapy for Metastatic 
Triple-Negative Breast Cancer (mTNBC)
Trial Phase
II
Clinical Indication
Metastatic Triple-Negative Breast Cancer
Trial Type
Interventional
Type of control
No Treatment Control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Cohort A - Pembrolizumab as 2L+ monotherapy for mTNBC
Cohort B - Pembrolizumab as 1L monotherapy for PD-L1 (+)
mTNBC
Cohort C - Expansion of the PD-L1 strong (+) subpopulation from 
Cohort A
Number of trial subjects
Approximately 285 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 30--36
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, eligible subjects will receive treatment on Day 1 of each 3-week 
dosing cycle.  Treatment with pembrolizumab as single agent will 
continue until disease progression is confirmed by the Investigator/local 
radiology review, unacceptable adverse event(s), intercurrent illness that 
prevents further administration of treatment, Investigator’s decision to
discontinue subject’s treatment with pembrolizumab, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, subject receives 24 months of study medication, 
or administrative reasons requiring cessation of treatment.
Subjects receiving pembrolizumab who attain a complete response (CR)
may consider stopping trial treatment if they meet criteria for holding 
therapy. Subjects who stop trial treatment 24 months after initiation 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 the subject meets the criteria for retreatment after 
experiencing disease progression and the trial is ongoing.
After the end of treatment, each patient will be followed for 30 days for 
adverse event monitoring [serious adverse events (SAEs) and events of 
clinical interest (ECIs) will be collected for 90 days after the end of 
 
 
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treatment or until the patient initiates new anticancer therapy, but for at 
least 30 days after the end of treatment, whichever is earlier].
Subjects who discontinue treatment for reasons other than disease 
progression will have post-treatment follow-up for disease status until 
disease progression, initiating a non-study cancer treatment, death, 
withdrawing consent, becoming lost to follow-up, or the end of the study.
All subjects will be followed by telephone for overall survival (OS) until 
death, withdrawal of consent, becoming lost to follow-up or the end of the
study.
Once the subject has achieved the study objective or study has ended, the 
subject is discontinued from this study and will be enrolled in an extension
study to continue protocol-defined assessments and treatment.
A list of abbreviations used in this document can be found in Section 12.5.
2.0 TRIAL DESIGN
Trial Design
2.1
Definitions
Line of treatment for metastatic triple-negative breast cancer (mTNBC):
Second line and above (2L+) monotherapy: for subjects with centrally confirmed mTNBC, 
who have received at least one systemic treatment for metastatic breast cancer and have 
documented disease progression on or after the most recent therapy.  Subjects must have 
been previously treated with an anthracycline and a taxane in the (neo)adjuvant or metastatic 
setting.
First line (1L) monotherapy: for subjects with centrally confirmed PD-L1 (+) mTNBC, 
who have not received any prior systemic treatment for metastatic breast cancer.
Study cohorts:
Cohort A - Pembrolizumab as 2L+ monotherapy for mTNBC
Cohort B - Pembrolizumab as 1L monotherapy for PD-L1 (+) mTNBC 
Cohort C - Expansion of the PD-L1 strong (+) subpopulation from Cohort A
This is a two-part, non-randomized,
multi-site, open-label trial of pembrolizumab 
monotherapy in subjects with metastatic triple-negative breast cancer (mTNBC).  
Part 1: Approximately 240 subjects will be enrolled in 2 cohorts, Cohort A (2L+
monotherapy for mTNBC independent of PD-L1 status, ~160 subjects) and Cohort B (1L
monotherapy for PD-L1 (+) mTNBC, ~80 subjects) to examine the efficacy and safety of 
single agent pembrolizumab in the treatment of mTNBC. Cohorts A and B will be enrolled 
in parallel.  
Randomization Ratio
N/A
 
 
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The relationship between response to treatment and PD-L1 protein expression in mTNBC 
will be explored in Cohort A. Furthermore, two interim analyses (IA 1 and 2) are planned 
for Cohort A. 
First Interim Analysis: Subjects in Cohort A will initially be enrolled independent of tumor 
PD-L1 status. A futility analysis (Interim Analysis 1, IA 1) will be done on the PD-L1 (-)
subpopulation of Cohort A to evaluate response in this group.  If treatment with 
pembrolizumab is found to be futile in subjects with PD-L1 (-) tumors, then further 
enrollment in Cohort A will be limited to subjects with PD-L1 (+) tumors, including PD-L1 
strong (+) tumors.
Second Interim Analysis: IA 2 may be done in Cohort A to look at responses in subjects 
with PD-L1 strong (+) tumors.  In this subpopulation, at least 10 subjects with PD-L1 strong 
(+) tumors need to be enrolled for response assessment and at least one responder is required 
to consider initiating Part 2 after enrollment in Cohort A is completed.  Additional subjects 
beyond the planned 160 subjects may be enrolled in Cohort A to identify at least 10 subjects 
with PD-L1 strong (+) tumors.
Results of both interim analyses (IA 1 and IA 2) will be reviewed by an internal unblinded 
biomarker statistician who will report the outcome to the clinical team.
Part 2: Taking into account  that higher tumor PD-L1 expression, as determined by a 
prototype immunohistochemistry (IHC) assay, is associated with increased probability of 
response to pembrolizumab in different tumor types, such as advanced NSCLC [Garon et al., 
ESMO 2014], we may examine whether the same holds true in mTNBC. To this effect, if at 
least one responder is observed in 10-15 subjects with PD-L1 strong (+) tumors from Cohort 
A, Part 2 of the study may be initiated.  In this case, up to an additional ~40-45 subjects with 
PD-L1 strong (+) tumors may be enrolled in a third cohort, Cohort C, to expand the PD-L1 
strong (+) subpopulation from Cohort A for further analysis.  Enrollment may continue until 
up to ~55 subjects with PD-L1 strong (+) tumors have enrolled in Cohorts A and C
combined.  Cohort C will not open until Cohort A has been fully enrolled.
The primary efficacy objectives are:
1. Cohort A: To estimate the Objective Response Rate (ORR) to pembrolizumab as 
2L+ monotherapy for PD-L1 (+) centrally confirmed mTNBC and centrally 
confirmed mTNBC independent of PD-L1 status (all comers), based on RECIST 1.1 
as assessed by central imaging vendor.
2. Cohorts A+C: To estimate the ORR to pembrolizumab as 2L+ monotherapy in 
subjects with PD-L1 strong (+) centrally confirmed mTNBC, based on RECIST 1.1 
as assessed by central imaging vendor.
All subjects in this study will be required to provide a fresh biopsy of a tumor lesion to be 
evaluated at a central laboratory for PD-L1 expression by immunohistochemistry (IHC) and 
triple-negative status for breast cancer.  Samples will be sent to a central laboratory for real 
time evaluation to ensure adequate tumor tissue is present and to fulfill eligibility 
requirements.  Subjects must have measureable metastatic disease, based on Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by the central imaging vendor, 
 
 
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and will be treated with single agent pembrolizumab at 200 mg intravenously (IV) every 3 
weeks (Q3W).
Treatment with pembrolizumab monotherapy will continue until disease progression is 
confirmed by the Investigator/local radiology review, unacceptable adverse events (as 
reported by the site), intercurrent illness that prevents further administration of treatment, 
Investigator’s decision to discontinue subject’s treatment with pembrolizumab, subject
withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, completion of 24 months of treatment with pembrolizumab, or 
administrative reasons requiring the cessation of treatment. Subjects who attain complete 
response (CR) confirmed by the Investigator/local radiology review may consider stopping 
trial treatment after receiving at least 24 weeks of treatment and at least two pembrolizumab 
administrations after initial evidence of CR.  Subjects who discontinue treatment after 24 
months of therapy for reasons other than disease progression or intolerability or who 
discontinue treatment after attaining a CR may be eligible for up to one year of retreatment 
after they have experienced disease progression by tumor imaging.  The decision to retreat 
will be at the discretion of the Investigator, only if no cancer treatment was administered 
since the last dose of pembrolizumab, the subject still meets the safety parameters listed in 
the Inclusion/Exclusion criteria and the trial remains open (refer to Section 7.1.5.2.1 for 
further details).  
After treatment discontinuation, each subject will be followed for 30 days for adverse event 
monitoring [serious adverse events (SAEs) and events of clinical interest (ECIs) will be 
collected for 90 days after the end of treatment or until the patient initiates new anticancer 
therapy, but for at least 30 days after the end of treatment, whichever is earlier].  Subjects 
who discontinue for reasons other than disease progression will have post-treatment follow-
up for disease status every 9 weeks (± 7 days) in the first year and every 12 weeks (84 ± 7 
days) after year 1 until disease progression is confirmed by the Investigator/local radiology 
review, a non-study cancer treatment is initiated, consent is withdrawn, death, becoming lost 
to follow-up, or the end of study. After trial discontinuation, all subjects will be followed by 
telephone for overall survival (OS) approximately every 12 weeks or more frequently as 
requested by the Sponsor until death, consent is withdrawn, becoming lost to follow-up, or 
the end of study.
This study will 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
2.2
The trial design for each cohort is depicted in schematics below.
The study will begin by enrolling subjects in Cohorts A and B of Part 1.
 
 
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Cohort A will enroll subjects receiving pembrolizumab as 2L+ monotherapy and is displayed 
in Figure 1.  
Figure 1
Cohort A: 2L+ Monotherapy for mTNBC - Study Schematic†
†
A futility analysis (IA 1) for subjects with PD-L1 (-) tumors will be performed on Cohort A.  During the 
futility analysis, Cohort A will continue to enroll subjects independent of tumor PD-L1 status, provided that 
they have measurable metastatic disease confirmed by the central imaging vendor and submit an evaluable 
new tumor biopsy.  It is possible that following futility analysis, subjects with PD-L1 (-) tumors may be 
excluded from the study, if no benefit was observed in this subgroup.  
††    Confirmed by the Investigator/local radiology review
Subjects must:

have  centrally confirmed mTNBC, and

have received at least one systemic treatment for metastatic breast cancer, and

have documented disease progression on or after the most recent therapy, and

have been previously treated with an anthracycline and a taxane in the 
(neo)adjuvant or metastatic setting, and  

provide evaluable new tumor biopsy for PD-L1 IHC, and

have measurable metastatic disease based on RECIST 1.1 as assessed by the 
central   imaging vendor
Enrollment is independent of tumor PD-L1 status†
~160 subjects will be enrolled for efficacy and for exploring 
whether response to pembrolizumab is associated with PD-L1 
protein expression in mTNBC
Pembrolizumab 200 mg IV Q3W
Progressive Disease†† / 
Cessation of Study Therapy
Protocol Specified 
Follow-up
Rollover to 
extension study
 
 
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Cohort B will enroll subjects receiving pembrolizumab as 1L monotherapy and is displayed 
in Figure 2.
Figure 2
Cohort B: 1L Monotherapy for PD-L1 (+) mTNBC - Study Schematic†
†
Cohort B will enroll subjects in parallel to Cohort A. 
††    Confirmed by the Investigator/local radiology review
Subjects must:

have  centrally confirmed mTNBC, and

have received  no systemic treatment for metastatic breast cancer, and

provide evaluable new tumor biopsy for PD-L1 IHC, and

have measurable metastatic disease based on RECIST 1.1 as assessed by 
the central imaging vendor
Enrollment is limited to subjects with PD-L1 (+) tumors
~80 subjects will be enrolled for efficacy
Pembrolizumab 200 mg IV Q3W
Progressive Disease†† / 
Cessation of Study Therapy
Protocol Specified 
Follow-up
Rollover to 
extension study
 
 
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Cohort C may be initiated, only if at least one responder is observed in at least 10 subjects 
with PD-L1 strong (+) tumors from Cohort A.  Cohort C will start enrolling subjects with 
PD-L1 strong (+) tumors receiving pembrolizumab as 2L+ monotherapy after enrollment in 
Cohort A has been completed and is displayed in Figure 3.
Figure 3
Cohort C: Expansion of the PD-L1 strong (+) subpopulation from Cohort A -
Study Schematic 
††    Confirmed by the Investigator/local radiology review
Progressive Disease†† / 
Cessation of Study Therapy
Protocol Specified 
Follow-up
Pembrolizumab 200 mg IV Q3W
Subjects must:

have centrally confirmed mTNBC, and

have received at least one systemic treatment for metastatic breast cancer, and

have documented disease progression on or after the most recent therapy, and

have been previously treated with an anthracycline and a taxane in the 
(neo)adjuvant or metastatic setting, and  

provide evaluable new tumor biopsy for PD-L1 IHC, and

have measurable metastatic disease based on RECIST 1.1 as assessed by the 
central imaging vendor 
Enrollment is limited to subjects with PD-L1 strong (+) tumors
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1. Objective (Cohort A): To estimate the Objective Response Rate (ORR) to 
pembrolizumab as 2L+ monotherapy for PD-L1 (+) centrally confirmed mTNBC and 
centrally confirmed mTNBC independent of PD-L1 status (all comers), based on 
RECIST 1.1 as assessed by the central imaging vendor.
2. Objective (Cohorts A+C): To estimate the ORR to pembrolizumab as 2L+
monotherapy in subjects with PD-L1 strong (+) centrally confirmed mTNBC, based 
on RECIST 1.1 as assessed by the central imaging vendor.
3. Objective (Cohorts A-C): To determine the safety and tolerability of pembrolizumab
monotherapy for mTNBC across cohorts and by PD-L1 status within lines of 
treatment for mTNBC.
Secondary Objective(s) & Hypothesis(es)
3.2
Key Secondary Objectives (*centrally confirmed):
1. Objective: To estimate the Duration of Response (DOR) to pembrolizumab as 2L+ 
monotherapy for PD-L1 (+) mTNBC* (Cohort A), mTNBC* independent of PD-L1 
status (Cohort A), and PD-L1 strong (+) mTNBC* (Cohorts A+C), based on 
RECIST 1.1 as assessed by the central imaging vendor.  
2. Objective: To estimate the Disease Control Rate (DCR), Progression-Free Survival 
(PFS) and Overall Survival (OS) in patients receiving pembrolizumab as 2L+ 
monotherapy for PD-L1 (+) mTNBC* (Cohort A), mTNBC* independent of PD-L1 
status (Cohort A), and PD-L1 strong (+) mTNBC* (Cohorts A+C), based on 
RECIST 1.1 as assessed by the central imaging vendor.
Other (non-key) Secondary Objectives (*centrally confirmed):
1. Objective (Cohort B):  To estimate the antitumor efficacy (as measured by ORR, 
DOR, DCR, PFS, and OS) of pembrolizumab as 1L monotherapy for PD-L1 (+)
mTNBC*, based on RECIST 1.1 as assessed by the central imaging vendor.
2. Objective (Cohort A): To explore the association between PD-L1 protein expression 
by IHC and antitumor efficacy of pembrolizumab in 2L+ monotherapy mTNBC
based on RECIST 1.1 as assessed by the central imaging vendor.
Exploratory Efficacy Objectives (*centrally confirmed)
3.3
1. Objective: To estimate
the antitumor efficacy of pembrolizumab as 2L+ 
monotherapy for PD-L1 (+) mTNBC* (Cohort A), mTNBC* independent of PD-L1 
status (Cohort A), and PD-L1 strong (+) mTNBC* (Cohorts A+C), based on 
immune-related Response Evaluation Criteria in Solid Tumor (irRECIST) as assessed 
by the central imaging vendor.  
 
 
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2. Objective (Cohort B):  To estimate the antitumor efficacy of pembrolizumab as 1L 
monotherapy for PD-L1 (+) mTNBC*, based on irRECIST as assessed by the central 
imaging vendor.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pharmaceutical and Therapeutic Background
4.1.1
Programmed Death-1 (PD-1) checkpoint inhibition and cancer treatment.  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 prognosis in various 
malignancies [2-14].  In particular, the presence of (Cluster of Differentiation 8 positive) 
CD8+ T cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory T cells seem to 
correlate with improved prognosis and long-term survival in many solid tumors [10, 15-21].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control [22].  The normal function of PD-1, expressed on the cell surface of 
activated T cells under healthy conditions, is to down-modulate unwanted or excessive 
immune responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is 
an immunoglobulin (Ig) superfamily member related to CD28 and Cytotoxic T-Lymphocyte-
Associated Protein 4 (CTLA-4), which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structures of 
murine PD-1 alone [23] and in complex with its ligands were first resolved [24, 25], and 
more recently the nuclear magnetic resonance (NMR)-based structure of the human PD-1 
extracellular region and analyses of its interactions with its ligands were also reported [26].  
PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-
type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) 
and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T cell stimulation, 
PD-1 recruits the tyrosine phosphatases Src-Homology 2 domain-containing phosphatase-1 
and -2 (SHP-1 and SHP-2) to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules, such as CD3ζ, Protein Kinase C theta (PKCθ) and 
Zeta-chain-Associated Protein kinase 70 (ZAP70), which are involved in the CD3 T cell 
signaling cascade [27].  The mechanism by which PD-1 down-modulates T cell responses is 
similar to, but distinct from that of CTLA-4 [28].  PD-1 was shown to be expressed on 
activated lymphocytes, including peripheral CD4+ and CD8+ T cells, B cells, regulatory T 
cells (Tregs) and Natural Killer (NK) cells [29]. Expression has also been shown during 
thymic development on CD4-CD8- (double negative) T cells [30], as well as subsets of 
macrophages [31] and dendritic cells [32]. The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types [33]. PD-L1 is expressed 
 
 
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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 [33]. Both ligands are type I 
transmembrane 
receptors 
containing 
both 
Immunoglobulin 
Variable 
(IgV)-
and 
Immunoglobulin Constant (IgC)-like domains in the extracellular region and 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-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.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T cell inhibitor [34, 
35], which, via its interaction with the PD-1 receptor on tumor-specific T cells, plays a 
critical role in immune evasion by tumors [36].  As a consequence, the PD-1/PD-L1 pathway 
is an attractive target for therapeutic intervention in cancer [37].
PD-1 immune checkpoint inhibition - Preclinical studies. 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 ultimately leads to tumor rejection, 
either as a monotherapy or in combination with other treatment modalities [38-44].  Anti-
mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor responses in 
models of squamous cell carcinoma, pancreatic carcinoma, melanoma, acute myeloid 
leukemia and colorectal carcinoma [41, 43-46].  In such studies, tumor infiltration by CD8+ 
T cells and increased interferon gamma (IFN-γ), granzyme B and perforin expression were 
observed, indicating that the mechanism underlying the antitumor activity of PD-1 
checkpoint inhibition involved local infiltration and activation of effector T cell function in 
vivo [43]. Experiments have confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a 
monotherapy, as well as in combination with chemotherapy, in syngeneic mouse tumor 
models (see the Investigator’s Brochure).
Pembrolizumab – Clinical trials. Pembrolizumab [KEYTRUDA® (US); previously known 
as lambrolizumab, MK-3475 and 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. Pembrolizumab was recently 
approved in the United States (US) for the treatment of advanced, unresectable or metastatic 
malignant melanoma, and for use in melanoma patients with disease progression after prior 
treatment with (a) ipilimumab or (b) a BRAF inhibitor, in the case of BRAF V600-mutant 
disease [47]. It is the first anti-PD-1 therapy to receive regulatory approval in the US, and is 
currently under regulatory review in the European Union (EU).
Melanoma (KN 001): Pembrolizumab was administered intravenously at a dose of 10 mg/kg 
every 2 or 3 weeks or 2 mg/kg every 3 weeks in patients with advanced melanoma, both 
those who had received prior treatment with the immune checkpoint inhibitor ipilimumab 
and those who had not. Tumor responses were assessed every 12 weeks. A total of 135 
patients with advanced melanoma were treated. Common adverse events attributed to 
treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low 
grade. The confirmed response rate across all dose cohorts, evaluated by the central imaging
vendor according RECIST 1.1, was 38% [95% confidence interval (CI), 25 to 44], with the 
highest confirmed response rate observed in the cohort that received 10 mg/kg every 2 weeks 
 
 
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(52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who 
had received prior ipilimumab treatment and those who had not (confirmed response rate, 
38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable 
in the majority of patients (median follow-up, 11 months among patients who had a 
response); 81% of the patients who had a response (42 of 52) were still receiving treatment at 
the time of analysis in March 2013. The overall median progression-free survival (PFS)
among the 135 patients was longer than 7 months [48].
In an open-label, international, multicenter expansion cohort of a phase 1 trial, patients (aged 
≥18 years) with advanced melanoma whose disease had progressed after at least two 
ipilimumab doses were randomly assigned with a computer-generated allocation schedule 
(1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 
weeks until disease progression, intolerable toxicity, or consent withdrawal. 173 patients 
received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration 
was 8 months. ORR was 26% at both doses - 21 of 81 patients in the 2 mg/kg group and 20 
of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0·96). Treatment was well 
tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-
related deaths [49].
NSCLC (KN 001): A phase I study included 450 patients with NSCLC who had received 
prior chemotherapy, 305 patients (67.7 %) were eligible for therapy based on PD-L1 tumor 
expression. Strong PD-L1 expression was defined as staining ≥50% of tumor cells, weak PD-
L1 expression was 1-49% of tumor cells. Approximately 25% of samples were classified as 
strong staining [Gandhi et al., AACR Annual Meeting 2014]. Pembrolizumab was 
administered as 10 mg/kg IV every 2 weeks or every 3 weeks. In preliminary data reported 
on the 159 patients with tumors that were positive for expression of PD-L1, the response rate 
was 23%, median time to response was 9 weeks, and duration of response was 31 weeks. The 
response rate (RR) was similar for Q2W dosing (26%) or Q3W dosing (21%) prompting an 
expansion of enrollment of an additional cohort of patients with Q3W dosing. In 35 patients 
with tumors that were PD-L1 (-), the response rate was 9%, and median time to response was 
longer at 14 weeks [Garon et al., ASCO 2014]. In treatment-naïve patients, PFS was 27 
weeks with a 24-week PFS rate of 51%. In the same group, median overall survival (OS) had 
not been yet reached and 6-month OS rate was 86%. In previously treated patients, median 
PFS was 10 weeks, and 24-week PFS rate was 26%. The median OS was 8.2 months and 6-
month OS rate was 59%. In pooled population, median PFS was 13 weeks and 24-week PFS 
rate 30%; the median OS was 8.2 months with 6-month OS rate of 64%. The data for PD-L1 
staining using the clinical trial IHC assay was available for nearly half of the patients.  In 
these patients, the objective response rate (ORR), PFS (hazard ratio, HR, 0.52), and OS (HR, 
0.59) were higher in patients with strong PD-L1 expression (≥50% staining) than in patients 
with weak/negative PD-L1 expression [Garon et al., ESMO 2014].
Gastric cancer (KN 012): The safety, tolerability, and antitumor activity of pembrolizumab 
in gastric cancer were assessed in a phase Ib study. PD-L1 expression was assessed in 
archival tumor samples from patients with recurrent/metastatic adenocarcinoma of the 
stomach or gastroesophageal junction. Eligible patients with PD-L1 staining in stroma or 
≥1% of tumor cells were enrolled and treated with pembrolizumab 10 mg/kg every 2 weeks 
for up to 24 months or until complete response, disease progression, or unacceptable toxicity. 
 
 
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Of the 162 patients screened, 65 (40%) were PD-L1-positive of which 39 enrolled: 19 from 
Asia Pacific, 20 from rest of world. Median age was 63 years, and 72% of patients were men. 
Patients from Asia Pacific were more heavily pretreated than patients from rest of world (≥2 
prior therapies in 79% vs 55%). Median follow-up duration was approximately 6 months. 
The ORR (confirmed and unconfirmed) was 31.6% in Asia Pacific and 30% in the rest of 
world. Responses were ongoing for 6/6 Asia Pacific patients and 5/6 patients from the rest of 
world (median response duration not reached; range 8+ to 20+ weeks). The most common 
adverse events deemed treatment-related by investigators were hypothyroidism and fatigue. 
Grade ≥3 adverse events deemed treatment-related occurred in 3 patients (1 each for hypoxia, 
peripheral neuropathy, and pneumonitis). Evidence of an association between PD-L1 
expression and PFS (p = 0.032) and ORR (p = 0.071) was observed [Muro et al., ESMO 
2014].
Urothelial tract cancer (KN 012): Archival or newly obtained tumor samples from patients 
with advanced carcinoma of the renal pelvis, ureter, bladder, or urethra were screened for 
PD-L1 expression using a prototype IHC assay. PD-L1 expression in stroma or ≥1% of 
tumor cells was required for study entry. Patients received pembrolizumab 10 mg/kg every 2 
weeks until complete response, progression, or unacceptable toxicity. Patients deriving 
benefit could remain on pembrolizumab beyond initial progression. Response was assessed 
every 8 weeks per RECIST 1.1 by an independent central imaging vendor (primary efficacy 
endpoint). In total 33 patients were enrolled, including 30 with transitional cell histology and 
3 with non-transitional cell or mixed histology. Median age was 70 years (range 44-85), 70% 
had Eastern Cooperative Oncology Group performance status (ECOG PS) 1, 52% received 
≥2 prior therapies for advanced disease, 21% had liver metastases; and 22 patients (67%) 
received ≥3 pembrolizumab doses. Median follow-up duration was 11 months (range 10-13), 
and 7 patients (21%) remained on therapy. The ORR by the central imaging vendor was 
24.1%, with 10.3% complete responses. Response duration was 16 to 40+ weeks (median not 
reached), with 6 of 7 responses ongoing. In the patients evaluable for response, median PFS 
was 8.6 weeks. In all patients, median OS was 9.3 months (6-months OS rate, 58%). Adverse 
events were reported in 61% of patients (≥1 drug-related), most commonly fatigue, 
peripheral oedema, and nausea; 4 patients (12%) reported grade 3-4 drug-related adverse 
events, with only rash seen in more than 1 patient [Plimack et al., ESMO 2014].
Head and neck cancer (KN 012): During screening, PD-L1 expression in archival or newly 
obtained tumor samples was assessed using a prototype IHC assay; PD-L1 expression in 
stroma or ≥1% of tumor cells was required for study entry. Pembrolizumab 10 mg/kg was 
given every 2 weeks until complete response, progression, unacceptable toxicity, physician 
decision, or consent withdrawal. Adverse events were recorded throughout the study. 
Response was assessed every 8 weeks. Primary endpoint was ORR per RECIST 1.1. Out of 
104 head and neck cancer patients screened, 81 (78%) were PD-L1-positive of which 61 
enrolled, and 60 received ≥1 pembrolizumab dose: 23 Human Papilloma Virus (HPV)-
positive, 37 HPV-negative. After a median follow-up of 10.2 months, 15 patients (25%) 
remained on pembrolizumab. The ORR (confirmed and unconfirmed) per RECIST 1.1 by 
investigator review was 20%, and response duration ranged from 8+ to 41+ weeks (median 
not reached). Nine of 11 responders had a smaller target lesion burden at baseline. The ORR 
was similar in HPV-positive and HPV-negative patients, whereas PFS and OS were longer in 
HPV-positive patients. PD-L1 expression was positively correlated with ORR (p = 0.018) 
 
 
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and PFS (p = 0.024). The ORR was 50% in the 12 patients with high PD-L1 expression. 
Drug-related adverse events of any grade occurred in 58% of patients (grade ≥3 in 17%). The 
most common drug-related adverse events were fatigue (18%), pruritus (10%), and nausea 
(8%). There were no drug-related deaths [Chow et al., ESMO 2014].
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung 
cancer, a number of other advanced solid tumor indications and in hematologic malignancies.  
For study details, please refer to the Investigator’s Brochure (IB).
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Excluding basal cell and squamous cell skin cancers, breast cancer is the most commonly 
diagnosed malignancy in women, accounting for 29% of all new cancers.  It is also the 
second leading cause of cancer death (after lung cancer) among women.  About 232,670 new 
cases of breast cancer and 40,000 deaths due to breast cancer are expected in women in the 
United States in 2014 [50].  Triple-negative breast cancer (TNBC) is phenotypically defined 
by a lack of estrogen receptor (ER) and progesterone receptor (PR) expression and the 
absence of human epidermal growth factor receptor-2 (HER2) overexpression and/or 
amplification [51].  TNBC represents 15-20% of all breast cancers [52] and is overlapping, 
but not synonymous, with the basal-like subtype defined by gene expression, as about 70% of 
TNBCs have basal-like characteristics [53, 54].
TNBC is a molecularly heterogeneous disease and includes tumor subsets with different 
prognosis.  For example, the claudin-low subtype, which is characterized by low expression 
of claudin genes and often presents with an intense immune cell infiltrate, stem cell features, 
and epithelial-to-mesenchymal transition (EMT), is associated with poor prognosis [55]. 
Recent gene expression profiling has identified up to six distinct TNBC subtypes (two basal-
like, an immunomodulatory, a mesenchymal, a mesenchymal stem-like and a luminal 
androgen receptor subtype) [56].
TNBC is associated with younger age at diagnosis, premenopausal status, African American 
race, more advanced disease stage, higher grade, high mitotic indices, family history of 
breast cancer, Breast Cancer 1 (BRCA1) mutations, and more aggressive behavior than other 
breast cancer subtypes [52].  As reported in a seminal study on TNBC, 34% of all patients 
with TNBC experience distant recurrence with a median distant recurrence-free survival 
(DRFS) of 2.6 years, compared to a distant recurrence rate of 20% and a median DRFS of 5 
years in other breast cancer subtypes; the peak of recurrence for TNBC is within 1-3 years 
after initial diagnosis, and decreases significantly thereafter; patients with TNBC also have 
shorter median OS compared to patients with non-TNBC (4.2 versus 6.0 years) [51].  Finally, 
patients with TNBC tend to relapse with distant metastases rather than local recurrences and 
are more likely to develop visceral metastases, including central nervous system (CNS) 
involvement [57]. 
Treatment of TNBC is challenging and represents an area of unmet medical need, as these 
tumors lack therapeutic targets, such as ER and HER2, and become rapidly resistant to 
 
 
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chemotherapy upon local recurrence and/or metastasis (even though they are often sensitive 
to cytotoxic drugs at initial presentation) [58]. The majority of patients with metastatic 
TNBC (mTNBC) have experienced relapse after neoadjuvant or adjuvant therapy for early or 
locally advanced disease.  In a frequently referenced study, the median OS of all (at any line 
of therapy) patients with mTNBC was 13.3 months; median duration of first line (1L) 
therapy for mTNBC was 11.9 weeks; 80% of patients received second line (2L) therapy with 
a median duration of 9 weeks, and about 50% received third line (3L) therapy with a median 
duration of 4 weeks [59].
Immune checkpoint inhibition for the treatment of TNBC. Several studies have 
demonstrated that presence of tissue infiltrating lymphocytes (TILs) is the most consistent 
prognostic factor in TNBC, thus implicating the immune system in the pathophysiology and 
potentially the treatment of such tumors.  Greater lymphocytic infiltration confers better 
prognosis in TNBC, independent of systemic therapy [60, 61].  In addition, unsupervised 
gene expression profiling of TNBCs has identified a gene signature enriched for cytotoxic 
CD8+ T cell genes and natural killer cell (NKC) activity, which is predictive of good clinical 
outcome [62].  These findings suggest that inhibition of immune checkpoints has the 
potential to improve TNBC prognosis by increasing the efficacy of tumor-associated immune 
response in eliminating breast cancer cells [63]. 
Targeting the PD-1 immune checkpoint for the treatment of TNBC. The PD-1 ligand, 
PD-L1, is not detected in normal breast tissue, but has been reported to be expressed in about 
half of all breast cancers, particularly in hormone receptor (HR)-negative and high grade, 
proliferative tumors [64].  In addition, the presence of regulatory T cells, tumor PD-L1 
expression, and PD-1–positive TILs has been associated with high histologic grade, ER 
negativity, and prominent tumor lymphocytic infiltration [65]. In an independent study, PD-
L1 was found expressed in 23% of breast cancer specimens and it was again associated with 
age, tumor size, American Joint Committee on Cancer (AJCC) primary tumor classification, 
tumor grade, lymph node status, absence of ER expression, and high expression of the 
proliferation marker Ki-67 [66].  A recent publication reported that PD-L1 messenger 
ribonucleic acid (mRNA) is expressed in nearly 60% of breast tumors, independently of HR 
status, and is positively correlated with PD-L1 protein expression and increased TILs [67].  
Another study mining the Cancer Genome Atlas (TCGA) RNA sequencing data showed that 
PD-L1 gene expression is significantly higher in TNBCs compared to non-TNBCs, and is 
associated with Phosphatase and TEnsin Homolog (PTEN) loss; in the same study, PD-L1 
was found expressed in 20% of TNBCs [68].  Finally, in an abstract presented in the 2014 
American Society of Clinical Oncology (ASCO) Annual meeting, it was reported that PD-L1 
protein levels are positively correlated with expression of other immune regulators, such as 
CTLA-4 and Indoleamine 2,3-DiOxygenase 1 (IDO1), and with androgen receptor (AR)-
negative and BRCA1-mutant TNBC (Basu et al).  Despite their discordance in the reported 
absolute PD-L1 levels in breast tumors, the aforementioned studies clearly demonstrate that 
TNBCs are characterized by PD-L1 positivity and presence of TILs, and thus suggest that 
PD-1 immune checkpoint inhibition is a therapeutic strategy worthy of further investigation 
for the treatment of this aggressive breast cancer subtype.  
KN 012 - Clinical data supporting pembrolizumab use for the treatment of mTNBC.  In 
the first report of clinical activity of an immune checkpoint inhibitor in TNBC, a Merck-
 
 
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sponsored multi-center, non-randomized Phase Ib trial (KN 012) showed that single agent 
pembrolizumab given at 10 mg/kg Q2W is a well-tolerated and effective treatment with 
significant therapeutic activity in a subset of heavily pre-treated patients with mTNBC.  
Methods: PD-L1 expression in ≥1% tumor cells or in stroma [i.e., PD-L1 (+) mTNBC)] was 
required for study entry.  Tumor PD-L1 status was determined by immunohistochemical 
analysis of archival tumor specimens using the Merck proprietary 22C3 antibody.  Primary 
objectives of this study were to determine the safety, tolerability, and antitumor activity of 
pembrolizumab in patients with PD-L1 (+) mTNBC. Secondary objectives included
assessments of progression-free survival (PFS), overall survival (OS), and duration or 
response (DOR).  Adverse events (AEs) reported in any patient receiving at least 1 dose of 
study treatment were monitored and graded using National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v. 4.0).  Radiographic 
imaging was obtained every 8 weeks and evaluated by both investigator and an independent 
radiologist to assess clinical responses as defined by RECIST 1.1. 
Results: A total of 32 female patients with a median age of 50.5 years (range 29-72 years) 
and PD-L1 (+) mTNBC were enrolled in the study. Most of these patients had received and 
progressed on multiple lines of therapy for advanced disease (the median number of prior 
treatments in the metastatic setting was 3). According to data through 06-Nov-2014, five 
patients (15.6%) experienced at least one drug-related serious adverse event (SAE); each of 
four patients experienced one of the following: Grade 3 anemia, headache, aseptic meningitis 
or pyrexia, and a fifth patient experienced Grade 5 disseminated intravascular coagulation 
(DIC) with thrombocytopenia and decreased blood fibrinogen. Of the 27 patients with 
centrally confirmed measurable disease, one patient (3.7%) had a complete response (CR), 4
patients (14.8%) had a confirmed partial response (PR), 25.9% had stable disease (SD), and 
44.4% had progressive disease (PD), as assessed by the central imaging vendor. As of 06-
Nov-2014, the median duration of response had not been reached (range 15 to 40+ weeks),
and three patients (1 CR; 2 PR) were still on treatment after at least 11 months.
KN 086: Subjects receiving pembrolizumab as 2L+ monotherapy for mTNBC (Cohorts 
A and C)
1. Rationale for using pembrolizumab as 2L+ monotherapy for mTNBC. Patients 
with TNBC whose disease has progressed on at least one systemic treatment for 
mTNBC have dismal prognosis with a median PFS of 2-3 months and OS of 9-12 
months [75].  Nearly all have been previously treated with anthracycline(s) and 
taxane(s), and will receive single agent chemotherapy as a 2L+ regimen [75].  As no 
specific chemotherapy has been established as standard of care (SOC) for mTNBC, 
any of the following drugs may be used: another taxane, capecitabine, gemcitabine, 
vinorelbine, eribulin, liposomal doxorubicin, ixabepilone.  To date, no mTNBC-
focused clinical trial has evaluated the efficacy of any of the above mentioned agents; 
historical data comes from pre-specified (1 study) and, more commonly, retrospective 
TNBC subgroup analysis of randomized Phase III studies in metastatic breast cancer 
(mBC), all subtypes or excluding HER2-positive disease) (Table 1). In a retrospective 
TNBC subgroup analysis of the randomized Phase III RIBBON-2 trial, which 
investigated the combination of bevacizumab with chemotherapy for metastatic breast 
 
 
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cancer (mBC) [76], single agent taxane, gemcitabine, capecitabine, or vinorelbine as 
2L mono-therapy for mTNBC resulted in an ORR of 18%, PFS of 2.7 months, and 
OS of 12.6 months [77]. In the EMBRACE Phase III open-label, randomized study 
comparing eribulin to treatment of physician’s choice (TPC, including single agent 
taxane, gemcitabine, capecitabine, vinorelbine) as 3L+ therapy for mBC (all 
subtypes), eribulin was superior to TPC for all mBC subtypes considered collectively, 
as it showed an ORR of 12%, PFS of 3.7 months, and OS of 13.1 months compared 
to ORR of 5%, PFS of 2.1 months, and OS of 10.6 months (HR 0.81; P = 0.041) for 
TCP. Eribulin was most effective in patients with hormone-receptor (HR)-negative 
tumors and TNBCs, who had a 34% and 29% reduction in risk of death, respectively; 
according to retrospective subgroup analysis, for eribulin-treated TNBC patients, 
ORR was not reported, PFS was 2.8 months and OS was 12.4 months [78].  In the 
Phase III study comparing the combination of capecitabine and ixabepilone to single 
agent capecitabine as 2L+ treatment for mBC, capecitabine showed an ORR of 9%, 
PFS of 2.1 months, and OS of 9 months in mTNBC, according to a pre-specified 
subgroup analysis [79]. As mentioned earlier, the response rate to pembrolizumab 
monotherapy in PD-L1 (+) mTNBC was 18.5% based on RECIST 1.1 as assessed by 
the central imaging vendor (KN 012) and, as of 06-Nov-2014, the median duration of 
response had not been reached (range 15 to 40+ weeks) and 3 patients (1 SD, 2 PR) 
were still on treatment after at least 11 months.  Based on these data, and taken into 
account the results from published studies [77-79], pembrolizumab is active (and 
well-tolerated) as monotherapy in heavily pretreated patients with mTNBC and, thus, 
worthy of further investigation.
 
 
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Table 1
Efficacy of Currently Used Monotherapy Regimens in mTNBC
Study
Line 
Tx
Drug/Drug 
Combo
ORR%/PFSmo/OSm
o
Reference
Meta-analysis of 3 Phase 
III 
trials: 
E2100, 
AVADO, 
RIBBON-1 
(TNBC subgroup) 
1L
Paclitaxel 
or 
docetaxel 
or 
cape
23/5.4/17.5
[69]
RIBBON-2 Phase III-
TNBC subgroup
2L
Taxane 
or 
cape or gem 
or vinorelbine
18/2.7/12.6
[77]
Phase III (#301)-
TNBC subgroup
1-3L
Eribulin
NR/NR/14.4
(Kaufman,
SABCS 2012)
Phase III (#301)-
TNBC subgroup  
1-3L
Cape
NR/NR/9.4
EMBRACE Phase III 
TNBC subgroup 
*mBC, all subtypes
3L+
Eribulin
(12)*/2.8/12.4
[78]
EMBRACE Phase III-
*mBC, all subtypes
3L+
Taxanes 
or 
cape or gem 
or vinorelbine 
(5/2.1/10.6)*
Phase 
III-prespecified 
TNBC subgroup analysis
2L+
Capecitabine
9/2.1/9
[79]
2. Rationale for including subjects with PD-L1 (-) tumors in Cohort A. The KN 012 
TNBC proof-of-concept data was obtained in patients with PD-L1 (+) mTNBC 
tumors (i.e., PD-L1 staining in ≥1% tumor cells or in stroma); no data is currently 
available on the performance of pembrolizumab in mTNBC patients with PD-L1 (-)
tumors.  Due to the limited efficacy of treatment options currently available in later 
line mTNBC, patients with PD-L1 (-) tumors may benefit from pembrolizumab.  The 
performance of pembrolizumab in these patients will be explored and a futility 
analysis will be conducted as described in Section 8.1.  Should the efficacy of 
pembrolizumab be non-futile in this subgroup, then enrollment of patients with PD-
L1 (-) tumors will continue in future studies.
3. Rationale for investigating the antitumor efficacy of pembrolizumab as 2L+ 
monotherapy for PD-L1 strong (+) mTNBC (Cohorts A+C).
Results from KN 
012 suggested that higher PD-L1 score by IHC may be associated with increased 
probability of response to pembrolizumab in mTNBC (logistic regression analysis 
 
 
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showed statistical significance with one-sided p-value of 0.020). Furthermore, ORR, 
PFS (HR 0.52), and OS (HR 0.59) in response to pembrolizumab monotherapy for 
advanced NSCLC were higher in patients with strong PD-L1 expression (≥50% 
staining) than in patients with weak/negative PD-L1 expression (<50%) [Garon et al., 
ESMO 2014]; evidence of an association between PD-L1 expression and PFS (p = 
0.032) and ORR (p = 0.071) was also observed in gastric cancer [Muro et al., ESMO 
2014].
KN 086: Subjects receiving pembrolizumab as 1L monotherapy for mTNBC (Cohort B)
Rationale for investigating pembrolizumab as 1L monotherapy for PD-L1 (+)
mTNBC. As mentioned above, the TNBC proof-of-concept data available from KN 
012 is limited to patients with PD-L1 (+) mTNBC tumors. Given that: (1) the 
prevalence of PD-L1 tumor positivity in mTNBC was around 58% in the screening 
phase for subject enrollment to KN 012, (2) the response rate to pembrolizumab 
monotherapy in PD-L1 (+) mTNBC was 18.5% based on RECIST 1.1 as assessed by 
the central imaging vendor (KN 012), (3) similar to NSCLC, subjects with PD-L1 (-)
tumors may benefit less from pembrolizumab monotherapy than subjects with PD-L1 
(+) tumors, and (4) subjects receiving 1L therapy for mTNBC have several treatment 
options, including combination regimens with ORR of 30-40% [69-74] and 
monotherapies with ORR around 23% [69], enrollment to Cohort B will be limited to 
subjects with PD-L1 (+) tumors.  Should treatment with pembrolizumab as 2L+ 
monotherapy be non-futile in the PD-L1 (-) subpopulation from Cohort A, enrollment 
of subjects with PD-L1 (-) tumors will be considered in future larger studies of 
pembrolizumab as 1L monotherapy for mTNBC. 
The objective of Cohort B is to provide further data assessing the performance of 
single agent pembrolizumab as 1L monotherapy for mTNBC to support future trials 
of pembrolizumab as early therapy for mTNBC.  
Rationale for requiring central confirmation of TNBC status. Several studies have 
reported discordance in evaluation of ER, PR and HER2 status between local and central 
laboratories, due to both technical issues in IHC testing and interpretation issues in
fluorescent in-situ hybridization (FISH) testing [80-82]. It is, thus, recommended that central 
testing should be performed to determine trial eligibility, particularly in large studies 
involving multiple collaborating institutions in several countries [80].
Rationale for Dose Selection/Regimen/Modification
4.2.2
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, 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 2 weeks (Q2W)
•
Clinical data showing meaningful improvement in benefit-risk, including overall 
survival at 200 mg Q3W across multiple indications, and
 
 
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•
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based PK analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naive, 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 versus 10 mg/kg 
Q3W (KN001 B2, KN001 D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 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 conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Secondly, 
a physiologically based PK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed dose was 
selected for evaluation across all pembrolizumab protocols.
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy endpoints
The primary efficacy objectives of KN 086 are to estimate the ORR to pembrolizumab as 
2L+ monotherapy for PD-L1 (+) centrally confirmed mTNBC (Cohort A), 
centrally 
confirmed mTNBC independent of PD-L1 status (Cohort A), and PD-L1 strong (+) centrally 
confirmed mTNBC (Cohorts A+C), based on RECIST 1.1 as assessed by the central imaging 
vendor. 
The first key secondary objective is to evaluate the DOR to pembrolizumab as 2L+ 
monotherapy for PD-L1 (+) centrally confirmed mTNBC (Cohort A), centrally confirmed 
 
 
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mTNBC independent of PD-L1 status (Cohort A), and PD-L1 strong (+) centrally confirmed 
mTNBC (Cohorts A+C), based on RECIST 1.1 as assessed by the central imaging vendor.
The second key secondary objective is to estimate the DCR, PFS and OS in subjects 
receiving pembrolizumab as 2L+ monotherapy for PD-L1 (+) centrally confirmed mTNBC
(Cohort A),, centrally confirmed mTNBC independent of PD-L1 status (Cohort A), and PD-
L1 strong (+) centrally confirmed mTNBC (Cohorts A+C), based on RECIST 1.1 as assessed 
by the central imaging vendor.
Other (non-key) secondary efficacy objective is to evaluate the antitumor activity of 
pembrolizumab as 1L monotherapy for PD-L1 (+) centrally confirmed mTNBC (Cohort B), 
based on RECIST 1.1 as assessed by the central imaging vendor. 
Exploratory efficacy objectives are to evaluate the antitumor activity of pembrolizumab as 
2L+ monotherapy for PD-L1 (+) centrally confirmed mTNBC (Cohort A), centrally 
confirmed mTNBC independent of PD-L1 status (Cohort A), and PD-L1 strong (+) centrally 
confirmed mTNBC (Cohorts A+C), based on irRECIST* as assessed by the central imaging 
vendor; also, to evaluate the antitumor activity of pembrolizumab as 1L monotherapy for PD-
L1 (+) centrally confirmed mTNBC (Cohort B), based on irRECIST as assessed by the 
central imaging vendor.
As a supportive analysis, the antitumor activity of pembrolizumab as 2L+ and 1L 
monotherapy for mTNBC will also be evaluated based on RECIST 1.1 as assessed by 
Investigators/local radiology review.  
*Rationale for use of irRECIST criteria: Immunotherapeutic agents may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses, which may 
be functionally anergic prior to treatment. 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 (transient tumor flare). Thus, standard RECIST criteria may not 
provide a complete response assessment of immunotherapeutic agents,
such as 
pembrolizumab.  To address this issue, RECIST 1.1 with the adaptation outlined in Section 
7.1.2.6.5, termed irRECIST, will also be used. 
4.2.3.2
Safety endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with mTNBC (Cohorts A-C).  The primary safety analysis will be 
based on subjects who experienced toxicities as defined by CTCAE, Version 4.0 criteria. 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.
 
 
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4.2.3.3
PD-L1 Biomarker Endpoint
Given a positive correlation between pembrolizumab antitumor activity and PD-L1 tumor 
expression in advanced NSCLC [Garon et al., ESMO 2014] and gastric cancer [Muro et al., 
ESMO 2014], the association between PD-L1 protein expression by IHC and response to
single agent pembrolizumab for mTNBC will be evaluated as a (non-key) secondary 
objective, based on RECIST 1.1 as assessed by the central imaging vendor.
4.2.3.4
Pharmacokinetic Endpoints
Pharmacokinetics of pembrolizumab will be explored per the existing modeling analysis plan 
(MAP). 
4.2.3.5
Biomedical Exploratory Endpoints
Fresh tumor biopsies will be used for PD-L1 assessment by IHC.  Archival tumor biopsies 
will also be obtained, when available, to compare the performance of the PD-L1 IHC assay 
in archived versus fresh biopsies, so that it may be possible to use archival tumor specimens 
in future clinical studies.
Additional biomarker and other biomedical research to identify factors important for 
predicting responsiveness or resistance to pembrolizumab therapy in mTNBC will also be 
pursued.  Pre-treatment, post-treatment and at the time of disease progression tumor biopsies 
and blood samples (including serum and plasma) will be collected. Tumor and blood 
specimens will be evaluated by histopathologic, transcriptional, genomic [including targeted 
next generation sequencing (NGS), whole exome sequencing (WES) and whole genome 
sequencing (WGS)], and proteomic analyses, as described below.
Assays may include, but are not be limited, to:
Immunohistochemistry (IHC)
In addition to determining PD-L1 expression in tumor tissues by IHC as described earlier,
other exploratory biomarkers (e.g. PD-1 expression, markers of T cell phenotype) may also 
be evaluated.
Tissue Infiltrating Lymphocytes (TILs)
TILs have been shown to provide prognostic and potentially predictive value, particularly in 
TNBC [67, 83-85] and HER2-overexpressing breast cancer [84, 86, 87]. Hematoxylin and 
eosin (H&E)-stained breast tumor sections can be evaluated for TILs, according to a recently 
published standardized methodology [3] (Salgado et al. Harmonization of the evaluation of 
TILs in breast cancer: Recommendation by an international TILs-working group 2014. 
Annals Oncology, Epub 9Sept2014).
 
 
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Transcriptional analyses
Messenger RNA (mRNA) expression profiling in tumor specimens and 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.  The hypothesis to be tested is that 
pembrolizumab induces responses in tumors that reflect an inflammatory/immune cell-rich
phenotype based on gene expression signatures capturing PD-L1 and IFN-γ 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.
Genomic analyses
The application of new technologies such as NGS, WES, WGS, has provided the opportunity 
to define certain tumor types at the genetic level as being ‘hypermutated’ and to detect the 
presence of specific T cell clones within the tumor microenvironment or in the peripheral 
blood [88-90].  It is possible that the hypermutated state (and/or increased T cell clonality) or 
the hypomutated state (and/or lack of dominant T cell clones) may correlate with response to 
pembrolizumab in TNBC.  
In addition, understanding somatic and germline genetic determinants of drug response is an 
important endeavor during medical research.  Targeted NGS will be used to evaluate whether 
somatic genetic variations, i.e., in tumors, circulating tumor cells (CTCs) and circulating 
tumor deoxyribonucleic acid (DNA) [91], and/or germline DNA mutations correlate with 
response to pembrolizumab in mTNBC.  Particular emphasis will be placed on the following 
biological determinants/pathways: PhosphoInositide-3-Kinase (PI3K), PTEN, BRCA1/2, 
Epidermal Growth Factor Receptor (EGFR), Mitogen-Activated Protein Kinase Kinase 
(MAPKK, also known as MEK), Fibroblast Growth Factor Receptor (FGFR), Hepatocyte 
Growth Factor Receptor (HGFR, also known as MET), and Notch signaling [92-95]. If 
genetic variation is found to predict efficacy or adverse events, this data might inform 
optimal use of pembrolizumab in future studies enrolling subjects with TNBC.
Proteomic analyses
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released 
into the blood [96].  Enzyme-linked immunoassay can measure PD-L1 in serum and correlate 
this expression with response to pembrolizumab therapy and PD-L1 protein in the tumor.  
Blood would be a less invasive component 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 and/or mass spectrometry.  This 
approach could identify novel protein biomarker(s) that could aid in patient selection for 
pembrolizumab therapy in TNBC.
 
 
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Circulating myeloid-derived suppressor cells
There is recent evidence for increased circulating myeloid-derived suppressor cells (MDSCs) 
in several cancers, and these cells may correlate with increased response of melanoma 
patients to ipilimumab [97].  Using MDSCs as a biomarker could be beneficial, as MDSCs
can be assessed in peripheral blood. In KN 086, MDSCs will be collected prior to treatment 
and at several times following initiation of treatment to explore their potential utility as a 
biomarker that predicts response to pembrolizumab in TNBC.
4.2.3.6
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. 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
4.3
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
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Female and male subjects of at least 18 years of age with metastatic triple-negative breast 
cancer (mTNBC) will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
For Cohorts A and C (2L+ monotherapy), potential subjects must:
1. Have received at least one systemic treatment for metastatic breast cancer and have 
documented disease progression on or after the most recent therapy.  Subjects must 
have been previously treated with an anthracycline and a taxane in the (neo)adjuvant 
or metastatic setting.
Note for Cohort A:  In the event that the interim analysis shows that pembrolizumab 
monotherapy is futile in subjects with PD-L1 (-) mTNBC, subsequent enrollment to
Cohort A may be limited to subjects with PD-L1 (+) tumors.  If this is the case, sites will 
be notified via a Protocol Clarification Letter.
For the purposes of this study, neoadjuvant and/or adjuvant chemotherapy regimens do 
not count as a prior line of therapy.
For Cohort B (1L monotherapy), potential subjects must:
2. Have not received prior systemic anti-cancer therapy for mTNBC, and
3. Have PD-L1 (+) mTNBC.
For the purposes of this study, neoadjuvant and/or adjuvant chemotherapy regimens do
not count as a prior line of therapy.
For Cohort C (2L+ monotherapy), potential subjects must:
4. Have PD-L1 strong (+) mTNBC, i.e. subject’s tumor must meet or exceed the PD-L1 
cut point for high positivity.
For all cohorts, potential subjects must:
5. 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.
6. Be 18 years of age on day of signing informed consent.
7. Be a female or male subject with mTNBC.  Central determination of triple-negative 
breast cancer status is required for enrollment.  
 
 
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8. Have provided tumor tissue for PD-L1 biomarker analysis from a newly obtained 
core or excisional biopsy of a not-previously-irradiated metastatic tumor lesion 
(mandatory).  Adequacy of the biopsy specimen for PD-L1 biomarker analysis must 
be confirmed by the central analysis laboratory.  Repeat samples may be required if 
adequate tissue is not provided. 
a.
Note:  Subjects for whom tumor biopsies cannot be newly obtained (e.g. 
inaccessible tumor or subject safety concern) may submit an archived
metastatic tumor specimen only upon agreement from the Sponsor.
b. Note:  If emerging data demonstrates that there is no difference in the clinical 
utility of PD-L1 assessment in newly obtained samples relative to archived 
ones, then archived samples may be acceptable without Sponsor agreement.  
If this is the case, sites will be notified via an Administrative Memo.
c.
Note:  For subjects with mTNBC at the time of initial breast cancer diagnosis, 
who did not have breast surgery and/or breast radiation therapy, a newly 
obtained core or excisional biopsy from the existing breast tumor mass may be 
obtained for eligibility determination.
9. Have measurable metastatic disease based on RECIST 1.1 as determined by the 
central imaging vendor. Tumor lesions situated in a previously irradiated area are 
considered measurable, if radiographic progression has been demonstrated in such 
lesions.
a.
Note:  The same imaging modality, acquisition and technical parameters 
should be used throughout the study for tumor imaging.
10. Have a performance status of 0 or 1 on the ECOG Performance Scale.  Assessment 
should be performed within 10 days of treatment initiation.
11. 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 childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.
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.
Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
12. Demonstrate adequate organ function as defined in Table 2.  All screening labs 
should be performed within 10 days of treatment initiation.
 
 
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Table 2
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 without transfusion or EPO dependency
Renal
Creatinine OR
Measured or calculateda creatinine clearance
(CrCl)
[Glomerular filtration rate (GFR) can also be 
used in place of creatinine or CrCl]
≤1.5 X upper limit of normal (ULN) OR
≥30 mL/min for subject with creatinine levels > 1.5 X institutional 
ULN
Hepatic
Total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ULN for subjects with total bilirubin levels 
>1.5xULN
Aspartate aminotransferase [AST (SGOT)]
and alanine aminotransferase [ALT (SGPT)]
≤ 2.5 X ULN  
Albumin
≥3.0 g/dL
Lactate Dehydrogenase (LDH)
< 2.5 X ULN
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated 
Partial 
Thromboplastin 
Time 
(aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants
aCreatinine clearance should be calculated per institutional standard.
13. Female subjects of childbearing potential should 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.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy, or has participated in a study 
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.
Note: Subjects who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent or device.
2. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs).  Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
 
 
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replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic 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.  
4. Has had a prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic 
treatment 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 at least 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 alopecia of any grade 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 progressed or required active treatment 
within the last 5 years. 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.
7. Has radiographically detectable (even if asymptomatic and/or previously treated)
central nervous system (CNS) metastases and/or carcinomatous meningitis. Brain
imaging at screening is required.
8. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis or a history of interstitial lung disease..
9. Has an active infection requiring systemic therapy.
10. 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.
11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
12. 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.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with 
an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, 
CD137) or has participated in Merck MK-3475 trials.
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
 
 
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15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
16. Has received a live vaccine within 30 days of planned start of study therapy.
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed.
17. 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)
5.2
The treatment to be used in this trial is outlined below in Table 3.
Table 3
Trial Treatment
Drug
Dose
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 3 week 
cycle
Experimental
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
Study drug 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 will be administered as a 30 minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  Details on preparation and administration of pembrolizumab are 
provided in the Pharmacy Manual.  
 
 
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5.2.1.2
Dose Modification (Escalation/Titration/Other)
Pembrolizumab dose reductions are not applicable to this study.  However, pembrolizumab 
must be withheld for drug-related toxicities and severe or life-threatening AEs as described 
in Table 4 below. If a dose must be held/delayed do not complete a cycle visit until the 
subject is dosed again. When pembrolizumab is restarted, this dose would be considered Day 
1 of the missed cycle.
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These immune-related adverse events (irAEs) may occur 
shortly after the first dose or several months after the last dose of 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 4.  See Section 5.6 for supportive care guidelines, 
including use of corticosteroids.
 
 
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
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 subjects for signs and symptoms of 
pneumonitis

Evaluate subjects 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 subjects 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).

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects 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 subjects with T1DM 

Administer anti-hyperglycemic in 
subjects with hyperglycemia 

Monitor subjects 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:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
AE=adverse event; ALT=alanine aminotransferase; AST= aspartate aminotransferase; CTCAE= Common Toxicity Criteria for Adverse Events; 
GI=gastrointestinal; irAE=immune related adverse event; IV=intravenous; T1DM=Type 1 diabetes mellitus. 
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). 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 as well as in the Sponsor data 
collector.
Timing of Dose Administration
5.2.2
Pembrolizumab should be administered on Day 1 of each three week cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  On Cycle 1 Day 1 trial treatment should begin on the day of allocation or as close as 
possible to the date on which the subject is allocated/assigned. After Cycle 1 Day 1, trial 
treatment may be administered up to 3 days before or 3 days after the scheduled Day 1 of 
each cycle due to administrative reasons.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator, site personnel, and subject 
will know the treatment administered.
The subject-level PD-L1 biomarker results in Cohort A will be masked in the database to the 
investigator and the study team at the Sponsor including clinical, statistical, statistical 
programming, and data management personnel.
Access to the PD-L1 subject-level 
biomarker results will be limited to designated team at the Sponsor (see Section 8.2.1) who 
will be responsible for data review to ensure validity of results but who will have no other 
responsibilities associated with the study. 
Randomization or Treatment Allocation
5.3
Centralized
interactive voice response system / integrated web response system 
(IVRS/IWRS) will be utilized.  Subjects will be assigned to all study therapies in an 
unblinded fashion.  Subjects participating in this trial will be allocated by non-random 
assignment.
Stratification
5.4
No stratification based on age or other characteristics will be used in this trial.
 
 
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Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
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
5.5.1
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 28 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.
Prohibited Concomitant Medication
5.5.2
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 

Radiation therapy
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with Sponsor (except during screening).  

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, rabies, BCG, and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist ®) are 
live attenuated vaccines and are not allowed.
 
 
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
Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest (ECI) of suspected immunologic etiology or from symptomatic brain 
metastasis(es) [also during whole brain radiation therapy (WBRT)].  The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor.
o
Note: Inhaled steroids are allowed for management of asthma.
o
Note:  Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to 
IV contract dye) is permitted.
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.
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
5.6
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined along with the dose modification 
guidelines in Section 5.2.1.2 (Table 4) and in greater detail in the ECI guidance document. 
Where appropriate, these guidelines include the use of oral or intravenous 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 the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document.
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab.
 
 
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Table 5
Infusion Reaction 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 and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration.
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine **
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
 
 
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Contraception
5.7.2
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined 
as 1) surgically sterilized, or 2) postmenopausal (a woman who 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 either 
be 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 study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide as per local regulations or 
guidelines.  Appropriate hormonal contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including oral, 
subcutaneous, intrauterine, or intramuscular agents).
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject.
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
5.7.3
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, 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.
 
 
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Use in Nursing Women
5.7.4
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.  
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
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 
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.

The subject is lost to follow-up
A subject must be discontinued from treatment (but should 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

Confirmed radiographic disease progression per the terms outlined in Section 
7.1.2.6.5
Note: For unconfirmed radiographic disease progression, please see Section 7.1.2.6.5

Unacceptable adverse experiences as described in Section 5.2.1.2

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment

Intercurrent illness other than another malignancy, as noted above, that prevents 
further administration of treatment

Recurrent Grade 2 pneumonitis

Investigator’s decision to withdraw the subject from study treatment

The subject has a confirmed positive serum pregnancy test
 
 
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
Noncompliance with trial treatment or procedure requirements

Completed 24 months of treatment with pembrolizumab 
Note: 24 months of study medication is calculated from the date of first dose.  
Subjects who stop pembrolizumab after 24 months may be eligible for up to one year 
of additional study treatment if they progress after stopping study treatment at 24 
months 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 and events of 
clinical interest will be collected for 90 days after the end of treatment or 30 days after the 
end of treatment if the subject initiates new anticancer therapy, whichever is earlier, 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.
Discontinuation of Study Therapy after CR
5.8.1
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 and had at least two 
treatments with pembrolizumab 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 via the Second Course Phase at the discretion of 
the investigator if:

No cancer treatment was administered since the last dose of pembrolizumab

The subject meets the safety parameters listed in the Inclusion/Exclusion criteria

The trial is ongoing  
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 as the primary 
endpoint in this trial.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
 
 
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Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).  Upon study completion, participants are discontinued and enrolled in a 
pembrolizumab extension study.
Clinical Criteria for Early Trial Termination
5.11
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete as assessed by the 
Sponsor
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. 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
6.1
Trial Period:
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:
-56 to -1
-28 to -1
-10 to -1
± 3d
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days
post discon
(± 3 days)
Every 9 
weeks
post 
discon
(± 7 
days)
Every 12 
weeks
(± 7 days)
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
Clinical Procedures/Assessments
Review Adverse Eventsh
X
X
X
X
X
X
X
X
X
X
Xi
Xi
12-Lead Electrocardiogram [(ECG) 
(Local]
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs, Weight and Heightj
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
Obtain randomization number and study 
drug information using IVRS/IWRS
Xk
Pembrolizumab Administration k
X k
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Status c
<- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ->
X
Laboratory Procedures/Assessments:  
Analysis performed by LOCAL 
 
 
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Trial Period:
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:
-56 to -1
-28 to -1
-10 to -1
± 3d
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days
post discon
(± 3 days)
Every 9 
weeks
post 
discon
(± 7 
days)
Every 12 
weeks
(± 7 days)
laboratory
Pregnancy Test – Serum or Urinel
X
Blood for menopausal status (if 
applicable) m
X
PT/INR and aPTTn
Xo
CBC with Differentialp
Xo
X
X
X
X
Xq
X
Xr
Chemistry Panelp
Xo
X
X
X
X
Xq
X
Xr
Urinalysis
Xo
T3, FT4 and TSHq
Xo
X
X
Xq
Xr
Laboratory Procedures/Assessments:
Analysis performed by CENTRAL 
laboratory
Blood for Pharmacokineticss,t
Xs
Xs
Xs
Xs
Xs
Blood for Anti-Drug (pembrolizumab) 
Antibodiess
Xs
Xs
Xs
Xs
Xs
Blood for Geneticsu
X
Blood for plasma for Correlative Studiesv
X
X
Blood for serum for Correlative Studiesv
X
X
Blood for DNA for Correlative Studiesw
X
X
X
X
Blood for RNA for Correlative Studiesw
X
X
X
X
Blood for MDSC Assaysw
X
X
X
X
Efficacy Measurements
Tumor Imaging
Xx
Xy
Xy
Xz
Xb
Brain Imaging
Xx
Tumor Tissue Collection
Newly Obtained (required) and Archival 
(if available) Tissue Collection for 
biomarker analysisaa
Xaa
Xbb
 
 
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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
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by tumor imaging every 9 weeks (± 7 days)
in the first year and every 12 weeks (84 ± 7 days) after year 1 until (1) the start of new anti-cancer treatment, (2) disease progression as assessed by the investigator/site radiologist, (3) death, or (4) the 
end of the study, whichever occurs first.
c.
After the start of new anti-cancer treatment or documented disease progression as assessed by the Investigator/local radiologist, the subject should be contacted by telephone approximately every 12 
weeks to assess for survival status.  Updated survival status may be requested by the Sponsor at any time during the course of the study.  Upon Sponsor notification, all subjects 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 subjects that have a death event previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted.  Study personnel will access IVRS/IWRS to obtain randomization number and study drug assignment. Cycle 1 treatment must 
be given within 3 days of randomization number assignment in IVRS/IWRS.
e.
Written informed consent must be obtained prior to performing any protocol specified procedure.  Please note that the window for acquiring the “newly obtained” tissue specimen is within 56 days of 
the first dose of study drug and written consent should be obtained prior to acquiring the specimen if a biopsy for the study is performed.  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 window specified for screening procedures (e.g., within 28 days prior to the first dose of trial 
treatment for required lab tests).  Screening number will be assigned when the study 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 28 days of screening visit. Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit.  Record 
all medications taken for SAEs as defined in Section 7.2
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 end of treatment or 
30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.  Afterwards, report only SAEs and ECIs that are related to trial treatment.   
j.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening visit only. Vital signs will be collected at screening, prior to the 
administration of each dose of trial treatment at every cycle and at treatment discontinuation.
k.
Study personnel will access IVRS/IWRS to obtain randomization number and study drug assignment.  Pembrolizumab is given as a 200 mg dose on the first day of each 3 week cycle.   Cycle 1 
treatment must be given within 3 days of randomization number assignment in IVRS/IWRS.  
l.
For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to first dose of trial treatment. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
m.
Blood for menopausal status may be required for certain subjects as described in Section 7.1.3.2.
n.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  
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.
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.  
q.
Blood draws for thyroid function tests should be done prior to dosing at the scheduled timepoint, however results can be reviewed after dosing.  These tests are to be repeated every 2 cycles after Cycle 
6.
r.
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.
s.
Both PK and anti-pembrolizumab antibody for subjects who receive pembrolizumab; Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 6, 8 and every 4 
cycles thereafter, 30 days after discontinuation of study drug, and 3 months after discontinuation of study drug (or until the subject starts new anti-cancer therapy). All pre-dose trough PK samples 
should be drawn within 24 hours before infusion of pembrolizumab.  
t.
PK for pembrolizumab sample collection only: Additional post-dose peak PK samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 8.  An additional single PK 
sample should be drawn at 24 hours (Day 2), between 72 and 168 hours (Day 4-8) and 336 hours (Day 15) after Cycle 1 dosing.
u.
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.  Detailed 
instructions for the collection and management of these specimens are provided in the Procedures Manual and Section 12.2.
v.
Blood for serum and blood for plasma correlative studies is to be collected only predose at Cycle 1. See Procedures Manual. 
w.
Blood samples for RNA, DNA, and MDSCs for correlative studies should be collected predose at Cycles 1, 2, and 3, and again at treatment discontinuation. MDSCs will only be collected in the
participating countries as described in the Procedures Manual.   Collection and processing instructions for all correlative study samples can also be found in the Procedures Manual.
x.
The initial tumor imaging and brain imaging will be performed within 28 days prior to the date of allocation.  Tumor imaging performed as part of routine clinical management are acceptable for use as 
screening imaging if they are of diagnostic quality and performed within 28 days prior to the date of allocation. Measureable disease based on RECIST 1.1 must be confirmed by the central imaging 
 
 
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vendor before enrollment.  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. Refer to Section 7.1.2.6.3 of the protocol and site imaging manual (SIM). If FDG-PET or MRI are also obtained at baseline or follow up as part of SOC and clinically 
indicated; send to vendor.
y.
The first on-study tumor imaging time point will be performed at 9 weeks (± 7 days) after the date of allocation and then every 9 weeks (± 7 days) thereafter or more frequently if clinically indicated in 
the first year.  After 12 months, imaging frequency should be reduced to every 12 weeks (84 ± 7 days). Timing of tumor imaging should follow calendar days and should not be adjusted due to dose 
modifications.  The same imaging technique should be used in a subject throughout the trial.  On-study scheduled or unscheduled imaging should be submitted immediately to the central imaging 
vendor.  Refer to the SIM for detailed imaging information.
z.
In subjects who discontinue study therapy without disease progression, tumor imaging should be performed at the time of treatment discontinuation (i.e., date of discontinuation ± 4 week window).  If a 
previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, then tumor imaging at treatment discontinuation is not required.
aa.
Baseline tumor tissue for biomarker analysis from a newly obtained core or excisional biopsy [fine needle aspirate (FNA) not adequate] (must be provided (mandatory) to the central vendor prior to 
randomization and an archival tissue sample (if available) will also be collected.  Adequacy of the fresh mandatory biopsy specimen for PD-L1 biomarker analysis must be confirmed by the central 
laboratory before enrollment.  Detailed instructions for tissue collection, processing and shipment of both the fresh mandatory tumor tissue and the optional archival tumor tissue 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.
bb.
An optional newly obtained core or excisional biopsy (FNA not adequate) is requested at any time point during the study, (preferably as close to dosing at C4 as possible).  A biopsy is also requested at
the time of discontinuation for progression, but will not be required.  
 
 
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Second Course Phase (Retreatment)
6.2
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:
± 3
± 3
± 3
± 3
± 3
At time of discon
30 days post 
discon
Every 9 
weeks post 
discon
Every 12 
weeks
Administrative Procedures
Eligibility Criteriae
X
Concomitant Medication Reviewf
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
Xg
Xg
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
Xh
X
X
Vital Signs and Weighti
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
Pembrolizumab Administrationj
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Status c
<- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ->
X
Laboratory Procedures/Assessments:  Analysis 
performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCGk
X
PT/INR and aPTT
Xl
Complete Blood Count (CBC) with Differentialm
Xl
X
X
X
X
X
X
Xn
Chemistry Panelm
Xl
X
X
X
X
X
X
Xn
Urinalysis
X
T3, FT4 and TSHm
Xl
X
Xh
Xn
Efficacy Measurements
Tumor Imagingo
X
X
Xp
X
 
 
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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.
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by tumor 
imaging every 9 weeks (63 ± 7 days) in the first year and every 12 weeks (84 ± 7 days) after year 1 until (1) the start of new anti-cancer treatment, (2) disease progression 
as assessed by the investigator/site radiologist, (3) death, or (4) the end of the study, whichever occurs first.
c.
After the start of new anti-cancer treatment or documented disease progression as assessed by the Investigator/local radiologist, the subject should be contacted by 
telephone approximately every 12 weeks to assess for survival status.  Updated survival status may be requested by the Sponsor at any time during the course of the study. 
Upon Sponsor notification, all subjects 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 subjects 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 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 SAEs as defined in Section 
7.2.
g.
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 end of treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.  Afterwards, report only SAEs and ECIs 
that are related to trial treatment.
h.
To be repeated every 2 cycles after Cycle 5.
i.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.
j.
Pembrolizumab is given as a 200 mg dose on the first day of each 3 week cycle.  Subjects who restart treatment should resume at the same dose and cycle interval which 
they were receiving prior to discontinuation.
k.
For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to first dose of trial retreatment. If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
l.
Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of pembrolizumab.  See Section 7.1.3 for 
details regarding laboratory tests.
m.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  Blood draws for thyroid function tests should be done prior to dosing at the 
scheduled timepoint, however results can be reviewed after dosing.  See Section 7.1.3 for details regarding laboratory tests.
n.
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.
o.
Tumor imaging must be performed within 28 days prior to restarting treatment with pembrolizumab. Tumor imaging should continue to be performed every 9 weeks (63 ± 
7 days) after the date of allocation or more frequently if clinically indicated in the first year.  After 12 months, imaging frequency should be reduced to every 12 weeks (84 
± 7 days).  Tumor imaging timing should follow calendar days and should not be adjusted for any dose modifications.  The same image modality acquisition and technical 
parameters should be used throughout the study.  
p.
In subjects who discontinue study therapy without confirmed disease progression, tumor imaging should be performed at the time of treatment discontinuation (i.e., date of 
discontinuation ± 4 week window).  If previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, then tumor imaging at treatment 
discontinuation in not required.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
General Informed Consent
7.1.1.1.1
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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Consent and Collection of Specimens for Future Biomedical Research
7.1.1.1.2
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
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.
7.1.1.4
Medical History
Demographic information and 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 mTNBC cancer will be recorded separately and 
not listed as medical history.  As well, any autoimmune disorders, regardless of onset date, 
should be recorded.
Disease Details
7.1.1.4.1
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s metastatic triple-negative breast cancer.
Menopausal Status
7.1.1.4.2
The investigator or qualified designee will obtain details regarding the subject’s menopausal 
status.  
 
 
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7.1.1.5
Prior and Concomitant Medications Review
Prior Medications
7.1.1.5.1
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before first dose of trial medication.  Prior treatment for breast cancer will be 
recorded separately and not listed as a prior medication.
Prior Treatment Details for Breast Cancer
7.1.1.5.1.1
The investigator or qualified designee will review and record all prior cancer treatments 
including systemic treatments, radiation and surgeries.  For Cohorts A and C documentation 
of disease progression on or after the most recent therapy will be collected.  Sites should 
obtain a dated imaging report documenting progressive disease on or after the most recent 
treatment.
Concomitant Medications
7.1.1.5.2
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
7.1.1.5.2.1
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.  
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
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.  
7.1.1.7
Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
randomization number. The randomization number identifies the subject for all procedures 
 
 
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occurring after treatment allocation. 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.
All subjects will be assigned a randomization number, however all subjects will receive the 
same pembrolizumab 200 mg every three weeks (Q3W) as trial treatment by non-random 
assignment in an unblinded fashion.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab doses require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff.
The total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance to each dose administered. The instructions for preparing and 
administering pembrolizumab will be provided in the Pharmacy Manual.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse events will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE Version 4.0 (see Appendix 12.7).  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 all AEs of unknown etiology 
associated with pembrolizumab 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); see the separate ECI 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.
7.1.2.2
Physical Exam
Full Physical Exam
7.1.2.2.1
The investigator or clinical designee will perform a complete (full) physical exam during the 
screening period and at discontinuation of treatment.  Clinically significant abnormal 
 
 
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findings should be recorded as medical history.  A full physical exam should be performed as 
specified in the Trial Flow Chart.  After the first dose of trial treatment new clinically 
significant abnormal findings should be recorded as AEs.
Directed Physical Exam
7.1.2.2.2
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
dosing on Day 1 of each treatment cycle.  New clinically significant abnormal findings 
should be recorded as AEs.
7.1.2.3
Vital Signs
The investigator or qualified designee will take vital signs 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.
7.1.2.4
12-Lead Electrocardiogram
A standard 12-lead ECG will be performed using local standard procedures once at 
screening.  Clinically significant abnormal findings should be recorded as medical history. 
Additional time points may be performed as clinically necessary.
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG status (see Appendix 12.4) at 
screening, prior to dosing on Day 1 of each treatment cycle and at discontinuation of trial 
treatment as specified in the Trial Flow Chart.
7.1.2.6
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the SIM.  Tumor imaging may be performed by computed tomography (CT-chest, 
abdomen, pelvis) (strongly preferred) 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.  If 
clinically indicated, sites may also obtain MRI or FDG-PET if it is part of the institutional 
standards to evaluate baseline bone metastasis.  If considered positive per site interpretation, 
they should be sent to the central imaging vendor, in addition to the bone scan.
A central imaging vendor using RECIST 1.1 will be used to determine subject eligibility. 
The central imaging vendor will receive all scheduled images at the timepoints specified in 
the Study Flow Chart from the sites as well as any unscheduled imaging data.  All tumor 
 
 
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imaging, including confirmatory tumor imaging, should be submitted to the central imaging 
vendor for evaluation and should be submitted in a timely fashion.  
The Sponsor will also receive results
for a retrospective analysis of treatment 
response/progression to be performed by the central imaging vendor, using RECIST 
1.1/irRECIST.
Imaging data will be documented in the Sponsor data collector on the 
appropriate electronic case report forms (eCRFs).
Treatment decisions will be based on the site’s assessment of tumor response and 
progression.
Baseline Tumor Imaging
7.1.2.6.1
To meet screening criteria, tumor imaging must be performed within 28 days prior to the date 
of allocation.  The baseline tumor imaging (CT strongly preferred) should be submitted
immediately to the central imaging vendor for determination of measurable disease per 
RECIST 1.1 and inclusion into the study.  Central imaging vendor confirmation of this 
eligibility criterion is required prior to allocation of the subject.
Tumor imaging performed as part of routine clinical management are acceptable for use as 
the screening imaging if they are of diagnostic quality, meet the requirements specified in the 
SIM, and are performed within 28 days prior to the date of allocation.  
In addition, brain imaging is required at screening for all subjects to confirm that there are no
detectable brain metastases present at baseline.  MRI is the preferred imaging modality 
however CT is acceptable if an MRI is clinically contraindicated.  
A bone scan should be performed at screening for all subjects with known bone metastases or 
active bone pain, and for subjects with new symptoms concerning of osseous metastasis [e.g., 
new bone pain and/or new persistently elevated alkaline phosphatase (AP)].
On Study Tumor Imaging 
7.1.2.6.2
The first post treatment tumor imaging assessment should be performed at 9 weeks (63 days 
± 7 days) from the date of allocation.  Thereafter, subsequent tumor imaging should be 
performed every 9 weeks (63 days ± 7 days) or more frequently, if clinically indicated.  After 
12 months, imaging frequency should be reduced to every 12 weeks (84 ± 7 days).    Imaging 
should follow calendar days and not be delayed for any dose interruptions that may occur.
Per RECIST 1.1, partial or complete response should be confirmed by a repeat tumor 
imaging not less than 4 weeks from the date the response was first documented.  The tumor 
imaging for confirmation of response may be performed at the earliest 4 weeks after the first 
indication of response, or at the next scheduled tumor imaging, whichever is clinically
indicated.  
Imaging should continue to be performed until disease progression, the start of new anti-
cancer treatment, withdrawal of consent, death, or notification by the SPONSOR, whichever 
occurs first.  Disease progression may be confirmed at least 4 weeks after the first tumor 
imaging indicating progressive disease in clinically stable subjects.  
 
 
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Subjects who have unconfirmed disease progression may continue on treatment until 
progression is confirmed (or possibly even later) provided they have met the conditions 
detailed in Section 7.1.2.6.5.
Bone Scans and X-Rays
7.1.2.6.3
Subjects with new symptoms concerning of osseous metastasis [e.g., new bone pain and/or 
new persistently elevated alkaline phosphatase (AP)] a bone scan should be obtained.  
Additionally, plain X-ray evaluation should be obtained for symptomatic sites with negative 
bone scan evaluations.   If clinically indicated, sites may also obtain MRI or FDG-PET if it is 
part of the institutional standards to evaluate new osseous update.  If the additional imaging 
modalities confirm site based progression by RECIST 1.1, they should be sent to the central 
imaging vendor, in addition to the bone scan.
Subjects achieving Complete Response should have a bone scan if one was obtained at 
baseline and was positive for metastatic disease.
RECIST 1.1
7.1.2.6.4
RECIST 1.1 will be applied by the central imaging vendor retrospectively as the primary 
measure for assessment of tumor response.  All tumor imaging should be submitted to the 
central imaging vendor.
irRECIST 
7.1.2.6.5
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immuno-therapeutics.  
irRECIST will be used by site investigators and local radiology review to assess tumor 
response and progression, and make treatment decisions. This data will be collected in the 
clinical database.
irRECIST will be used by the central imaging vendor, however, this evaluation will be done
retrospectively.
irRECIST takes into account the clinical condition/stability of subjects, as described in 
Table 6, in addition to response or progression via tumor imaging
Clinically stable is defined by the following criteria:

Absence of symptoms and signs indicating clinically significant progression of
disease, including worsening of laboratory values

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
 
 
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Table 6
irRECIST: Tumor Imaging and Treatment after 1st Radiologic Evidence of PD or
SD, CR or PR
Clinically Stable
Clinically Unstable
Tumor Imaging
Treatment
Tumor Imaging
Treatment
1st radiologic 
evidence of PD
Repeat tumor
imaging at > 4 
weeks at site to 
confirm PD
May continue 
study treatment at 
the site 
Investigator’s 
discretion while 
awaiting 
confirmatory scan 
by site
Repeat tumor 
imaging at > 4 
weeks to confirm 
PD by the site 
investigator/local 
radiology review
Discontinue 
treatment
Repeat tumor 
imaging confirms 
PD
No additional
tumor imaging 
required
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor).
No additional
tumor imaging 
required
N/A
Repeat tumor 
imaging shows 
SD, PR or CR
Continue 
regularly 
scheduled tumor
imaging 
assessments 
Continue study 
treatment at the 
site Investigator’s 
discretion
Continue regularly 
scheduled tumor
imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per site 
Investigator’s 
discretion.  Next 
tumor imaging 
should occur 
according to the 
every 9 week (63
± 7 days) imaging 
schedule in the 
first year or every 
12 weeks after one 
year.
In determining whether or not the tumor burden has increased, decreased or stayed stable, 
site investigators should consider all target lesions as well as non-target lesions (please refer 
to the SIM).
Any subject deemed clinically unstable should be discontinued from trial treatment at first 
evidence of progressive disease by tumor imaging and is not required to have repeat tumor 
imaging for confirmation.
For a clinically stable subject with first radiologic evidence of progressive disease (i.e., 
unconfirmed progression of disease), it is at the discretion of the site investigator/local 
radiology review to continue treating the subject with the assigned treatment per protocol 
until progression of disease is confirmed by the site investigator/local radiology review at 
least 28 days from the date of the tumor imaging first suggesting PD.  If progression is not
confirmed on the subsequent tumor imaging, the subject should continue to receive study 
therapy and have tumor imaging performed every 9 weeks (± 7 days) in the first year or 
 
 
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every 12 weeks after the first year, or sooner if clinically indicated, to monitor disease
status. If radiologic progression is confirmed by subsequent tumor imaging, then the subject 
will be discontinued from trial treatment.
NOTE: If a subject with confirmed progression by tumor imaging (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 burden at the confirmatory scan, an exception may 
be considered to continue treatment upon consultation with the Sponsor.
Subjects exhibiting toxicity from trial therapy as outlined in Sections 5.2.1 and 7.2 may 
NOT continue to receive trial therapy. 
NOTE:  In subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
every 9 weeks (± 7 days) in the first year and every 12 weeks (84 ± 7 days) after year 1 until 
(1) the start of new anti-cancer treatment, (2) disease progression (3) death, or (4) the end of 
the study, whichever occurs first.
The same imaging modality (i.e., CT or MRI), acquisition and technical parameters should 
be used throughout the study for a given subject.
Additional information is included in the SIM.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 7.
 
 
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Table 7
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)d
Platelet count
Alanine aminotransferase (ALT)
Protein
aPTT d
White Blood Cell -
WBC (total and 
differential)
Aspartate aminotransferase (AST)
Specific gravity 
Total thriiodothyronine (T3)e
Red Blood Cell 
Count
Bicarbonate b
Microscopic exam, 
if abnormal results 
are noted
Free thyroxine (FT4)
Absolute 
Neutrophil Count
Calcium
Urine pregnancy 
testa
Thyroid stimulating hormone 
(TSH)
Absolute 
Lymphocyte 
Count
Chloride
FSH, estradiol f
Creatinine
Blood for correlative studies
Glucose
Blood for genetics
Lactate Dehydrogenase
Blood for MDSCs
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin is 
elevated above the upper limit of 
normal
Total protein
Blood Urea Nitrogen
Carbon dioxide (CO2 or 
bicarbonate)b
Uric acid
Ureac
a Perform on women of childbearing potential only.  Urine pregnancy test is preferred.  If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required.
b If considered standard of care in your region.  If these tests are not done as part of standard of care in your region 
then these tests do not need to be performed.
c Blood Urea Nitrogen is preferred; if not available urea may be tested.
d 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.
e Total T3 is preferred; if not available free T3 may be tested.
f Blood for menopausal status is only required for some subjects as described in Section 7.1.3.2
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.
 
 
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7.1.3.2
Blood for Menopausal Status
Blood for evaluation of postmenopausal status (FSH and estradiol) will be evaluated if clear 
documentation of post-menopausal status in not obtained.   
The menopausal status (pre- or post-menopausal) for all subjects younger than age 60 must 
be determined at screening according to the definitions below.   The date of the subject’s last 
menstrual period (LMP), bilateral ovariectomy/oophorectomy status (if applicable) and, 
when indicated, serum FSH and estradiol levels, must be assessed and recorded in the 
eCRFs.
Pre-menopausal

≤12 months since LMP 
OR

Biochemical evidence of pre-menopausal status according to serum FSH and estradiol 
levels and local institutional guidelines
Post-menopausal

Subject has undergone prior bilateral ovariectomy/oophorectomy 
OR

>12 months since LMP and no hysterectomy, hormone replacement, estrogen 
receptor antagonist, chemotherapy or ovarian suppression at any time since LMP 
OR

Biochemical evidence of post-menopausal status according to serum FSH and 
estradiol levels and local institutional guidelines.
Blood collection at screening for biochemical evidence of menopausal status (FSH and 
estradiol) will be needed if patient:
1. Is ≤ 60 years old, and 
2. has not had a bilateral oophorectomy, and
3. has not had a menstrual period for at least 12 months, and 
4. had a hysterectomy or was on hormone replacement, estrogen receptor antagonist, 
chemotherapy or ovarian suppression at any time since LMP.
7.1.3.3
Pharmacokinetic/Pharmacodynamic Evaluations
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of anti-pembrolizumab antibodies (ADA) and PK are currently 
planned as shown in the Trial Flowchart.  Blood samples collected for PK and ADA may 
only be stored at this time.  Further analysis may be performed, if required.  If ongoing PK 
and/or ADA sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued.
 
 
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Blood Collection for Serum Pembrolizumab Pharmacokinetics - PK
7.1.3.3.1
Sample collection, storage and shipment instructions for serum PK samples will be provided 
in the Procedures Manual.
Blood Collection for Anti-Drug (Pembrolizumab) Antibodies - ADA 
7.1.3.3.2
Sample collection, storage and shipment instructions for anti-drug antibody samples will be 
provided in the Procedures Manual.
7.1.3.4
Tumor Tissue Collection
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 as well HR, PR, and 
HER2 negative status.
The tumor tissue must be received by the central vendor and be 
deemed adequate for evaluation in real time prior to subject allocation for all cohorts.  
Testing for hormone receptor status will be performed with commercially validated assays 
that meet the following requirements:
a) Estrogen receptor (ER) negative status is defined as <1% tumor cells 
positive for ER by IHC, irrespective of staining intensity 
b) Progesterone receptor (PR) negative status is defined as <1% tumor cells 
positive for PR by IHC, irrespective of staining intensity
c) HER2 negative status is determined by: 

IHC 1+, as defined by incomplete membrane staining that is 
faint/barely perceptible and within >10% of invasive tumor cells, 
or

IHC 0, as defined by no staining observed or membrane staining that is 
incomplete and is faint/barely perceptible and within ≤10% of the 
invasive tumor cells, 
or

FISH negative based on:
Single-probe average HER2 copy number <4.0 signals/cell, or
Dual-probe HER2/CEP17 ratio <2.0 with an average HER2 copy 
number <4.0 signals/cell
Newly-obtained specimens of tissue can be collected up to 8 weeks (56 days) prior to Day 1
provided the proper consent has been obtained.  Newly obtained tumor tissue should be 
submitted in formalin (preferred) or as formalin-fixed paraffin embedded tumor tissue 
 
 
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blocks.  If after agreement with the Sponsor unstained slides are submitted, the slides should 
be freshly cut and submitted to the testing laboratory within 14 days from site slide 
sectioning date otherwise a new specimen will be requested.  
Additionally, if available, archived tumor tissue specimens from prior biopsies will be 
collected for determination of tumor PD-L1 status to compare biomarker expression in 
archived specimens against the in newly obtained tumor tissue that is collected as a 
requirement for entry into the trial.  If after agreement with the Sponsor unstained slides are 
submitted, the slides should be freshly cut and submitted to the testing laboratory within 14 
days from site slide sectioning date otherwise a new specimen will be requested.  
Tumor tissue collected may also be used to support analysis of exploratory biomarkers as 
described in Section 4.2.3.5.
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.  Details 
regarding time points for collection of tumor tissue are outlined in the Study Flow Chart –
Section 6.1.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
7.1.3.5
Correlative Blood Collections – Samples for Correlative, Genetic, and 
Circulating MDSC Analyses
Details regarding time points for blood collection to support analysis of exploratory 
biomarkers presented in Section 4.2.3.5 are outlined in the Study Flow Chart – Section 6.1.
Samples for planned, exploratory genetic analysis of DNA should be drawn unless there is a 
documented law or regulation prohibiting collection, or unless the IRB/IEC does not approve 
of the collection.
Blood for correlative biomarker studies should be collected prior to treatment at each 
specified cycle and at treatment discontinuation.
MDSCs will only be collected in the participating countries as described in the Procedures 
Manual.   
Detailed instructions for sample collection, processing and shipment are provided in the 
Procedures Manual.
7.1.3.6
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA

Leftover tumor tissue 
 
 
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Other Procedures
7.1.4
7.1.4.1
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 who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab 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 are expected 
to return to the site for a Safety Follow-up Visit (described in Section 7.1.5.3.2) and then 
proceed to the Follow-up Period of the study (described in Section 7.1.5.3.3).
Withdrawal From Future Biomedical Research
7.1.4.1.1
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
 
 
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7.1.4.3
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 satisfaction of entry criteria and trial 
assessments and routine safety evaluation of subjects 

Imaging equipment – as required for study objectives

Drug administration equipment –
as required for storage, preparation and 
administration (infusion) of pembrolizumab
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Pharmacy 
Manual and Site Imaging Manual.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
Written consent for the main study must be obtained prior to performing any protocol
specific procedure including the mandatory newly obtained (fresh) tumor biopsy that is 
required for eligibility. Potential subjects will be evaluated to determine that they fulfill the 
entry requirements as set forth in Section 5.1. Visit requirements are outlined in Section 6.0 
– Trial Flow Chart. 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:

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).
 
 
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
Initial tumor imaging must be performed within 28 days prior to the date of 
allocation.

A “newly obtained” tumor biopsy sample may be obtained within approximately 56
days of the first dose of trial treatment. See Section 7.1.3.4 for additional details 
regarding tumor tissue requirements.
Screening procedures may be repeated after consultation with the Sponsor.  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.
7.1.5.2
Treatment Cycles
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
Second Course Phase (Retreatment Period)
7.1.5.2.1
Subjects who stop pembrolizumab with SD or better may be eligible for up to an additional 
17 cycles (approximately one year) of pembrolizumab therapy if they progress after stopping 
study treatment.  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:

Either 
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and

Was treated for at least 8 cycles (24 weeks) with pembrolizumab before 
discontinuing therapy

Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared
OR
o
Had SD, PR or CR and stopped pembrolizumab treatment after 35 administrations 
(approximately 24 months) of study therapy for reasons other than disease 
progression or intolerability
AND

Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab

Did not receive any anti-cancer treatment since the last dose of pembrolizumab
 
 
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
Has a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrates adequate organ function as detailed in Section 5.1.2

Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  

Female subject 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 been free from menses for > 1 year.

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.

The subject meets the safety parameters listed in the inclusion/exclusion criteria.

The trial is ongoing.
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year.
An objective response or disease progression that occurs during the Second Course Phase for 
a subject will not be counted as an event for the primary analysis of either endpoint in this 
trial.
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
7.1.5.3
Post-Treatment 
Discontinuation Visit
7.1.5.3.1
The Discontinuation Visit should occur at the time study treatment is discontinued for any
reason.  If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at
the time of the mandatory Safety Follow up Visit, procedures do not need to be repeated.  
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.  Specific procedure-
related details are provided above in Section 7.1 – Trial Procedures.  Additional details 
regarding subject withdrawal and discontinuation are presented in Section 5.8.
Safety Follow-up Visit
7.1.5.3.2
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-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
 
 
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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 regardless of causality.  Beyond 90 days, 
only SAE and ECIs that are considered related to trial treatment should be reported.
Subjects who are eligible for retreatment with pembrolizumab (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.
Follow-up Visits
7.1.5.3.3
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 9 weeks (63 ± 7 days) in the 
first year and every 12 weeks (84 ± 7 days) after year 1 by tumor imaging to monitor disease 
status.  The Sponsor may request survival status to be assessed at additional time points 
during the course of the study (not to exceed approximately 12 weeks).  Every effort should 
be made to collect information regarding disease status until the start of new anti-cancer 
therapy, disease progression, death, end of study or if the subject begins retreatment with 
pembrolizumab 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 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.
Survival Follow-up
7.1.5.3.4
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the Survival Follow-Up Phase and should be contacted by 
telephone approximately every 12 weeks to assess for survival status until death, withdrawal 
of consent, or the end of the study, whichever occurs first.  
7.1.5.4
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 subjects 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 
subjects that have a previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
 
 
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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 
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 
7.2.1
Sponsor
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab.  In the event of overdose, the subject should be
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided 
if clinically indicated
 
 
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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
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies  must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
 
 
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●
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 8 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 (see 
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 
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 outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be 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, 
 
 
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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).
3. Additional adverse events:
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-Related 
Adverse Event Guidance Document”).  This document can be found in the administrative 
binder and provides guidance regarding identification, evaluation and management of ECIs 
and irAEs.  
ECIs (both non-serious and serious adverse events) 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, regardless of attribution to trial treatment, 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.  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. 
 
 
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7.2.3.3
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
7.2.4
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4. 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 8
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
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
Trial Governance and Oversight
7.3
Data Monitoring Committee
7.3.1
There will be no data monitoring committee.
The interim analyses will be conducted by the Sponsor.  The main Sponsor study team will 
remain blinded to PD-L1 scores of subjects in Cohort A.
An unblinded biomarker statistician who has the access to subject level PD-L1 score for 
biomarker cutoff analysis will inform the main study team about the outcome of both interim 
analyses (IA 1 and IA 2) and whether the pre-specified go/no go decision criteria is met. For 
additional information please see Section 8.2.1 and Section 8.2.9.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after 
the study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to 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 the conduct of any analysis, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study. A biomarker analysis plan will be provided. Post hoc exploratory 
analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
In addition, a separate analysis plan document will be issued prior to biomarker unblinding 
for each of the following laboratory procedures and assessments: (1) Biomarkers (detailed in 
Section 7.1.3.4 and 7.1.3.5) and their association with antitumor efficacy and (2) 
Pharmacokinetic and pharmacodynamics evaluation (detailed in Section 7.1.3.3)
Study Design Overview
A Phase II Clinical Trial of Pembrolizumab as Monotherapy in Subjects 
with Metastatic Triple-Negative Breast Cancer (mTNBC)
Treatment Assignment
Treatment assignment is open label. 
Analysis Populations
Efficacy: All Subjects as Treated (ASaT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
Objective Response Rate (ORR)
Statistical Methods for Key ORR estimation 
 
 
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Efficacy Analyses

2L+ population
o
PD-L1 (+) population (Cohort A)
o
Overall population (Cohort A)
o
PD-L1 strong (+) population (Cohorts A+C)

1L population (Cohort B)

Counts and percentages

95% Agresti-Coull confidence intervals  
Statistical Methods for Key 
Safety Analyses
Counts and percentages of AEs will be provided.  Confidence intervals
for rates of AEs of clinical interest will be computed using the exact 
binomial method.
Interim Analyses

Futility analysis for 2L+ subjects (Cohort A) with PD-L1 (-)
tumors based on no progression
o
~25 PD-L1 (-) subjects
o
If no response or stable disease, continue 2L+ 
population (Cohort A) in PD-L1 (+) patients only 

Evaluation of expansion to Cohort C for PD-L1 strong (+)
population based on ORR.
o
~10 patients evaluable through response, progression or 
18-week scan, whichever comes first.
o
Cohort C may start if ≥ 1 responses observed
The final analysis of Cohorts A and C combined is to be completed when 
subjects are evaluable through response, progression or 18-week scan, 
whichever comes first.
Multiplicity
This is an estimation study. No multiplicity adjustment will be applied.
Sample Size 
The planned sample size is up to approximately 285 subjects. 

~160 subjects in the 2L+ overall population (Cohort A)

~93/160 2L+ subjects (~58%) expected to be PD-L1 (+), if PD-L1 
(-) is not futile at the futility analysis; ~135 2L+ subjects expected 
to be PD-L1 (+), if PD-L1 (-) is discontinued after the futility 
analysis

~55 PD-L1 strong (+) subjects (Cohort C and PD-L1 strong (+)
subgroup from Cohort A)

~80 PD-L1 (+) first line subjects (Cohort B)
Statistical Analysis Plan
8.2
Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this study will be the responsibility of the 
clinical biostatistics department of the SPONSOR.
This trial is being conducted as an open-label non-randomized single-arm clinical trial for 
each cohort, i.e., subjects, investigators, and SPONSOR personnel will be aware of subject 
treatment assignments after each subject is enrolled and treatment is assigned. 
The 
investigator and 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 in Cohort A. A designated Sponsor team (may include unblinded Sponsor 
 
 
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statisticians, unblinded
Sponsor statistical programmers, unblinded Sponsor clinical 
scientists, unblinded clinical directors, and unblinded data management personnel) will have 
access to the subject-level PD-L1 results for the purpose of data review and will have no 
other responsibilities associated with the study. A summary of PD-L1 biomarker prevalence 
and biomarker cutoff analysis will be provided to the study team at the Sponsor by the 
unblinded Sponsor statistician. Biomarker cutoff analysis will inform the team about the 
outcome of the interim analyses and whether or not the pre-specified go/no go decision 
criteria are met. The estimation of tumor efficacy, e.g., ORR, DOR and DCR, etc. based on 
RECIST 1.1 by the central imaging vendor may be provided by the unblinded statistician 
while the trial is ongoing.
The Clinical Biostatistics department will generate the allocation schedule for study 
treatment assignment. Allocation will be implemented in an interactive voice response
system (IVRS).
Hypotheses/Estimation
8.2.2
This is an estimation study. Objectives of the study are stated in Section 3.0.
Analysis Endpoints
8.2.3
The efficacy and safety endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
8.2.3.1
Efficacy Endpoints
The primary efficacy endpoint is objective response rate (ORR), defined as the proportion of 
subjects in the analysis population who have complete response (CR) or partial response 
(PR), based on RECIST 1.1 by the central imaging vendor at any time during the study. As 
supportive analyses, ORR will also be evaluated by a) site investigator and local radiology 
review based on RECIST 1.1 and b) irRECIST by the central imaging vendor.
Secondary efficacy endpoints include:

Duration of response (DOR), defined as the time from first documented evidence of 
CR or PR until disease progression or death due to any cause, whichever occurs first, 
for subjects who demonstrate CR or PR, based on RECIST 1.1 by the central imaging 
vendor.

Disease control rate (DCR), defined as the percentage of subjects who have achieved
confirmed CR or PR or have demonstrated SD for at least 24 weeks prior to any 
evidence of progression, based on RECIST 1.1 by the central imaging vendor.

Progression-free survival (PFS), defined as the time from first dose of study 
medication to the first documented disease progression or death due to any cause, 
whichever comes first, based on RECIST 1.1 by the central imaging vendor. 
 
 
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
Overall survival (OS), defined as the time from first dose of study medication to 
death due to any cause.
As exploratory endpoints, DOR and DCR and PFS will also be evaluated based on a) 
RECIST 1.1 by study site and local radiology review and b) irRECIST by the central imaging
vendor.
8.2.3.2
Safety Endpoints
Safety measurements are described in Section 4.2.3.2 Safety Endpoints and Section 7.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, and vital signs. Safety parameters to be analyzed 
include, but are not limited to, AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, 
specific events will be collected and designated as events of clinical interest (ECIs) as 
described in Section 7.2.3.2.
8.2.3.3
Biomarker Endpoints
A separate biomarker SAP will be provided for the following endpoints/analyses.

The association between PD-L1 protein expression by IHC and antitumor activity to
pembrolizumab as monotherapy for mTNBC.

The association between antitumor activity of pembrolizumab in mTNBC and 
efficacy/resistance biomarkers, utilizing tumor and blood specimens obtained before/after 
treatment and at disease progression.

The performance comparison of PD-L1 assessment by IHC in newly-obtained vs. 
archived tumor samples.
8.2.3.4
Pharmacokinetic Endpoints
Pharmacokinetic parameters and the presence of anti-drug antibodies, following IV 
administration of 200 mg pembrolizumab Q3W as monotherapy in subjects with mTNBC
(details see Section 4.2.3.4.)
8.2.3.5
Other Endpoints
Other endpoints include association between genetic variation and response to the 
treatment(s) administered, variation across the human genome for the association with 
clinical data (details see Sections 4.2.3.5 and 4.2.3.6.) and the association between LDH and 
efficacy response to pembrolizumab as monotherapy for mTNBC.
 
 
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Analysis Populations
8.2.4
8.2.4.1
Efficacy Analysis Populations
The All-Subjects-as-Treated (ASaT) population, which consists of as all enrolled subjects 
who receive at least one dose of study medication with measurable metastatic disease at 
baseline, will serve as the primary population for the analyses of efficacy data in this trial. 
Details on the approach to handling missing data for efficacy analyses are provided in 
Section 8.2.5 Statistical Methods.
8.2.4.2
Safety Analysis Populations
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
8.2.5
8.2.5.1
Statistical Methods for Efficacy Analyses
Efficacy of pembrolizumab as 2L+ monotherapy for mTNBC will be evaluated primarily in 
PD-L1 (+) and overall population (all comers) in Cohort A, and also in subjects with PD-L1 
strong (+) tumors from Cohorts A and C combined.  Cohort A will be evaluated for 
association between PD-L1 biomarker expression and antitumor activity. 
A separate
biomarker SAP will be devoted to association between PD-L1 biomarker expression and 
antitumor activity analysis.
The primary efficacy endpoints are ORR based on RECIST 1.1 by the central imaging 
vendor in subjects with PD-L1 (+) mTNBC of Cohorts A, overall population (all comers) of 
Cohort A and in subjects with PD-L1 strong (+) mTNBC. The point estimate 95% Agresti-
Coull (A-C) confidence interval (CI) (as determined by the upper and lower 97.5% one-sided 
confidence bounds) will be provided based on normal approximation for the binomial 
distribution. Subjects without response data will be counted as non-responders.
Similarly, a supportive analysis to the primary method, ORR based on RECIST 1.1 by study 
site investigator and local radiology review will also be performed in the same fashion.
For the secondary endpoint of DCR, similar estimation methods used for ORR will be
applied.
For DOR, PFS and OS, Kaplan-Meier (KM) curves, median estimates, and survival at 6 and 
12 months based on the KM curves (95% CI is based on Greenwood's formula) will be 
provided as appropriate. Subjects without efficacy evaluation data or without survival data 
will be censored at Day 1.  The restricted mean survival time (RMST) for DOR will also be 
provided as a supportive analysis.  
 
 
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Censoring rules for DOR are summarized in Table 9. 
Table 9
Censoring Rules for DOR
Situation
Date of progression or censoring
Outcome
No progression nor death, no new anti-cancer 
therapy initiated
Last adequate assessment
Censor 
(non-event)
No progression nor death, new anti-cancer therapy 
initiated
Last adequate assessment before new anti-
cancer therapy initiated
Censor 
(non-event)
≥ 2 consecutive missed adequate disease 
assessments
Last adequate assessment prior to ≥ 
2 missed adequate disease assessments
Censor 
(non-event)
Death or  progression after ≤1 missed adequate 
disease assessments
Death or progression
End of response (Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation of 
response.  
Similar estimation methods will be applied to the efficacy analyses for the subjects with PD-
L1 (+) mTNBC in Cohort B.
Table 10 summarizes the key efficacy analyses for primary and secondary endpoints in this 
study.
 
 
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Table 10
Analysis Strategy for Primary/Secondary Efficacy Endpoints in Cohorts A and C
Endpoint/Variable
(Description, Time Point)
Statistical 
Method
Analysis 
Population
Missing Data Approach
Primary:
ORR, based on RECIST1.1 by the 
central imaging vendor
95% Agresti-
Coull CI
ASaT
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Subjects with missing 
data are considered non-
responders
Secondary:
Response duration (DOR)
Based on RECIST1.1
o
by the central imaging 
vendor
o
by study site investigator
and local radiology teview
Summary 
statistics using 
Kaplan-Meier 
method
All 
responders
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Non-responders are 
excluded in analysis
ORR
Based on RECIST1.1
o
by study site investigator
and local radiology review
Agresti-Coull
95% CI
ASaT
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Subjects with missing 
data are considered non-
responders
DCR
Based on RECIST1.1
o
by the central imaging 
vendor
o
by study site investigator 
and local radiology review
Agresti-Coull
95% CI
ASaT
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Subjects with missing 
data are considered non-
responders
Progression-free survival (PFS)
Based on RECIST1.1
o
by the central imaging 
vendor
o
by study site investigator 
and local radiology review
Summary 
statistics using 
Kaplan-Meier 
method
ASaT
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Censored at last 
assessment
Overall survival (OS) 
Summary 
statistics using 
Kaplan-Meier 
method
ASaT
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Censored at last 
assessment
95% confidence interval is determined by the upper and lower 97.5% one-sided confidence bounds.
Similar efficacy methods will be applied to Cohort B for subjects with PD-L1 (+) tumors 
receiving pembrolizumab as 1L monotherapy for mTNBC.
8.2.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs by cohort and total (combining 
across Cohorts A-C). Summary statistics (counts, percentage, mean, standard deviation, etc.) 
will be provided for the safety endpoints as appropriate.
The confidence interval for the 
 
 
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incidence rate of Grade 2 or higher adverse events with an immune etiology and the 
incidence rate of Grade 4/5 AEs will be provided as appropriate.  
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
8.2.5.3.1
Baseline characteristics will be assessed by the use of tables and/or graphs for each cohort.  
No statistical hypothesis tests will be performed on these characteristics.  The number and 
percentage of subjects screened, treated, primary reasons for screening failure, and 
discontinuation will be displayed.  Demographic variables (e.g., age, region), baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by cohort either by descriptive statistics or categorical tables.
Multiplicity
8.2.6
This is an estimation study. The estimation of ORR and associated 95% confidence intervals 
of ORR will be provided. No multiplicity adjustment will be applied in subjects with PD-L1 
(+) mTNBC of Cohorts A, overall population (all comers) of Cohort A and in subjects with 
PD-L1 strong (+) mTNBC.
There are also no hypotheses for other parameters of DOR, DCR, PFS, and OS or for Cohort 
B.
Sample Size and Power Calculations
8.2.7
The trial has a planned sample size of up to approximately N=285 subjects

N = ~160: 2L+ overall population (all comers; Cohort A)
o
Would expect N=93 PD-L1 (+) subjects based on 58% prevalence
o
Would expect N=135 PD-L1 (+) subjects if PD-L1 (-) patients are 
discontinued at interim analysis 

N = ~45: expansion for the 2L+ PD-L1 strong (+) population (Cohort C)
o
N ~ 55 expected for total PD-L1 strong (+) population (Cohort A subgroup + 
Cohort C) 

N = ~80: 1L PD-L1 (+) subjects (Cohort B)
 
 
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The study is for estimation. 
Table 11
Summary of Sample Size Calculation
Line of 
Therapy
Population
Cohort
N
Number of 
Observed 
Responders
ORR Estimates
95% A-C CI 
of ORR (%)
2L+
Overall 
population
A
160
24
15.0%
(10.2,21.4)
PD-L1 (+)
A
93
16
17.2%
(10.8, 26.2)
PD-L1 (+)
A
135
21
15.6%
(10.3, 22.7)
PD-L1 strong 
(+)
A+ C
55
11
20.0%
(11.4,32.5)
1L
PD-L1 (+)
B
80
24
30.0%
(21.0,40.8)
Details underlying the above summary calculations follow below.
ORR in the PD-L1 (+) and overall population in Cohort A
It is expected that ~160 subjects in Cohort A will be enrolled for investigating the association 
between PD-L1 protein expression by IHC and antitumor activity of pembrolizumab as 
monotherapy for mTNBC (Details in Biomarker Analysis SAP).
Similarly for the ORR in the PD-L1 (+) in Cohort A, if PD-L1 (-) is not futile at the futility 
analysis it is expected that ~93 subjects out of the ~160 enrolled subjects (~58% prevalence 
based on previous study) in Cohort A will have PD-L1 (+) expression.  With ~93 subjects, if 
there are at least 16 responders observed, the lower bound of the 95% CI for ORR will be 
above 10%.
If PD-L1 (-) is futile, there will be with ~135 subjects in Cohort A [excluding 25 PD-L1 (-)
in the futility analysis]. If there are at least 21 responders observed, the lower bound of the 
95% CI for ORR will be above 10%.
Similarly for the ORR in the overall population in Cohort A, if PD-L1 (-) is not futile, there
will be ~160 subjects. If there are at least 24 responders observed, the lower bound of the 
95% CI for ORR will be above 10%.
Table 12 shows the two-sided 95% A-C CI of ORR with different sample size for different 
observed response rates.
 
 
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Table 12
Two-sided 95% A-C CI of ORR with Different Sample Size 
Sample Size (N)
Number of Observed 
Responders
ORR Estimates
95% A-C CI of 
ORR (%)
93
10
10.8%
(5.8,18.9)
14
15.1%
(9.1,23.8)
16
17.2%
(10.8, 26.2)
19
20.4%
(13.4,29.8)
110
11
10.0%
(5.5,17.2)
17
15.5%
(9.8,23.5)
18
16.4%
(10.5, 24.5)
22
20.0%
(13.5,28.5)
135
14
10.4%
(6.2,16.8)
21
15.6%
(10.3,22.7)
27
20.0%
(14.1,27.6)
160
16
10.0%
(6.2,15.7)
24
15.0%
(10.2,21.4)
32
20.0%
(14.5,26.9)
170
17
10.0%
(6.3,15.5)
26
15.3%
(10.6,21.5)
34
20.0%
(14.6,26.7)
180
18
10.0%
(6.3,15.3)
27
15.0%
(10.5,21.0)
36
20.0%
(14.8,26.5)
ORR in PD-L1 strong (+) in Cohorts A + C
There will be ~55 subjects with PD-L1 strong (+) tumors enrolled in Cohort A and Cohort C.
Table 13 shows the two-sided 95% A-C CI of ORR with 55 evaluable subjects for different 
observed response rates.  With 55 subjects with PD-L1 strong (+) tumors, if there are at least 
11 responders observed, the lower bound of the 95% A-C CI for ORR will be above 10%.
 
 
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Table 13
Two-sided 95% A-C CI of ORR with 55 Evaluable Subjects
Number of Observed Responders
ORR Estimates
95% A-C CI of ORR (%)
6
10.9%
(4.7,22.2)
8
14.5%
(7.3,26.4)
9
16.4%
(8.6,28.5)
10
18.2%
(10.0,30.5)
11
20.0%
(11.4,32.5)
13
23.6%
(14.2,36.5)
14
25.5%
(15.7,38.4)
Table 14 shows the Two-sided exact 95% CI of AE Rate with 55 subjects.
Table 14
Two-sided 95% Exact CI of AE Incidence Rate with 55 Evaluable Subjects
Number of AE
AE Incidence Rate Estimates
95% CI of Incidence Rate (%)
6
10.9%
(4.1,22.2)
11
20.0%
(10.4,33.0)
17
30.9%
(19.1,44.8)
22
40.0%
(27.0,54.1)
28
50.9%
(37.1,64.6)
 
 
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ORR in PD-L1 (+) Cohort B
There will be ~80 subjects with PD-L1 (+) tumors enrolled in Cohort B.
Table 15 shows the two-sided 95% CI of ORR with 80 or 100 subjects for different observed 
response rates. 
Table 15
Two-sided 95% A-C CI of ORR with 80 or 100 Subjects
Sample Size (N)
Number of Observed 
Responders
ORR Estimates
95% CI of ORR (%)
80
12
15%
(8.6,24.6)
16
20%
(12.6,30.1)
20
25%
(16.7,35.6)
24
30%
(21.0,40.8)
28
35%
(25.4,45.9)
32
40%
(30.0,51.0)
36
45%
(34.6,55.9)
100
15
15%
(9.2,23.4)
20
20%
(13.3,29.0)
25
25%
(17.5,34.4)
30
30%
(21.9,39.6)
35
35%
(26.3,44.8)
40
40%
(30.9,49.8)
45
45%
(35.6,54.8)
Table 16 shows the Two-sided exact 95% CI of AE Rate with 80 subjects.
Table 16
Two-sided 95% Exact CI of AE Incidence Rate with 80 Evaluable Subjects
Number of AE
AE Incidence Rate Estimates
95% CI of Incidence Rate (%)
8
10.0%
(4.4,18.8)
16
20.0%
(11.9,30.4)
24
30.0%
(20.3,41.3)
32
40.0%
(29.2,51.6)
40
50.0%
(38.6,61.4)
 
 
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Subgroup Analyses and Effect of Baseline Factors
8.2.8
Subgroup analyses are planned for the efficacy analyses in the classification variables: 

Age category (≤50 vs. >50 years)

Menopausal status 

PD-L1 IHC expression [PD-L1 strong (+), PD-L1 (+), PD-L1 (-) and overall]

Previous Chemotherapy(2/3 L vs. 4L+)

Liver metastases (Presence vs. Absence) 
Interim Analyses
8.2.9
There are two interim analyses planned in this study. For Cohort A in Part 1, a futility 
analysis will be performed for subjects with PD-L1 (-) tumors and an interim analysis for 
potential efficacy expansion will be performed for subjects with PD-L1 strong (+) tumors in 
this cohort.  
The PD-L1 strong (+) population (10 or more subjects depending on the prevalence of PD-L1 
strong (+) tumors in the 2L+ population from Cohort A) may be expanded by continuing 
enrollment of subjects with PD-L1 strong (+) tumors into Cohort C, if at least one responder 
is observed in this subpopulation from Cohort A. The combined sample size of up to ~55
subjects with PD-L1 strong (+) tumors from Cohorts A and C is driven by the primary 
efficacy estimation for subjects with PD-L1 strong (+) tumors (with futility bound accounted 
for the IA in this subpopulation).
The detailed process is described as below:
1. Enrollment will begin independent of tumor PD-L1 status. 
2. A futility analysis will start when the first ~25 subjects with PD-L1 (-) tumors are 
evaluable through response, progression or 18-week tumor imaging, whichever 
comes first.  The purpose of this interim analysis is to check treatment futility for 
subjects with PD-L1 (-) tumors.  
3. If the futility boundary is not crossed, that is at least one subject with response or 
stable disease is observed in subjects with PD-L1 (-) tumors, the trial enrollment will 
continue as planned.  If the futility boundary is crossed for subjects with PD-L1 (-)
tumors, then such subjects may be excluded from further enrollment in the trial. That 
is, the trial will continue to only enroll subjects with PD-L1 (+) tumors until there are 
160 subjects in total.
4. An efficacy futility interim will also be performed for the PD-L1 strong (+)
subpopulation of Cohort A, and enrollment of Cohort C for PD-L1 strong (+) may be 
initiated if one or more responders are observed in at least 10 subjects from Cohort A.  
Figure 4 illustrates the study diagram for decision making (a study decision tree).
 
 
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Continue 
enrolling 
PD-L1 (-) to Cohort A 
(Next Page)
Y
N
IA1 in PD-L1 (-):
≥1 response or SD
Y
Only enroll PD-L1 (+)
to Cohort  A
IA2 in PD-L1 
strong (+): ≥1 
responder in 10 or 
more subjects?
May initiate C [PD-L1 strong 
(+)] until ~55 in (A+C)
FA
[Primary Objective 2]:
estimate ORR in PD-L1 strong 
(+) from A+C? 
FA 
[Primary Objective 1]: 
estimate ORR  in PD-L1 
(+) from A 
No 
Cohort 
C
N
 
 
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Figure 4
Decision Tree
Interim Analysis for Futility (IA1)
An interim futility check will be performed for the PD-L1 (-) population in Cohort A. 
Enrollment of PD-L1 (-) population will be stopped, if futility bound is reached. At least one 
subject without disease progression among the 25 subjects is needed for the further 
enrollment of subjects with PD-L1 (-) tumors. Table 17 lists the probability of stopping for 
futility at different true response rate in PD-L1 (-) based on different stopping rules.
IA1 in PD-L1 (-):
≥1 response or SD
Y
N
No 
Cohort 
C
Y
Continue to enroll 
all comers to Cohort  
A
IA2 in PD-L1 
strong (+): ≥1 
responder in 10 or 
more subjects?
May initiate C [PD-L1 strong 
(+)] until ~55 in (A+C)
FA
[Primary Objective 2]: 
estimate 
ORR in PD-L1 strong (+)
from A+C 
FA 
[Primary Objective 1]: 
estimate ORR in PD-L1 (+)
and all subjects from A 
 
 
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Table 17
Probability of Futility under Different True Response Rate§ in PD-L1 (-)
Response Rate§ in PD-L1 (-)
Probability of Futility in PD-L1 (-)
Rule of ≥ 1 Responder
or SD
Rule of ≥ 2 Responders or 
SD
1%
77.8%
97.4%
2%
60.3%
91.1%
5%
27.7%
64.2%
8%
12.4%
39.4%
10%
7.2%
27.1%
§Response rate: the proportion of responders (CR and PR) or subjects with stable disease.
Interim Analysis to Initiate Cohort C Expansion (IA 2)
IA2 (Cohort A) will be performed when at least 10 subjects with PD-L1 strong (+) tumors 
are evaluable through response, progression or 18-week scan, whichever comes first.    One
or more responses need to be observed in order to expand enrollment to additional subjects 
with PD-L1 strong (+) tumors (up to ~55 subjects in Cohorts A and C combined). Table 18
shows the probability to initiate Cohort C under different true ORR in PD-L1 strong (+)
subpopulation in Cohort A based on the rule of one or more responders.
Table 18
Probability to Initiate Cohort C under Different True ORR in PD-L1 Strong (+)
ORR in PD-L1 Strong (+)
Probability to Initiate Cohort C
10%
65.1%
15%
80.3%
18%
86.3%
20%
89.3%
25%
94.4%
30%
97.2%
Compliance (Medication Adherence)
8.2.10
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
 
 
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Extent of Exposure
8.2.11
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure 
for ASaT population.
Other Analyses
8.2.12
8.2.12.1
Biomarker Analyses
Biomarker endpoints including exploring the association between PD-L1 protein expression
by IHC and response to pembrolizumab as monotherapy for mTNBC to define the biomarker 
cut-point for mTNBC will be analyzed in a separate SAP by biomarker group.
8.2.12.2
Other Exploratory Analysis
The association between LDH and efficacy response to pembrolizumab as monotherapy for 
mTNBC may be explored.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 19.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 19
Product Descriptions
Product Name & Potency
Dosage Form
pembrolizumab 100 mg / 4mL
Solution for Infusion
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
 
 
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All supplies will be provided open label.  Pembrolizumab will be provided as non-kitted 
single vials or as single vials in a kit box.  
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.  Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
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
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
 
 
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except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative),
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identif ying 
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
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
 
 
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Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
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.
 
 
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Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection,
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
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 
 
 
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principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
 
 
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Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript. If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
 
 
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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.
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2.
Mei, Z., et al., Tumour-infiltrating inflammation and prognosis in colorectal cancer: 
systematic review and meta-analysis. Br J Cancer, 2014. 110(6): p. 1595-605.
3.
Salgado, R., et al., Harmonization of the evaluation of tumor infiltrating lymphocytes 
(TILs) in breast cancer: recommendations by an international TILs-working group 
2014. Ann Oncol, 2014.
4.
Schatton, T., et al., Tumor-infiltrating lymphocytes and their significance in 
melanoma prognosis. Methods Mol Biol, 2014. 1102: p. 287-324.
5.
Gooden, M.J., et al., The prognostic influence of tumour-infiltrating lymphocytes in 
cancer: a systematic review with meta-analysis. Br J Cancer, 2011. 105(1): p. 93-103.
6.
Schreiber, R.D., L.J. Old, and M.J. Smyth, Cancer immunoediting: integrating 
immunity's roles in cancer suppression and promotion. Science, 2011. 331(6024): p. 
1565-70.
7.
Bremnes, R.M., et al., The role of tumor-infiltrating immune cells and chronic 
inflammation at the tumor site on cancer development, progression, and prognosis: 
emphasis on non-small cell lung cancer. J Thorac Oncol, 2011. 6(4): p. 824-33.
8.
Talmadge, J.E., Immune cell infiltration of primary and metastatic lesions: 
mechanisms and clinical impact. Semin Cancer Biol, 2011. 21(2): p. 131-8.
9.
Shirabe, K., et al., Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
pathology and clinical management. Int J Clin Oncol, 2010. 15(6): p. 552-8.
10.
Nosho, K., et al., Tumour-infiltrating T-cell subsets, molecular changes in colorectal
cancer, and prognosis: cohort study and literature review. J Pathol, 2010. 222(4): p. 
350-66.
11.
Bellati, F., et al., Immunology of gynecologic neoplasms: analysis of the prognostic 
significance of the immune status. Curr Cancer Drug Targets, 2009. 9(4): p. 541-65.
12.
Oble, D.A., et al., Focus on TILs: prognostic significance of tumor infiltrating 
lymphocytes in human melanoma. Cancer Immun, 2009. 9: p. 3.
13.
Uppaluri, R., G.P. Dunn, and J.S. Lewis, Jr., Focus on TILs: prognostic significance 
of tumor infiltrating lymphocytes in head and neck cancers. Cancer Immun, 2008. 8: 
p. 16.
14.
Dunn, G.P., I.F. Dunn, and W.T. Curry, Focus on TILs: Prognostic significance of 
tumor infiltrating lymphocytes in human glioma. Cancer Immun, 2007. 7: p. 12.
15.
Chang, W.J., et al., Inflammation-related factors predicting prognosis of gastric 
cancer. World J Gastroenterol, 2014. 20(16): p. 4586-96.
 
 
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16.
Preston, C.C., et al., The ratios of CD8+ T cells to CD4+CD25+ FOXP3+ and 
FOXP3- T cells correlate with poor clinical outcome in human serous ovarian 
cancer. PLoS One, 2013. 8(11): p. e80063.
17.
Yoon, H.H., et al., Prognostic impact of FoxP3+ regulatory T cells in relation to 
CD8+ T lymphocyte density in human colon carcinomas. PLoS One, 2012. 7(8): p. 
e42274.
18.
Kim, S.T., et al., Tumor-infiltrating lymphocytes, tumor characteristics, and 
recurrence in patients with early breast cancer. Am J Clin Oncol, 2013. 36(3): p. 
224-31.
19.
Mathai, A.M., et al., Role of Foxp3-positive tumor-infiltrating lymphocytes in the 
histologic features and clinical outcomes of hepatocellular carcinoma. Am J Surg 
Pathol, 2012. 36(7): p. 980-6.
20.
Liu, F., et al., CD8(+) cytotoxic T cell and FOXP3(+) regulatory T cell infiltration in 
relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat, 
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Sheppard, K.A., et al., PD-1 inhibits T-cell receptor induced phosphorylation of the 
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Huang, X., et al., PD-1 expression by macrophages plays a pathologic role in 
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Pena-Cruz, V., et al., PD-1 on immature and PD-1 ligands on migratory human 
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Karim, R., et al., Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell 
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Taube, J.M., et al., Colocalization of inflammatory response with B7-h1 expression in 
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Sanmamed, M.F. and L. Chen, Inducible expression of B7-H1 (PD-L1) and its 
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Topalian, S.L., C.G. Drake, and D.M. Pardoll, Targeting the PD-1/B7-H1(PD-L1) 
pathway to activate anti-tumor immunity. Curr Opin Immunol, 2012. 24(2): p. 207-
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Hirano, F., et al., Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates 
cancer therapeutic immunity. Cancer Res, 2005. 65(3): p. 1089-96.
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Blank, C., et al., PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell 
receptor (TCR) transgenic CD8+ T cells. Cancer Res, 2004. 64(3): p. 1140-5.
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Weber, J., Immune checkpoint proteins: a new therapeutic paradigm for cancer--
preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol, 2010. 37(5): p. 
430-9.
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Strome, S.E., et al., B7-H1 blockade augments adoptive T-cell immunotherapy for 
squamous cell carcinoma. Cancer Res, 2003. 63(19): p. 6501-5.
42.
Spranger, S., et al., Mechanism of tumor rejection with doublets of CTLA-4, PD-
1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of 
CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer, 
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Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T 
cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc 
Natl Acad Sci U S A, 2010. 107(9): p. 4275-80.
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Pilon-Thomas, S., et al., Blockade of programmed death ligand 1 enhances the 
therapeutic efficacy of combination immunotherapy against melanoma. J Immunol, 
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death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin 
Cancer Res, 2007. 13(7): p. 2151-7.
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Zhang, L., T.F. Gajewski, and J. Kline, PD-1/PD-L1 interactions inhibit antitumor 
immune responses in a murine acute myeloid leukemia model. Blood, 2009. 114(8): p. 
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48.
Hamid, O., et al., Safety and tumor responses with lambrolizumab (anti-PD-1) in 
melanoma. N Engl J Med, 2013. 369(2): p. 134-44.
49.
Robert, C., et al., Anti-programmed-death-receptor-1 treatment with pembrolizumab 
in ipilimumab-refractory advanced melanoma: a randomised dose-comparison 
cohort of a phase 1 trial. Lancet, 2014. 384(9948): p. 1109-17.
50.
Siegel, R., et al., Cancer statistics, 2014. CA Cancer J Clin, 2014. 64(1): p. 9-29.
51.
Dent, R., et al., Triple-negative breast cancer: clinical features and patterns of 
recurrence. Clin Cancer Res, 2007. 13(15 Pt 1): p. 4429-34.
52.
Bauer, K.R., et al., Descriptive analysis of estrogen receptor (ER)-negative, 
progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the 
so-called triple-negative phenotype: a population-based study from the California 
cancer Registry. Cancer, 2007. 109(9): p. 1721-8.
53.
Sorlie, T., et al., Gene expression patterns of breast carcinomas distinguish tumor 
subclasses with clinical implications. Proc Natl Acad Sci U S A, 2001. 98(19): p. 
10869-74.
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Rakha, E.A. and I.O. Ellis, Triple-negative/basal-like breast cancer: review.
Pathology, 2009. 41(1): p. 40-7.
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Perou, C.M., Molecular stratification of triple-negative breast cancers. Oncologist, 
2011. 16 Suppl 1: p. 61-70.
56.
Lehmann, B.D., et al., Identification of human triple-negative breast cancer subtypes 
and preclinical models for selection of targeted therapies. J Clin Invest, 2011. 121(7): 
p. 2750-67.
57.
Lin, N.U., et al., Sites of distant recurrence and clinical outcomes in patients with 
metastatic triple-negative breast cancer: high incidence of central nervous system 
metastases. Cancer, 2008. 113(10): p. 2638-45.
58.
Arnedos, M., et al., Triple-negative breast cancer: are we making headway at least?
Ther Adv Med Oncol, 2012. 4(4): p. 195-210.
59.
Kassam, F., et al., Survival outcomes for patients with metastatic triple-negative 
breast cancer: implications for clinical practice and trial design. Clin Breast Cancer, 
2009. 9(1): p. 29-33.
60.
Mahmoud, S.M., et al., Tumor-infiltrating CD8+ lymphocytes predict clinical 
outcome in breast cancer. J Clin Oncol, 2011. 29(15): p. 1949-55.
 
 
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61.
Denkert, C., et al., Tumor-associated lymphocytes as an independent predictor of 
response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol, 2010. 28(1): p. 
105-13.
62.
Finak, G., et al., Stromal gene expression predicts clinical outcome in breast cancer.
Nat Med, 2008. 14(5): p. 518-27.
63.
Stagg, J. and B. Allard, Immunotherapeutic approaches in triple-negative breast 
cancer: latest research and clinical prospects. Ther Adv Med Oncol, 2013. 5(3): p. 
169-81.
64.
Ghebeh, H., et al., The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed 
in breast cancer patients with infiltrating ductal carcinoma: correlation with 
important high-risk prognostic factors. Neoplasia, 2006. 8(3): p. 190-8.
65.
Ghebeh, H., et al., FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate 
the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy.
BMC Cancer, 2008. 8: p. 57.
66.
Muenst, S., et al., Expression of programmed death ligand 1 (PD-L1) is associated 
with poor prognosis in human breast cancer. Breast Cancer Res Treat, 2014. 146(1): 
p. 15-24.
67.
Schalper, K., et al., In Situ Tumor PD-L1 mRNA Expression Is Associated with 
Increased TILs and Better Outcome in Breast Carcinomas Clin Cancer Res, 2014. 20: 
p. 2773.
68.
Mittendorf, E.A., et al., PD-L1 expression in triple-negative breast cancer. Cancer 
Immunol Res, 2014. 2(4): p. 361-70.
69.
Miles, D.W., et al., Biomarker results from the AVADO phase 3 trial of first-line 
bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J 
Cancer, 2013. 108(5): p. 1052-60.
70.
Liao, Y., et al., Acceptable but limited efficacy of capecitabine-based doublets in the 
first-line treatment of metastatic triple-negative breast cancer: a pilot study.
Chemotherapy, 2013. 59(3): p. 207-13.
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Staudacher, L., et al., Platinum-based chemotherapy in metastatic triple-negative 
breast cancer: the Institut Curie experience. Ann Oncol, 2011. 22(4): p. 848-56.
72.
Uhm, J.E., et al., Treatment outcomes and clinicopathologic characteristics of triple-
negative breast cancer patients who received platinum-containing chemotherapy. Int 
J Cancer, 2009. 124(6): p. 1457-62.
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O'Shaughnessy, J., et al., Iniparib plus chemotherapy in metastatic triple-negative 
breast cancer. N Engl J Med, 2011. 364(3): p. 205-14.
74.
Singh, J., et al., Phase 2 trial of everolimus and carboplatin combination in patients 
with triple negative metastatic breast cancer. Breast Cancer Res, 2014. 16(2): p. R32.
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Andre, F. and C.C. Zielinski, Optimal strategies for the treatment of metastatic triple-
negative breast cancer with currently approved agents. Ann Oncol, 2012. 23 Suppl 
6: p. vi46-51.
 
 
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Brufsky, A.M., et al., RIBBON-2: a randomized, double-blind, placebo-controlled, 
phase III trial evaluating the efficacy and safety of bevacizumab in combination with 
chemotherapy for second-line treatment of human epidermal growth factor receptor 
2-negative metastatic breast cancer. J Clin Oncol, 2011. 29(32): p. 4286-93.
77.
Brufsky, A., et al., Second-line bevacizumab-containing therapy in patients with 
triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial. Breast 
Cancer Res Treat, 2012. 133(3): p. 1067-75.
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Cortes, J., et al., Eribulin monotherapy versus treatment of physician's choice in 
patients with metastatic breast cancer (EMBRACE): a phase 3 open-label 
randomised study. Lancet, 2011. 377(9769): p. 914-23.
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Pivot, X.B., et al., Activity of ixabepilone in oestrogen receptor-negative and 
oestrogen receptor-progesterone receptor-human epidermal growth factor receptor 
2-negative metastatic breast cancer. Eur J Cancer, 2009. 45(17): p. 2940-6.
80.
McCullough, A.E., et al., Central pathology laboratory review of HER2 and ER in 
early breast cancer: an ALTTO trial [BIG 2-06/NCCTG N063D (Alliance)] ring 
study. Breast Cancer Res Treat, 2014. 143(3): p. 485-92.
81.
Goss, P.E., et al., Adjuvant lapatinib for women with early-stage HER2-positive 
breast cancer: a randomised, controlled, phase 3 trial. Lancet Oncol, 2013. 14(1): p. 
88-96.
82.
Perez, E.A., et al., HER2 testing by local, central, and reference laboratories in 
specimens from the North Central Cancer Treatment Group N9831 intergroup 
adjuvant trial. J Clin Oncol, 2006. 24(19): p. 3032-8.
83.
Adams, S., et al., Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-
Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer 
Trials: ECOG 2197 and ECOG 1199. J Clin Oncol, 2014.
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Loi, S., et al., Tumor infiltrating lymphocytes are prognostic in triple negative breast 
cancer and predictive for trastuzumab benefit in early breast cancer: results from the 
FinHER trial. Ann Oncol, 2014. 25(8): p. 1544-50.
85.
Cimino-Mathews, A., et al., Metastatic triple-negative breast cancers at first relapse 
have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: 
a pilot study. Hum Pathol, 2013. 44(10): p. 2055-63.
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Liu, S., et al., Prognostic significance of FOXP3+ tumor infiltrating lymphocytes in 
breast cancer depends on estrogen receptor and human epidermal growth factor 
receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast 
Cancer Res, 2014. 16(5): p. 432.
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Savas, P., et al., Oncogene addiction and immunity: clinical implications of tumour 
infiltrating lymphocytes in breast cancers overexpressing the HER2/neu oncogene.
Curr Opin Oncol, 2014. 26(6): p. 562-7.
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Briggs, S. and I. Tomlinson, Germline and somatic polymerase epsilon and delta 
mutations define a new class of hypermutated colorectal and endometrial cancers. J 
Pathol, 2013. 230(2): p. 148-53.
 
 
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Dewey, F.E., et al., Clinical interpretation and implications of whole-genome 
sequencing. JAMA, 2014. 311(10): p. 1035-45.
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Vollan, H.K., et al., A tumor DNA complex aberration index is an independent 
predictor of survival in breast and ovarian cancer. Mol Oncol, 2014.
91.
Ignatiadis, M. and S.J. Dawson, Circulating Tumor Cells and Circulating tumor DNA 
for precision medicine: Dream or reality? Ann Oncol, 2014.
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Prat, A., et al., Predicting response and survival in chemotherapy-treated triple-
negative breast cancer. Br J Cancer, 2014. 111(8): p. 1532-41.
93.
Kriegsmann, M., et al., Mutational profiles in triple-negative breast cancer defined by 
ultradeep multigene sequencing show high rates of PI3K pathway alterations and 
clinically relevant entity subgroup specific differences. Oncotarget, 2014.
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Banerji, S., et al., Sequence analysis of mutations and translocations across breast 
cancer subtypes. Nature, 2012. 486(7403): p. 405-9.
95.
Cancer Genome Atlas, N., Comprehensive molecular portraits of human breast 
tumours. Nature, 2012. 490(7418): p. 61-70.
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Rossille, D., et al., High level of soluble programmed cell death ligand 1 in blood 
impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a 
French multicenter clinical trial. Leukemia, 2014.
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Pico de Coana, Y., et al., Ipilimumab treatment results in an early decrease in the 
frequency of circulating granulocytic myeloid-derived suppressor cells as well as 
their Arginase1 production. Cancer Immunol Res, 2013. 1(3): p. 158-62.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.6 – Future Biomedical 
Research will be used to study various causes for how subjects may respond to a 
drug/vaccine.  Future biomedical research specimen(s) will be stored to provide a 
resource for future trials conducted by Merck focused on the study of biomarkers 
responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease.  The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
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 
 
 
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does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
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.
 
 
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6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
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.
 
 
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9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. [insert: 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. 
OR Buccal swab specimens will be collected inside the cheek with no associated 
venipuncture to obtain the specimen. Therefore, there will not be an additional risk for 
the subject.]
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 
 
 
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specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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ECOG Performance Status
12.4
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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Abbreviations
12.5
Abbreviation/Term
Definition
1L
First Line
AE
Adverse Event
ADA
Anti-Drug Antibodies
AJCC
American Joint Committee on Cancer
ALT
Alanine Aminotransferase
AP
Alkaline Phosphatase
aPTT
Activated Partial Thromboplastin Time
AR
Androgen Receptor
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
β-hCG
β-human Chorionic Gonadotropin
BRCA
Breast Cancer 1
CBC
Complete Blood Count
CD8+
Cluster of Differentiation 8 positive
CI
Confidence Interval
CNS
Central Nervous System
CR
Complete Response
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCs
Circulating Tumor Cells
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
DIC
Disseminated Intravascular Coagulation
DKA
Diabetic Ketoacidosis
DNA
Deoxyribonucleic acid
DRFS
Distant Recurrence-Free Survival
ECG
Electrocardiogram
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
eCRFs
Electronic Case Report Forms
EGFR
Epidermal Growth Factor Receptor
EMT
Epithelial-to-Mesenchymal Transition
ER
Estrogen Receptor
ERC
Ethics Review Committee
EU
European Union
FAS
Full Analysis Set
FBR
Future Biomedical Research
 
 
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Abbreviation/Term
Definition
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FGFR
Fibroblast Growth Factor Receptor
FISH
Fluorescent In-Situ Hybridization
FNA
Fine Needle Aspirate
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GI
Gastrointestinal
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
H&E
Hematoxylin and Eosin
HER2
Human Epidermal Growth Factor Receptor 2
HGFR
Hepatocyte Growth Factor Receptor
HIV
Human Immunodeficiency Virus
HPV
Human Papilloma Virus
HR
Hormone Receptor
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDO1
Indoleamine 2,3-DiOxygenase 1
IgC
Immunoglobulin Constant
IHC
Immunohistochemistry
INR
International Normalized Ratio
irAEs
Immune-related Adverse Events
IRB
Institutional Review Board
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
Kg
Kilogram
KM
Kaplan-Meier
KN
KEYNOTE
mAb
Monoclonal Antibody
MAPKK
Mitogen-Activated Protein Kinase Kinase 
mcL
Microliters
Mg
Milligram
Mg/kg
Milligram per Kilogram
mL
milliliter
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 
 
 
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Abbreviation/Term
Definition
Inc.
NA or N/A
Not Applicable
NCI
National Cancer Institute
NGS
Next Generation Sequencing
NK
Natural Killer
NMR
Nuclear Magnetic Resonance
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-counter
PD
Progressive Disease
PD-1
Programmed Death Receptor-1
PD-L1
Programmed Death - Ligand 1
PD-L2
Programmed Death - Ligand 2
PFS
Progression-Free Survival
PGt
Pharmacogenetic
PI3K
PhosphoInositide-3-Kinase 
PIN
Personal Identification Number
PK
Pharmacokinetic
PK-PD
Pharmacokinetic-Pharmacodynamic
PKCθ
Protein Kinase C theta
PO
Oral Administration
PR
Progesterone Receptor
PR
Partial Response
PS
Performance Status
PT
Prothrombin Time
PTEN
Phosphatase and TEnsin Homolog
Q3W
Every 3 Weeks
Q2W
Every 2 Weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SHP-1
Src-Homology 2 domain-containing phosphatase-1
SHP-2
Src-Homology 2 domain-containing phosphatase-2
SIM
Site Imaging Manual
SOC
Standard of Care
SOP
Standard Operating Procedures
T3
Total thriiodothyronine
 
 
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Abbreviation/Term
Definition
T4
Free tyroxine 
TCGA
The Cancer Genome Atlas
T1DM
Type-1 Diabetes Mellitus
TILs
Tumor-Infiltrating Lymphocytes
TPC
Treatment of Physician’s Choice
Tregs
Regulatory T Cells
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
V-type
Ig Variable-type
WBC
White Blood Cell
WES
Whole Exome Sequencing
WGS
Whole Genome Sequencing
ZAP70
Zeta-chain-Associated Protein kinase 70
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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Supplemental SAP
17 June 2016– AMENDMENT #1
TABLE OF CONTENTS
TABLE OF CONTENTS......................................................................................1
LIST OF TABLES................................................................................................2
LIST OF FIGURES ..............................................................................................3
1. INTRODUCTION ..........................................................................................4
2. SUMMARY OF CHANGES..........................................................................4
3. ANALYTICAL AND METHODOLOGICAL DETAILS.......................4
3.1 Statistical Analysis Plan Summary...........................................................4
3.2 Responsibility for Analyses/In-House Blinding.......................................5
3.3 Hypotheses/Estimation .............................................................................6
3.4 Analysis Endpoints ...................................................................................6
3.5 Analysis Populations.................................................................................7
3.6 Statistical Methods....................................................................................8
3.7 Interim Analyses.....................................................................................11
3.8 Multiplicity .............................................................................................15
3.9 Sample Size and Power Calculations......................................................15
3.10
Subgroup Analyses and Effect of Baseline Factors..........................20
3.11
Compliance (Medication Adherence)...............................................20
3.12
Extent of Exposure............................................................................20
 
 
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LIST OF TABLES
Table 1
Censoring Rules for DOR.................................................................................... 9
Table 2
Analysis Strategy for Primary/Secondary Efficacy Endpoints in Cohorts A and 
C
........................................................................................................................... 10
Table 3
Probability of Futility under Different True Response Rate§ in PD-L1 (-) ....... 14
Table 4
Probability to Initiate Cohort C under Different True ORR in PD-L1 Strong (+)
........................................................................................................................... 15
Table 5
Summary of Sample Size Calculation ............................................................... 16
Table 6
Two-sided 95% A-C CI of ORR with Different Sample Size........................... 17
Table 7
Two-sided 95% A-C CI of ORR with 55 Evaluable Subjects........................... 18
Table 8
Two-sided 95% Exact CI of AE Incidence Rate with 55 Evaluable Subjects... 18
Table 9
Two-sided 95% A-C CI of ORR with 80 or 100 Subjects................................. 19
Table 10
Two-sided 95% Exact CI of AE Incidence Rate with 80 Evaluable Subjects... 20
 
 
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LIST OF FIGURES
Figure 1
Decision Tree..................................................................................................... 13
 
 
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SUPPLEMENTAL STATISTICAL ANALYSIS PLAN (SSAP)
1. 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. SUMMARY OF CHANGES 
Changes are based on the protocol amendment 01. 

Increased the subject number in Cohort B (1L, PD-L1+) from ~40 to ~80.

Updated primary efficacy objectives to indicate that estimation will be utilized 
instead of hypothesis testing.  The sections of statistical methods, multiplicity, sample 
size and power calculation and interim analysis were updated to align with this 
change.

Updated PD-L1 blinding and other standard language.

Removed subgroup analysis by BRAC1/2 status, specified Previous chemotherapy 
subgroups as 2/3 L vs. 4L+ and added subgroup of liver metastases

Added an exploratory endpoint on the association between LDH and response to 
pembrolizumab as monotherapy for mTNBC and corresponding  analysis

Added biomarker analysis methods
3. ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
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) (Sections 3.2 through 3.12).
In addition, a separate analysis plan document will be issued prior to biomarker unblinding 
for each of the following laboratory procedures and assessments: (1) Biomarkers (detailed in 
Protocol Section 7.1.3.4 and 7.1.3.5) and their association with antitumor efficacy and (2) 
Pharmacokinetic and pharmacodynamics evaluation (detailed in Protocol Section 7.1.3.3)
 
 
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Study Design Overview
A Phase II Clinical Trial of Pembrolizumab as Monotherapy in Subjects 
with Metastatic Triple-Negative Breast Cancer (mTNBC)
Treatment Assignment
Treatment assignment is open label. 
Analysis Populations
Efficacy: All Subjects as Treated (ASaT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
Overall Response Rate (ORR)
Statistical Methods for Key 
Efficacy Analyses
ORR estimation

2L+ population
o
PD-L1 (+) population (Cohort A)
o
Overall population (Cohort A)
o
PD-L1 strong (+) population (Cohorts A+C)

1L population (Cohort B)

Counts and percentages

95% Agresti-Coull confidence intervals  
Statistical Methods for Key 
Safety Analyses
Counts and percentages of AEs will be provided.  Confidence intervals 
for rates of AEs of clinical interest will be computed using the exact 
binomial method.
Interim Analyses

Futility analysis for 2L+ subjects (Cohort A) with PD-L1 (-) 
tumors based on no progression
o
~25 PD-L1 (-) subjects
o
If no response or stable disease, continue 2L+ 
population (Cohort A) in PD-L1 (+) patients only 

Evaluation of expansion to cohort C for PD-L1 strong (+) 
population based on ORR.
o
~10 patients evaluable through response, progression or 
18-week scan, whichever comes first.
o
Cohort C to start if ≥ 1 responses observed
The final analysis of Cohorts A and C combined is to be completed when 
subjects are evaluable through response, progression or 18-week scan, 
whichever comes first.
Multiplicity
This is an estimation study. No multiplicity adjustment will be applied.
Sample Size and Power
The planned sample size is up to approximately 285 subjects. 

~160 subjects in the 2L+ overall population (Cohort A)

~93/160 2L+ subjects (~58%) expected to be PD-L1 (+), if PD-L1 
(-) is not futile at the futility analysis; ~135 2L+ subjects expected 
to be PD-L1 (+), if PD-L1 (-) is discontinued after the futility 
analysis

~55 PD-L1 strong (+) subjects (Cohort C and  PD-L1 strong (+) 
subgroup from Cohort A)

~80 PD-L1 (+) first line subjects (Cohort B)
3.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
clinical biostatistics department of the SPONSOR.
 
 
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This trial is being conducted as an open-label non-randomized single-arm clinical trial for 
each cohort, i.e., subjects, investigators, and SPONSOR personnel will be aware of subject 
treatment assignments after each subject is enrolled and treatment is assigned.  The 
investigator and 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 in Cohort A. A designated Sponsor team (may include unblinded Sponsor 
statisticians, unblinded Sponsor statistical programmers, unblinded Sponsor clinical 
scientists, , unblinded clinical directors, and unblinded data management personnel) will have 
access to the subject-level PD-L1 results in Cohort A for the purpose of data review and will 
have no other responsibilities associated with the study. A summary of PD-L1 biomarker 
prevalence and biomarker cutoff analysis will be provided by the unblinded statistician. 
Biomarker cutoff analysis will inform the team about the outcome of the interim analyses and 
whether or not the pre-specified go/no go decision criteria are met. The estimation of tumor 
efficacy, e.g. ORR, DOR and DCR, etc. based on RECIST 1.1 by the central imaging vendor 
may be provided by another unblinded Sponsor statistician while the trial is ongoing. 
The Clinical Biostatistics department will generate the allocation schedule for study 
treatment assignment. Allocation will be implemented in an interactive voice response 
system (IVRS).
3.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Protocol Section 3.0. 
3.4
Analysis Endpoints
The efficacy and safety endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
3.4.1
Efficacy Endpoints
The primary efficacy endpoint is overall response rate (ORR), defined as the proportion of 
subjects in the analysis population who have complete response (CR) or partial response 
(PR), based on RECIST 1.1 by the central imaging vendor at any time during the study.  As 
supportive analyses, ORR will also be evaluated by a) site investigator and local radiology 
review based on RECIST 1.1 and b) irRECIST by the central imaging vendor.
Secondary efficacy endpoints include:

Duration of response (DOR), defined as the time from first documented evidence of 
CR or PR until disease progression or death due to any cause, whichever occurs first,
for subjects who demonstrate CR or PR, based on RECIST 1.1 by the central imaging 
vendor.

Disease control rate (DCR), defined as the percentage of subjects who have achieved 
confirmed CR or PR or have demonstrated SD for at least 24 weeks prior to any 
evidence of progression, based on RECIST 1.1 by the central imaging vendor.

Progression-free survival (PFS), defined as the time from first dose of study 
medication to the first documented disease progression or death due to any cause, 
whichever comes first, based on RECIST 1.1 by the central imaging vendor. 
 
 
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
Overall survival (OS), defined as the time from first dose of study medication to 
death due to any cause.
As exploratory endpoints, DOR and DCR and PFS will also be evaluated based on a) 
RECIST 1.1 by study site and local radiology review and b) irRECIST by the central imaging
vendor.
3.4.2
Safety Endpoints 
A description of safety measures is provided in Protocol Section 4.2.3.2 Safety Endpoints 
and Section 7.  
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, and vital signs. Safety parameters to be analyzed 
include, but are not limited to, AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, 
specific events will be collected and designated as events of clinical interest (ECIs) as 
described in Protocol Section 7.2.3.2.
3.4.3
Biomarker Endpoints
A separate biomarker SAP will be provided for the following endpoints/analyses.

The association between PD-L1 protein expression by IHC and antitumor activity to
pembrolizumab as monotherapy for mTNBC.

The association between antitumor activity of pembrolizumab in mTNBC and 
efficacy/resistance biomarkers, utilizing tumor and blood specimens obtained before/after 
treatment and at disease progression.

The performance comparison of PD-L1 assessment by IHC in newly-obtained vs. 
archived tumor samples.
3.4.4
Pharmacokinetic Endpoints
Pharmacokinetic parameters and the presence of anti-drug antibodies, following IV 
administration of 200 mg pembrolizumab Q3W as monotherapy in subjects with mTNBC 
(details see Protocol Section 4.2.3.4.)
3.4.5
Other Endpoints
Other endpoints include association between genetic variation and response to the 
treatment(s) administered,  variation across the human genome for the association with 
clinical data (details see Protocol Sections 4.2.3.5 and 4.2.3.6.) and the association between 
LDH and efficacy response to pembrolizumab as monotherapy for mTNBC.
3.5
Analysis Populations
3.5.1
Efficacy Analysis Populations
The All-Subjects-as-Treated (ASaT) population, which consists of as all enrolled subjects 
who receive at least one dose of study medication with measurable metastatic disease at 
baseline, will serve as the primary population for the analyses of efficacy data in this trial. 
 
 
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Details on the approach to handling missing data for efficacy analyses are provided in 
Section 3.6 Statistical Methods.
3.5.2
Safety Analysis Populations
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
3.6
Statistical Methods
3.6.1
Statistical Methods for Efficacy Analyses
Efficacy of pembrolizumab as 2L+ monotherapy for mTNBC will be evaluated primarily in 
PD-L1 (+) and overall population (all comers) in Cohort A, and also in subjects with PD-L1 
strong (+) tumors from Cohorts A and C combined.  .  Cohort A will be evaluated for 
association between PD-L1 biomarker expression and antitumor activity.
The primary efficacy endpoints are ORR based on RECIST 1.1 by the central imaging 
vendor in subjects with PD-L1 (+) mTNBC of Cohorts A, overall population (all comers) of 
Cohort A and in subjects with PD-L1 strong (+) mTNBC. The point estimate, 95% Agresti-
Coull confidence interval (as determined by the upper and lower 97.5% one-sided confidence 
bounds) will be provided based on normal approximation for the binomial distribution.  
Subjects without response data will be counted as non-responders.
Similarly, a supportive analysis to the primary method, ORR based on RECIST 1.1 by study 
site investigator and local radiology review will also be performed in the same fashion. 
For the secondary endpoint of DCR, similar estimation methods used for ORR will be 
applied.
For the secondary endpoint of DOR, the definitions are the following: 
For subjects who demonstrate CR or PR, duration of response is defined as the time from 
first documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first.
Subjects who are alive, have not progressed, have not initiated new anti-cancer treatment, 
and have not been determined to be lost to follow-up are considered ongoing responders at 
the time of analysis.
Censoring rules for DOR are summarized in Table 1.
 
 
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Table 1
Censoring Rules for DOR
Situation
Date of Progression or 
Censoring
Outcome
No progression nor death, no 
new anti-cancer therapy 
initiated
Last adequate disease 
assessment
Censor
(non-event)
No progression nor death, 
new anti-cancer therapy 
initiated
Last adequate disease 
assessment before new anti-
cancer therapy initiated
Censor
(non-event)
after ≥ 2 missed adequate 
disease assessments
Last adequate disease 
assessment prior to the after 
≥ 2 missed adequate disease 
assessments
Censor
(non-event)
Death or progression after ≤ 
1 missed adequate disease 
assessments
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered 
inadequate for evaluation of response.  
For DOR, PFS and OS, Kaplan-Meier (KM) curves, median estimates, and survival at 6 and 
12 months based on the KM curves (95% CI is based on Greenwood's formula) will be 
provided as appropriate.  Subjects without efficacy evaluation data or without survival data 
will be censored at Day 1.  The restricted mean survival time (RMST) for DOR will also be 
provided as a supportive analysis.  Similar estimation methods will be applied to the efficacy 
analyses for the subjects with PD-L1 (+) mTNBC in Cohort B.
Table 2 summarizes the key efficacy analyses for primary and secondary endpoints in this 
study.
 
 
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Table 2
Analysis Strategy for Primary/Secondary Efficacy Endpoints in Cohorts A 
and C
Similar efficacy methods will be applied to Cohort B for subjects with PD-L1 (+) tumors 
receiving pembrolizumab as 1L monotherapy for mTNBC.
3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs by PD-L1 status within cohort 
and total (combining across Cohorts A-C).  Summary statistics (counts, percentage, mean, 
standard deviation, etc.) will be provided for the safety endpoints as appropriate.  The 
Endpoint/Variable
(Description, Time Point)
Statistical 
Method
Analysis 
Population
Missing Data Approach
Primary:
ORR, based on RECIST1.1 by the 
central imaging vendor, 
95% Agresti-
Coull CI 
ASaT
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Subjects with missing 
data are considered non-
responders
Secondary:
Response duration (DOR) 
Based on RECIST1.1
o
by the central imaging 
vendor 
o
by study site investigator 
and local radiology review
Summary 
statistics using 
Kaplan-Meier 
method
All 
responders
- PD-L1 (+)
- overall 
- PD-L1 
strong (+)
Non-responders are 
excluded in analysis
ORR
Based on RECIST1.1
o
by study site investigator 
and local radiology review
Agresti-Coull 
95% CI
ASaT
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Subjects with missing 
data are considered non-
responders
DCR
Based on RECIST1.1
o
by the central imaging 
vendor
o
by study site investigator 
and local radiology review
Agresti-Coull 
95% CI
ASaT
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Subjects with missing 
data are considered non-
responders
Progression-free survival (PFS)
Based on RECIST1.1
o
by the central imaging 
vendor
o
by study site investigator 
and local radiology review
Summary 
statistics using 
Kaplan-Meier 
method
ASaT
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Censored at last 
assessment
Overall survival (OS) 
Summary 
statistics using 
Kaplan-Meier 
method
ASaT
- PD-L1 (+)
- overall
- PD-L1 
strong (+)
Censored at last 
assessment
95% confidence interval is determined by the upper and lower 97.5% one-sided confidence bounds.
 
 
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confidence interval for the incidence rate of Grade 2 or higher adverse events with an 
immune etiology and the incidence rate of Grade 4/5 AEs will be provided as appropriate.  
3.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
Baseline characteristics will be assessed by the use of tables and/or graphs for each cohort.  
No statistical hypothesis tests will be performed on these characteristics.  The number and 
percentage of subjects screened, treated, primary reasons for screening failure, and 
discontinuation will be displayed.  Demographic variables (e.g., age, region), baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by cohort either by descriptive statistics or categorical tables.
Biomarker Analyses
The evaluation of a general positive association between CPS and ORR will be investigated 
via standard logistic regression as well as generalized additive models. The potential to 
achieve a cut-off greater than CPS = 1% for defining a PD-L1 strongly positive population 
will involve a review of how the positive predictive value (PPV, response rate in those above 
a cut-off), negative predictive value (NPV, response rate in those below the cut-off), and 
fraction of patients defined as strongly positive change as a function of increasing cut-offs 
and whether there is evidence for a relative improvement in clinical utility relative to the 1% 
CPS cut-off. A PD-L1 strongly positive cut-off that maintains high NPV (e.g. near or above 
90%) while achieving meaningful enrichment of response and largely capturing patients 
showing durable clinical benefit is sought. The profiles of PPV, NPV, and the percentage of 
patients above a given cut-off along with intervals quantifying the uncertainty in those 
profiles will be estimated as a function of potential cut-offs.
Receiver operating 
characteristic curve analysis will also be used to understand the sensitivity and specificity 
profile and examine cut-offs that might be suggested based on the ROC curve and their 
appropriateness with regard to PPV and NPV. CPS ranges for any promising cut-offs will 
also have to be gauged in the context of practical implementation and interpretation by 
pathologists in clinical practice.
Exploratory Analyses
The association between LDH and efficacy response to pembrolizumab as monotherapy for 
mTNBC may be explored.
3.7
Interim Analyses
There are two interim analyses planned in this study. For Cohort A in Part 1, a futility 
analysis will be performed for subjects with PD-L1 (-) tumors and an interim analysis for 
potential efficacy expansion will be performed for subjects with PD-L1 strong (+) tumors in 
this cohort.  
The PD-L1 strong (+) population (10 or more subjects depending on the prevalence of PD-L1 
strong (+) tumors in the 2L+ population from Cohort A) may be expanded by continuing 
enrollment of subjects with PD-L1 strong (+) tumors into Cohort C, if at least one responder 
is observed in this subpopulation from Cohort A. The combined sample size of up to ~55
 
 
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subjects with PD-L1 strong (+) tumors from Cohorts A and C is driven by the primary 
efficacy hypothesis for subjects with PD-L1 strong (+) tumors (with futility bound accounted 
for the IA in this subpopulation).
The detailed process is described as below:
1. Enrollment will begin independent of PD-L1 tumor status. 
2. A futility analysis will start when the first ~25 subjects with PD-L1 (-) tumors are 
evaluable through response, progression or 18-week tumor imaging, whichever 
comes first.  The purpose of this interim analysis is to check treatment futility for 
subjects with PD-L1 (-) tumors.  
3. If the futility boundary is not crossed, that is at least one subject with response or 
stable disease is observed in subjects with PD-L1 (-) tumors, the trial enrollment will 
continue as planned.  If the futility boundary is crossed for subjects with PD-L1 (-)
tumors, then such subjects may be excluded from further enrollment in the trial. That 
is, the trial will continue to only enroll subjects with PD-L1 (+) tumors until there are 
160 subjects in total.
4. An efficacy futility interim will also be performed for the PD-L1 strong (+)
subpopulation of Cohort A, and enrollment of Cohort C for PD-L1 strong (+) may be 
initiated if one or more responders are observed in at least 10 subjects from Cohort A.  
Figure 1 illustrates the study diagram for decision making (a study decision tree).
 
 
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Figure 1
Decision Tree
IA1 in PD-L1 (-):
≥1 response or SD
Y
N
No 
Cohort 
C
Y
Continue to enroll all 
comers to Cohort  A
IA2 in PD-L1 
strong (+): ≥1 
responder in 10 or 
more subjects?
May initiate C [PD-L1 strong 
(+)] until ~55 in (A+C)
FA
[Primary Hypothesis 1]:
Estimate ORR in PD-L1 
strong (+) from A+C?
FA 
[Primary Hypothesis 2]: 
estimate ORR  in PD-L1 
(+) from A
Continue 
enrolling 
PD-L1 (-) to Cohort A 
(Next Page)
Y
N
IA1 in PD-L1 (-):
≥1 response or SD
Y
Only enroll PD-L1 (+)
to Cohort  A
IA2 in PD-L1 
strong (+): ≥1 
responder in 10 or 
more subjects?
May initiate C [PD-L1 
strong (+)] until ~55 in 
(A+C)
FA
[Primary Hypothesis 1]:
estimate ORR in PD-L1 strong 
(+) from A+C
FA 
[Primary Hypothesis 2]: 
estimate ORR in PD-L1 
(+) from A
No 
Cohort 
C
N
 
 
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Interim Analysis for Futility (IA1)
An interim futility check will be performed for the PD-L1 (-) population in Cohort A. 
Enrollment of PD-L1 (-) population will be stopped, if futility bound is reached. At least one 
subject without disease progression among the 25 subjects is needed for the further 
enrollment of subjects with PD-L1 (-) tumors.  Table 3 lists the probability of stopping for 
futility at different true response rate in PD-L1 (-) based on different stopping rules.
Table 3
Probability of Futility under Different True Response Rate§ in PD-L1 (-)
Response Rate§ in PD-L1 (-)
Probability of Futility in PD-L1 (-)
Rule of ≥ 1 Responder 
or SD
Rule of ≥ 2 Responders or 
SD
1%
77.8%
97.4%
2%
60.3%
91.1%
5%
27.7%
64.2%
8%
12.4%
39.4%
10%
7.2%
27.1%
§Response rate: the proportion of responders (CR and PR) or subjects with stable disease.
Interim Analysis to Initiate Cohort C Expansion (IA 2)
IA2 (Cohort A) will be performed when at least 10 subjects with PD-L1 strong (+) tumors
are evaluable through response, progression or 18-week scan, whichever comes first.    One 
or more responses need to be observed in order to expand enrollment to additional subjects 
with PD-L1 strong (+) tumors (up to ~55 subjects in Cohorts A and C combined).  Table 4
shows the probability to initiate Cohort C under different true ORR in PD-L1 strong (+) 
subpopulation in Cohort A based on the rule of one or more responders.
 
 
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Table 4
Probability to Initiate Cohort C under Different True ORR in PD-L1 Strong (+)
ORR in PD-L1 Strong (+)
Probability to Initiate Cohort C
10%
65.1%
15%
80.3%
18%
86.3%
20%
89.3%
25%
94.4%
30%
97.2%
3.8
Multiplicity
This is an estimation study. The estimation of ORR and associated 95% confidence intervals 
of ORR will be provided. No multiplicity adjustment will be applied in ubjects with PD-L1 
(+) mTNBC of Cohorts A, overall population (all comers) of Cohort A and in subjects with 
PD-L1 strong (+) mTNBC.
There are also no hypotheses for other parameters of DOR, DCR, PFS, and OS or for Cohort 
B.
3.9
Sample Size and Power Calculations
The trial has a planned sample size of up to approximately N=285 subjects

N = ~160: 2L+ overall population (all comers; Cohort A)
o
Would expect N=93 PD-L1 (+) subjects based on 58% prevalence
o
Would expect N=135 PD-L1 (+) subjects if PD-L1 (-) patients are 
discontinued at interim analysis 

N = ~45: expansion for the 2L+ PD-L1 strong (+) population (Cohort C)
o
N ~ 55 expected for total PD-L1 strong (+) population (Cohort A subgroup + 
Cohort C) 

N = ~80: 1L PD-L1 (+) subjects (Cohort B)
The study is for estimation. 
 
 
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Table 5
Summary of Sample Size Calculation
Line of 
Therapy
Population
Cohort
N
Number of 
Observed 
Responders
ORR Estimates
95% A-C CI 
of ORR (%)
2L+
Overall 
population
A
160
24
15.0%
(10.2,21.4)
PD-L1 (+)
A
93
16
17.2%
(10.8, 26.2)
PD-L1 (+)
A
135
21
15.6%
(10.3, 22.7)
PD-L1 strong 
(+)
A+ C
55
11
20.0%
(11.4,32.5)
1L
PD-L1 (+)
B
80
24
30.0%
(21.0,40.8)
Details underlying the above summary calculations follow below.
ORR in the PD-L1 (+) and overall population in Cohort A
It is expected that ~160 subjects in Cohort A will be enrolled for investigating the association 
between PD-L1 protein expression by IHC and antitumor activity of pembrolizumab as 
monotherapy for mTNBC (Details in Biomarker Analysis SAP).
Similarly for the ORR in the PD-L1 (+) in Cohort A, if PD-L1 (-) is not futile at the futility 
analysis it is expected that ~93 subjects out of the ~160 enrolled subjects (~58% prevalence 
based on previous study) in Cohort A will have PD-L1 (+) expression.  With ~93 subjects, if 
there are at least 16 responders observed, the lower bound of the 95% CI for ORR will be 
above 10%.
If PD-L1 (-) is futile, there will be with ~135 subjects in Cohort A [excluding 25 PD-L1 (-) 
in the futility analysis]. If there are at least 21 responders observed, the lower bound of the 
95% CI for ORR will be above 10%.
Similarly for the ORR in the overall population in Cohort A, if PD-L1 (-) is not futile, there 
will be ~160 subjects. If there are at least 24 responders observed, the lower bound of the 
95% CI for ORR will be above 10%.
Table 6 shows the two-sided 95% A-C CI of ORR with different sample size for different 
observed response rates.
 
 
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Table 6
Two-sided 95% A-C CI of ORR with Different Sample Size 
Sample Size (N)
Number of Observed 
Responders
ORR Estimates
95% A-C CI of 
ORR (%)
93
10
10.8%
(5.8,18.9)
14
15.1%
(9.1,23.8)
16
17.2%
(10.8, 26.2)
19
20.4%
(13.4,29.8)
110
11
10.0%
(5.5,17.2)
17
15.5%
(9.8,23.5)
18
16.4%
(10.5, 24.5)
22
20.0%
(13.5,28.5)
135
14
10.4%
(6.2,16.8)
21
15.6%
(10.3,22.7)
27
20.0%
(14.1,27.6)
160
16
10.0%
(6.2,15.7)
24
15.0%
(10.2,21.4)
32
20.0%
(14.5,26.9)
170
17
10.0%
(6.3,15.5)
26
15.3%
(10.6,21.5)
34
20.0%
(14.6,26.7)
180
18
10.0%
(6.3,15.3)
27
15.0%
(10.5,21.0)
36
20.0%
(14.8,26.5)
ORR in PD-L1 strong (+) in Cohorts A + C
There will be ~55 subjects with PD-L1 strong (+) tumors enrolled in Cohort A and Cohort C.
Table 7 shows the two-sided 95% A-C CI of ORR with 55 evaluable subjects for different 
observed response rates.  With 55 subjects with PD-L1 strong (+) tumors, if there are at least 
11 responders observed, the lower bound of the 95% A-C CI for ORR will be above 10%.
 
 
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Table 7
Two-sided 95% A-C CI of ORR with 55 Evaluable Subjects
Number of Observed Responders
ORR Estimates
95% A-C CI of ORR (%)
6
10.9%
(4.7,22.2)
8
14.5%
(7.3,26.4)
9
16.4%
(8.6,28.5)
10
18.2%
(10.0,30.5)
11
20.0%
(11.4,32.5)
13
23.6%
(14.2,36.5)
14
25.5%
(15.7,38.4)
Table 8 shows the Two-sided exact 95% CI of AE Rate with 55 subjects.
Table 8
Two-sided 95% Exact CI of AE Incidence Rate with 55 Evaluable Subjects
Number of AE
AE Incidence Rate Estimates
95% CI of Incidence Rate (%)
6
10.9%
(4.1,22.2)
11
20.0%
(10.4,33.0)
17
30.9%
(19.1,44.8)
22
40.0%
(27.0,54.1)
28
50.9%
(37.1,64.6)
 
 
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ORR in PD-L1 (+) Cohort B
There will be ~80 subjects with PD-L1 (+) tumors enrolled in Cohort B. 
Table 9 shows the two-sided 95% CI of ORR with 80 or 100 subjects for different observed 
response rates. 
Table 9
Two-sided 95% A-C CI of ORR with 80 or 100 Subjects
Sample Size (N)
Number of Observed 
Responders
ORR Estimates
95% CI of ORR (%)
80
12
15%
(8.6,24.6)
16
20%
(12.6,30.1)
20
25%
(16.7,35.6)
24
30%
(21.0,40.8)
28
35%
(25.4,45.9)
32
40%
(30.0,51.0)
36
45%
(34.6,55.9)
100
15
15%
(9.2,23.4)
20
20%
(13.3,29.0)
25
25%
(17.5,34.4)
30
30%
(21.9,39.6)
35
35%
(26.3,44.8)
40
40%
(30.9,49.8)
45
45%
(35.6,54.8)
Table 10 shows the Two-sided exact 95% CI of AE Rate with 80 subjects.
 
 
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Table 10
Two-sided 95% Exact CI of AE Incidence Rate with 80 Evaluable Subjects
Number of AE
AE Incidence Rate Estimates
95% CI of Incidence Rate (%)
8
10.0%
(4.4,18.8)
16
20.0%
(11.9,30.4)
24
30.0%
(20.3,41.3)
32
40.0%
(29.2,51.6)
40
50.0%
(38.6,61.4)
3.10
Subgroup Analyses and Effect of Baseline Factors
Subgroup analyses are planned for the efficacy analyses in the classification variables: 

Age category (≤50 vs. >50 years)

Menopausal status 

PD-L1 IHC expression(PD-L1 strong (+), PD-L1 (+), PD-L1 (-) and overall)

Previous Chemotherapy (2/3 L vs. 4L+)

Liver metastases (Presence vs. Absence) 
3.11
Compliance (Medication Adherence)
A day within the study will be considered an On-Therapy day, if the subject receives the 
study medication infusion.  The number of Days on Therapy is the total number of days from 
the first day of study medication to the date of the last dose of study medication. 
Summary statistics for the number of Days on Therapy will be provided by treatment group 
for the FAS population.
3.12
Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion.  Summary statistics will be provided on Extent of Exposure 
for ASaT population.
 
 
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