Conditions: Triple Negative Breast Neoplasms
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1) Triple Negative Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety, tolerability and clinical activity of pembrolizumab (MK-3475) in combination with six chemotherapy regimens as neoadjuvant treatment for participants with triple negative breast cancer (TNBC).

Detailed description:

Arms:
arm 1: Participants receive pembrolizumab (K) 200 mg on Cycle 1 Day 1 followed by pembrolizumab 200 mg in Cycles 2-5 on Day 1 (once every 3 weeks; Q3W) PLUS nab-paclitaxel (KNp) starting at 125 mg/m\^2 in Cycles 2-5 on Days 1, 8 and 15 (once each week; QW). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via intravenous (IV) infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. arm 2: Participants first receive KNpCb Regimen 1 which consists of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS nab-paclitaxel (KNp) starting at 100 mg/m\^2 in Cycles 2-5 on Days 1, 8 and 15 (QW) PLUS carboplatin (Cb) starting at Area Under the Curve (AUC) 6 in Cycles 2-5 on Day 1 (Q3W). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via IV infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. arm 3: Participants first receive KNpCb Regimen 2 which consists of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS nab-paclitaxel (KNp) starting at 125 mg/m\^2 in Cycles 2-5 on Days 1, 8 and 15 (QW) PLUS carboplatin (Cb) starting at AUC 5 in Cycles 2-5 on Day 1 (Q3W). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via IV infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. arm 4: Participants first receive KNpCb Regimen 3 which consists of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS nab-paclitaxel (KNp) starting at 125 mg/m\^2 in Cycles 2-5 on Days 1, 8 and 15 (QW) PLUS carboplatin (Cb) starting at AUC 2 in Cycles 2-5 on Days 1, 8 and 15 (QW). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via IV infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. arm 5: Participants first receive KTCb Regimen 1 which consists of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS paclitaxel (T) starting at 80mg/m\^2 in Cycles 2-5 on Days 1, 8, and 15 (QW) PLUS carboplatin (Cb) starting at AUC 5 in Cycles 2-5 on Day 1 (Q3W). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via IV infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days. arm 6: Participants first receive KTCb Regimen 2 which consists of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS paclitaxel (T) starting at 80mg/m\^2 in Cycles 2-5 on Days 1, 8, and 15 PLUS carboplatin (Cb) starting at AUC 2 in Cycles 2-5 on Days 1, 8 and 15 (QW). This will be followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W). All treatments will be administered via IV infusion except for doxorubicin (A), which will be administered via IV injection. Each cycle is 21 days.

Interventions: intervention 1: Pembrolizumab intervention 2: Nab-paclitaxel intervention 3: Anthracycline (doxorubicin) intervention 4: Cyclophosphamide intervention 5: Carboplatin intervention 6: Paclitaxel
Intervention descriptions: intervention 1: 200 mg administered Q3W as an IV infusion. intervention 2: 125 mg/m\^2 or 100 mg/m\^2 administered weekly as an IV infusion, according to allocation. intervention 3: 60 mg/m\^2 administered Q3W as an IV injection. intervention 4: 600 mg/m\^2 administered Q3W as an IV infusion. intervention 5: AUC 6 or AUC5 administered Q3W as an IV infusion, or AUC2 administered weekly as an IV infusion, according to allocation. intervention 6: 80 mg/m\^2 or 70 mg/m\^2 administered weekly as an IV infusion, according to allocation.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02622074 
Document Date: 
19-Apr-2018 
A Phase 1b Study to Evaluate safety and clinical activity of 
Pembrolizumab (MK-3475) in combination with 
Chemotherapy as Neoadjuvant Treatment for Triple Negative 
Breast Cancer (TNBC) -(KEYNOTE 173) 


Product:  MK-3475 
1
Protocol/Amendment No.: 173-05 
MK-3475-173-05 Final Protocol
19-Apr-2018
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, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase 1b Study to Evaluate safety and clinical activity of Pembrolizumab (MK-3475) in 
combination with Chemotherapy as Neoadjuvant Treatment for Triple Negative Breast 
Cancer (TNBC) - (KEYNOTE 173)
IND NUMBER:  124,442
EudraCT NUMBER:  2015-002405-11
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
2.1
Trial Diagram........................................................................................................ 18
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 19
Primary Objective(s) & Hypothesis(es) .............................................................. 19
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 20
3.2
Exploratory Objectives......................................................................................... 20
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 21
Background ........................................................................................................... 21
4.1
Pharmaceutical and Therapeutic Background .................................................... 21
4.1.1
4.1.1.1
Disease Background..................................................................................... 21
4.1.1.2
Current and Emerging Neoadjuvant Treatments for TNBC ........................ 21
4.1.1.3
Targeting PD-1 immune checkpoints for cancer treatment ......................... 23
4.1.1.4
Targeting PD-1 immune checkpoints for TNBC ......................................... 24
Summary of Pembrolizumab Clinical Activities ................................................ 24
4.1.2
4.1.2.1
Summary of Pembrolizumab Clinical Activities in solid tumors ................ 24
4.1.2.2
Summary of pembrolizumab clinical activity in metastatic TNBC ............. 25
Rationale................................................................................................................ 25
4.2
Rationale for the Trial and Selected Subject Population .................................... 25
4.2.1
Rationale for Dose Selection/Regimen............................................................... 26
4.2.2
4.2.2.1
Rationale for Testing Pembrolizumab in combination with the selected 
TNBC neoadjuvant regimens....................................................................... 26
4.2.2.2
Rationale of selecting pembrolizumab 200mg Q3W dose .......................... 27
4.2.2.3
Starting Dose for This Trial ......................................................................... 29
4.2.2.4
Maximum Dose/Exposure for This Trial..................................................... 30
4.2.2.5
Rationale for Dose Interval and Trial Design .............................................. 31
Rationale for Endpoints ...................................................................................... 31
4.2.3
 
 
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4.2.3.1
Safety Endpoints .......................................................................................... 31
4.2.3.2
Efficacy Endpoints....................................................................................... 32
4.2.3.3
Planned Exploratory Biomarker Research................................................... 32
4.2.3.4
Future Biomedical Research........................................................................ 33
Benefit/Risk ........................................................................................................... 33
4.3
5.0
METHODOLOGY ................................................................................................... 33
Entry Criteria........................................................................................................ 33
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 33
5.1.1
Subject Inclusion Criteria.................................................................................... 34
5.1.2
Subject Exclusion Criteria .................................................................................. 36
5.1.3
Trial Treatment(s) ................................................................................................ 37
5.2
Dose Selection/Modification .............................................................................. 38
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 38
5.2.1.2
Rules for Dose Finding ................................................................................ 38
5.2.1.3
Definition of Dose-Limiting Toxicities ....................................................... 39
5.2.1.4
Replacement of Subjects in Part 1 ............................................................... 40
5.2.1.5
Dose Modification ....................................................................................... 41
5.2.1.5.1
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab ..................................................................................... 41
5.2.1.5.2
Dose modification / Discontinuation Guidelines for Nab-paclitaxel, 
Paclitaxel, Carboplatin, Doxorubicin and Cyclophosphamide ............. 46
Timing of Dose Administration .......................................................................... 52
5.2.2
5.2.2.1
Pembrolizumab ............................................................................................ 52
5.2.2.2
Nab-paclitaxel.............................................................................................. 53
5.2.2.3
Paclitaxel...................................................................................................... 53
5.2.2.4
Carboplatin................................................................................................... 53
5.2.2.5
Cyclophosphamide....................................................................................... 53
5.2.2.6
Doxorubicin ................................................................................................. 53
Trial Blinding/Masking....................................................................................... 54
5.2.3
Randomization or Treatment Allocation............................................................ 54
5.3
Stratification.......................................................................................................... 54
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 54
5.5
Acceptable Concomitant Medications ................................................................ 54
5.5.1
 
 
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Prohibited Concomitant Medications.................................................................. 54
5.5.2
Rescue Medications & Supportive Care............................................................. 55
5.6
Supportive Care Guidelines for Pembrolizumab ................................................ 55
5.6.1
Supportive Care Guidelines for Chemotherapy Agents...................................... 56
5.6.2
Diet/Activity/Other Considerations..................................................................... 56
5.7
Diet...................................................................................................................... 56
5.7.1
Contraception...................................................................................................... 56
5.7.2
Pregnancy............................................................................................................ 57
5.7.3
Use in Nursing Women....................................................................................... 58
5.7.4
Subject Withdrawal/Discontinuation Criteria................................................... 58
5.8
Subject Replacement Strategy............................................................................. 59
5.9
Beginning and End of the Trial ........................................................................... 59
5.10
Clinical Criteria for Early Trial Termination ................................................... 59
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 60
7.0
TRIAL PROCEDURES ........................................................................................... 65
Trial Procedures ................................................................................................... 65
7.1
Administrative Procedures.................................................................................. 65
7.1.1
7.1.1.1
Informed Consent......................................................................................... 65
7.1.1.1.1
General Informed Consent.................................................................... 65
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 65
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 66
7.1.1.3
Subject Identification Card .......................................................................... 66
7.1.1.4
Medical History ........................................................................................... 66
7.1.1.4.1
Disease Details...................................................................................... 66
7.1.1.4.2
Menopausal Status ................................................................................ 66
7.1.1.5
Prior and Concomitant Medications Review ............................................... 66
7.1.1.5.1
Prior Medications.................................................................................. 66
7.1.1.5.2
Concomitant Medications..................................................................... 67
7.1.1.6
Assignment of Screening Number............................................................... 67
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 67
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 67
 
 
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Clinical Procedures/Assessments........................................................................ 67
7.1.2
7.1.2.1
Adverse Event Monitoring........................................................................... 67
7.1.2.2
12-Lead Electrocardiogram (ECG).............................................................. 68
7.1.2.3
Echocardiography (ECHO) or Multigated Acquisition (MUGA) Scan ...... 68
7.1.2.4
Physical Exam.............................................................................................. 68
7.1.2.4.1
Full Physical Exam ............................................................................... 68
7.1.2.4.2
Directed Physical Exam........................................................................ 68
7.1.2.5
Vital Signs.................................................................................................... 68
7.1.2.6
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 68
7.1.2.7
Tumor Tissue Biopsy and Sample Collection ............................................. 69
7.1.2.8
Imaging Disease Assessment....................................................................... 69
7.1.2.9
Definitive Surgery........................................................................................ 69
7.1.2.10 Determination of Disease progression......................................................... 70
7.1.2.10.1 irRECIST Assessment of Disease......................................................... 70
Laboratory Procedures/Assessments .................................................................. 72
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 72
7.1.3.2
Menopausal Status ....................................................................................... 74
7.1.3.3
Pregnancy Test............................................................................................. 74
7.1.3.4
Correlative Blood Collections – Samples for Correlative, Genetic, and 
Exploratory Biomarker Analyses................................................................. 74
7.1.3.5
Future Biomedical Research Sample Collection ......................................... 75
Other Procedures................................................................................................. 75
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 75
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 75
7.1.4.2
Blinding/Unblinding .................................................................................... 76
7.1.4.3
Calibration of Critical Equipment................................................................ 76
Visit Requirements.............................................................................................. 76
7.1.5
7.1.5.1
Screening...................................................................................................... 76
7.1.5.2
Treatment Cycles ......................................................................................... 77
7.1.5.3
Definitive Surgery........................................................................................ 77
7.1.5.4
Post-Treatment Visits................................................................................... 77
7.1.5.4.1
End of Treatment or Early Discontinuation Visit................................. 77
7.1.5.4.2
Safety Follow-up Visit.......................................................................... 77
 
 
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7.1.5.4.3
Follow-up for Disease Status and Survival........................................... 78
Assessing and Recording Adverse Events .......................................................... 78
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 79
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 79
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 80
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 80
7.2.3.2
Events of Clinical Interest............................................................................ 81
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
Communication of Cohort Dose Level Adjustment ........................................... 85
7.3.1
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 85
Statistical Analysis Plan Summary ..................................................................... 85
8.1
Responsibility for Analyses/In-House Blinding ................................................. 87
8.2
Hypotheses/Estimation ......................................................................................... 87
8.3
Analysis Endpoints ............................................................................................... 87
8.4
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..................................... 87
8.4.1
Safety Endpoints ................................................................................................. 87
8.4.2
Derivations of Efficacy/Immunogenicity/Pharmacokinetics Endpoints............. 87
8.4.3
Derivations of Safety Endpoints ......................................................................... 88
8.4.4
Analysis Populations............................................................................................. 88
8.5
Safety Analysis Populations ............................................................................... 88
8.5.1
Efficacy Analysis Populations ............................................................................ 88
8.5.2
Statistical Methods................................................................................................ 89
8.6
Statistical Methods for Efficacy Analyses.......................................................... 89
8.6.1
Statistical Methods for Safety Analyses ............................................................. 89
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 90
8.6.3
8.6.3.1
Demographic and Baseline Characteristics ................................................. 90
Interim Analyses ................................................................................................... 90
8.7
Multiplicity ............................................................................................................ 90
8.8
 
 
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Sample Size and Power Calculations .................................................................. 90
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 91
8.10
Compliance (Medication Adherence).................................................................. 92
8.11
Extent of Exposure................................................................................................ 92
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 92
Investigational Product ........................................................................................ 92
9.1
Packaging and Labeling Information ................................................................. 93
9.2
Clinical Supplies Disclosure................................................................................. 93
9.3
Storage and Handling Requirements.................................................................. 94
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 94
9.5
Standard Policies................................................................................................... 94
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 94
Confidentiality....................................................................................................... 94
10.1
Confidentiality of Data ....................................................................................... 94
10.1.1
Confidentiality of Subject Records ..................................................................... 94
10.1.2
Confidentiality of Investigator Information........................................................ 95
10.1.3
Confidentiality of IRB/IEC Information............................................................. 95
10.1.4
Compliance with Financial Disclosure Requirements....................................... 95
10.2
Compliance with Law, Audit and Debarment ................................................... 96
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 97
10.4
Quality Management System............................................................................... 98
10.5
Data Management................................................................................................. 98
10.6
Publications ........................................................................................................... 98
10.7
11.0
LIST OF REFERENCES....................................................................................... 100
12.0
APPENDICES......................................................................................................... 103
Merck Code of Conduct for Clinical Trials...................................................... 103
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 105
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs 
and 
Investigational Site Staff .................................................................................... 109
 
 
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ECOG Performance Scale.................................................................................. 120
12.4
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 121
12.5
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
12.6
Evaluating Response in Solid Tumors .............................................................. 122
Abbreviations ...................................................................................................... 123
12.7
13.0
SIGNATURES......................................................................................................... 126
Sponsor's Representative ................................................................................... 126
13.1
Investigator.......................................................................................................... 126
13.2
 
 
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LIST OF TABLES
    
Table 1
Dose levels in Cohorts A, B, C, D, E and F........................................................... 16
Table 2
Adequate Organ Function Laboratory Values ....................................................... 35
Table 3
Trial Treatments..................................................................................................... 37
Table 4
Dose-Limiting Toxicity Criteria ............................................................................ 40
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab.................................................................... 42
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines .............................................................................................................. 45
Table 7
Levels of dose reduction ........................................................................................ 47
Table 8
Dose modification guideline for nab-paclitaxel, paclitaxel and carboplatin ......... 48
Table 9
Dose Modification Guidelines for Doxorubicin and Cyclophosphamide (AC)..... 51
Table 10 Imaging and Treatment after First Radiologic Evidence of PD............................. 72
Table 11 Laboratory Tests..................................................................................................... 73
Table 12 Evaluating Adverse Events .................................................................................... 83
Table 13 Sample Size and Power Calculation with Various Scenarios................................ 91
Table 14 Probability of Observing DLTs at the Time of DLT Assessment in the first 3 
Cycles..................................................................................................................... 91
Table 15 Product Descriptions.............................................................................................. 93
 
 
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LIST OF FIGURES
Figure 1
Trial Diagram......................................................................................................... 19
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
3.2
Secondary Objective(s) & Hypothesis(es)
Updated 
objective 
regarding 
Event 
Free 
Survival (EFS) and Overall 
Survival (OS), changing the 
start point from surgery to 
first dose of trial treatment.
Revised 
for 
consistency 
with pembrolizumab trials 
in the neo-adjuvant setting.
8.1, 8.2, 8.7
Multiple sections
Updated/added 
text 
to 
reflect interim analyses.
To evaluate safety, EFS,
and OS.
8.4.3
Derivations of 
Efficacy/Immunogenicity/Pharmacokinetics 
Endpoints
Updated the definitions of 
EFS and OS.
Revised 
to 
align 
with 
updates 
to 
secondary 
objectives.
8.6.1
Statistical Methods for Efficacy Analyses
Updated the condition for 
sensitivity analysis of pCR.
Clarified 
the 
original 
requirement.  
8.6.2
Statistical Methods for Safety Analysis
Deleted the text regarding 
AE phasing.
Revised 
for 
consistency 
with pembrolizumab trials 
in the neo-adjuvant setting.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Multiple sections
Multiple sections
Minor 
typographical 
corrections/insertions.
Correct minor typographical 
errors
for 
clarity 
and 
consistency.
4.1
Background
Changed language regarding 
approved indications
The 
existing 
statement 
suggested that the drug gained 
an indication in the US for its 
mechanism and not its efficacy 
and safety. Wording to refer to 
Investigator brochure added to 
avoid additional revisions for 
new approval updates.
4.2.2.2
Rationale 
of 
selecting 
pembrolizumab 200mg Q3W 
dose
Minor 
revision 
to 
text 
regarding 
the 
selection 
of 
fixed-dose regimen
Updated for consistency with 
pembrolizumab documents.
5.2.1.5.1
Dose 
Modification 
and 
Toxicity 
Management 
Guidelines for Pembrolizumab
Modified to include required 
discontinuation for recurrence 
of Grade 2 pneumonitis 
Updated for consistency with 
pembrolizumab documents.
5.6.1
Supportive Care Guidelines for 
Pembrolizumab
Removed reference to ECI/ECI 
guidance 
document; 
update 
includes 
Grade 
2 
infusion 
reaction
Updated for consistency with 
pembrolizumab documents.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
A Phase 1b Open-Label Study to Evaluate Pembrolizumab plus 
Chemotherapy as Neoadjuvant Treatment for Triple Negative Breast 
Cancer (TNBC)
Trial Phase
1b
Clinical Indication
Neoadjuvant treatment for locally-advanced TNBC
Trial Type
Interventional
Type of control
No Treatment Control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Cohort A (KNp / KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + nab-paclitaxel (Np) weekly] x 4 cycles, 
followed by pembrolizumab + doxorubicin + cyclophosphamide 
(KAC) Q3W x 4 cycles 
Cohorts B & C (KNpCb / KAC): Single dose pembrolizumab (K), 
followed by [pembrolizumab (K) Q3W + nab-paclitaxel (Np) weekly 
+ carboplatin (Cb) Q3W] x 4 cycles, followed by pembrolizumab + 
doxorubicin + cyclophosphamide (KAC) Q3W x 4 cycles.
Cohort D (KNpCb / KAC): Single dose pembrolizumab (K), followed 
by [pembrolizumab (K) Q3W + nab-paclitaxel (Np) weekly + 
carboplatin (Cb) weekly] x 4 cycles, followed by pembrolizumab + 
doxorubicin + cyclophosphamide (KAC) Q3W x 4 cycles.
Cohorts E (KTCb / KAC): Single dose pembrolizumab (K), followed 
by [pembrolizumab (K) Q3W + paclitaxel (T) weekly + carboplatin 
(Cb) Q3W] x 4 cycles, followed by pembrolizumab + doxorubicin + 
cyclophosphamide (KAC) Q3W x 4 cycles. 
Cohort F (KTCb / KAC): Single dose pembrolizumab (K), followed 
by [pembrolizumab (K) Q3W + paclitaxel (T) weekly + carboplatin 
(Cb) weekly] x 4 cycles, followed by pembrolizumab + doxorubicin + 
cyclophosphamide (KAC) Q3W x 4 cycles.
Note: each cycle = 21 days
Number of trial subjects
Approximately 100 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 50
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the main part of the trial for 
approximately 42 weeks from the time the subject signs the Informed 
Consent Form through the 30-day follow up visit following definitive 
surgery.  After a screening phase of ~28 days, each subject will be 
receiving study treatment based on the assigned cohort and dose level 
for approximately 27 weeks (9 cycles).  An End of Treatment/Early 
Discontinuation
Visit will be scheduled 3-6 weeks following 
discontinuation of treatment but prior to definitive surgery.  Each 
subject will undergo definitive surgery 3-6 weeks after discontinuation 
of trial treatment. Approximately 30 days following definitive surgery,
each subject will attend a safety Follow Up Visit.  Subjects will be 
followed for 30 days following surgery for all adverse events and 90 
 
 
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days for all serious adverse events (or 30 days following definitive 
surgery if the subject initiates new anticancer therapy, whichever is 
earlier). After surgery, subject’s disease follow-up (e.g. imaging 
assessments and clinical evaluations) and anticancer treatment for 
recurrent or metastatic disease will be at the discretion of subject’s 
treating physician per local standard of care.
However, the 
investigator or site staff will contact the subject via telephone every 12 
weeks for up to 24 months to obtain information regarding subject’s 
disease and survival status.
A list of abbreviations used in this document can be found in Section 12.7.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a Phase 1b, multi-center, open-label study to evaluate safety, tolerability and clinical 
activity of pembrolizumab in combination with two chemotherapy regimens as neoadjuvant 
treatment for triple negative breast cancer (TNBC). 
A commonly used standard neoadjuvant regimen for TNBC is a weekly taxane (e.g. 
paclitaxel) for 12 weeks followed by an anthracycline (e.g. doxorubicin 60mg/m2) plus 
cyclophosphamide at 600mg/m2 (AC) every 3 weeks (Q3W) for 4 cycles. The chemotherapy 
regimens included in this study are built upon the aforementioned regimen and on emerging 
clinical trial data. Pembrolizumab in combination with these regimens will be studied in the 
following six cohorts:   

Cohort A (KNp/ KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + nab-paclitaxel (Np) weekly] x 4 cycles (1 cycle = 21 
days), followed by KAC Q3W x 4 cycles

Cohorts B & C (KNpCb / KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + nab-paclitaxel (Np) weekly + carboplatin (Cb) Q3W] x 
4 cycles, followed by pembrolizumab + doxorubicin + cyclophosphamide (KAC) 
Q3W x 4 cycles.

Cohort D (KNpCb / KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + nab-paclitaxel (Np) weekly + carboplatin (Cb) weekly] 
x 4 cycles, followed by pembrolizumab + doxorubicin + cyclophosphamide (KAC) 
Q3W x 4 cycles. Please refer to Table 1 for specific dose levels.

Cohorts E (KTCb / KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + paclitaxel (T) weekly + carboplatin (Cb) Q3W] x 4 
cycles, followed by pembrolizumab + doxorubicin + cyclophosphamide (KAC) Q3W 
x 4 cycles. 

Cohort F (KTCb / KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + paclitaxel (T) weekly + carboplatin (Cb) weekly] x 4 
cycles, followed by pembrolizumab + doxorubicin + cyclophosphamide (KAC) Q3W 
x 4 cycles.
Randomization Ratio
N/A
 
 
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In all six cohorts, the dose and schedule of pembrolizumab will be fixed at 200mg Q3W; and 
a commonly used AC dose/schedule will be used, i.e. doxorubicin 60mg/m2 Q3W plus 
cyclophosphamide 600mg/m2 Q3W. The starting dose level of nab-paclitaxel is 125mg/m2
weekly in Cohorts A, C, & D and 100mg/m2 weekly in Cohort B. The starting dose level of 
paclitaxel is 80mg/m2 weekly in Cohorts E and F.  The starting dose level for carboplatin is 
AUC 6 Q3W in Cohort B, AUC 5 Q3W in Cohort C and E and AUC 2 QW in Cohorts D and 
F.
The study includes two parts. Part 1 is to determine a recommended Phase 2 dose (RP2D) of 
the combination regimen for Cohorts A, B, C, D, E and F respectively. Part 2 will consist of 
the expansion of the appropriate RP2D Cohort as defined in Section 5.2.1.2. 
 
 
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Predefined Dose Levels for Cohorts A, B, C, D, E and F
Predefined dose levels for Cohort A to F are shown in Table 1. 
Table 1
Dose levels in Cohorts A, B, C, D, E and F
Dose 
Level 
(DL)
Regimen Code
Dose levels for KNp or 
KNpCb
Dose levels for KAC
Cohort A
K: 200 mg Q3W x 4 
cycles
A: 60 mg/m2 x 4 cycles
C: 600 mg/m2 x 4 
cycles
DL1* 
KNp125 / KAC
K: 200 mg Q3W x 4 cycles
Np: 125 mg/m2 weekly x 12 
wks
DL -1
KNp100 / KAC
K: 200 mg Q3W x 4 cycles
Np: 100 mg/m2 weekly x 12 
wks
Cohort B
DL1
KNp100CbAUC6 / 
KAC
K: 200 mg Q3W x 4 cycles
Np: 100 mg/m2 weekly x 12 
wks
Cb: AUC6 Q3W x 4 cycles
Cohort C
DL1*
KNp125CbAUC5 / 
KAC
K: 200 mg Q3W x 4 cycles
Np: 125 mg/m2 weekly x 12 
wks
Cb: AUC5 Q3W x 4 cycles
DL -1
KNp100CbAUC5 / 
KAC
K: 200 mg Q3W x 4 cycles 
Np: 100 mg/m2 weekly x 12 
wks
Cb: AUC5 Q3W x 4 cycles
Cohort D
DL1*
KNp125CbAUC2 / 
KAC
K: 200 mg Q3W x 4 cycles
Np: 125 mg/m2 weekly x 12 
wks
Cb: AUC2 weekly x 12 wks
DL -1
KNp125CbAUC1.5 / 
KAC
K: 200 mg Q3W x 4 cycles 
Np: 125 mg/m2 weekly x 12 
wks
Cb: AUC1.5 weekly x 12 
wks
Cohort E
DL1*
KP80CbAUC5 / KAC
K: 200 mg Q3W x 4 cycles
T: 80 mg/m2 weekly x 12 
wks
Cb: AUC5 Q3W x 4 cycles
DL -1
KP70CbAUC5 / KAC
K: 200 mg Q3W x 4 cycles 
T: 70 mg/m2 weekly x 12 
wks
Cb: AUC5 Q3W x 4 cycles
 
 
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Dose 
Level 
(DL)
Regimen Code
Dose levels for KNp or 
KNpCb
Dose levels for KAC
Cohort F
DL1*
KP80CbAUC2 / KAC
K: 200 mg Q3W x 4 cycles
T: 80 mg/m2 weekly x 12 
wks
Cb: AUC2 weekly x 12 wks
DL -1
KP80CbAUC1.5 / 
KAC
K: 200 mg Q3W x 4 cycles 
T: 70 mg/m2 weekly x 12 
wks
Cb: AUC1.5 weekly x 12 
wks
* Note that DL1 is the starting dose level.
K=pembrolizumab; Np=nab-paclitaxel; T= paclitaxel Cb=carboplatin; AC=doxorubicin+cyclophosphamide; Q3W=every 
3 weeks.
Regimen Dose Finding Decision
The tolerability of each regimen dose level will be evaluated based on the assessment of dose 
limiting toxicities (DLTs). The decisions to stay at or de-escalate a dose level will depend on 
the evaluation of DLTs during the DLT evaluation period of the first part of the combinations 
in all cohorts which is defined as from Day 1 of Cycle 1 through the end of Cycle 3. 
Tolerability of KAC will be evaluated based on the DLT rates of subjects treated during the 
DLT evaluation period for KAC, which is defined as from Day 1 of Cycle 6 through the end 
of Cycle 7.  Detailed dose finding rules are provided in Section 5.2.1.2; DLT criteria are 
provided in Section 5.2.1.3.
The study is enrolling Cohorts C and D.
Cohorts E and F will begin enrollment 
simultaneously upon approval of Amendment 04. Each group will enroll 10 subjects and 
eligible subjects will be randomly assigned to one of these groups. Decisions regarding de-
escalation will be based on evaluating DLTs in accordance with the rules described in 
Section 5.2.1.2. Cohorts A and B have completed enrollment of 10 subjects. Cohorts C, D, E 
and F may be expanded depending on the demonstrated efficacy.
Regardless of which cohort or regimen dose level that a subject has been assigned, each 
subject will first receive a single dose of pembrolizumab 200mg as Cycle 1, followed by 4 
cycles of KNp (Cohort A), KNpCb (Cohorts B, C, and D) or KTCb (Cohorts E and F) as 
Cycle 2 to Cycle 5, and then followed by 4 cycles of KAC as Cycle 6 to Cycle 9. Addition of 
one cycle of pembrolizumab alone allows for evaluation of potential early changes in the 
tumor after exposure to pembrolizumab. 
Confirmation of TNBC Status: Subject’s TNBC status for eligibility at Screening will be 
based on the evaluation by the local pathologist in accordance with the criteria described in 
Section 5.1.2. However, a formalin-fixed paraffin-embedded (FFPE) tumor tissue sample or 
slides obtained at subject’s initial diagnosis must be submitted to a designated central 
laboratory for retrospective confirmation of subject’s TNBC status.  
Tumor biopsy for Translational Research: All subjects are required to have 2 separate 
tumor core needle biopsies, utilizing multiple passes, at Screening after all other eligibility 
 
 
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criteria have been met and at end of Cycle 1 following the first dose of pembrolizumab. The 
biopsy at the end of Cycle 1 is required but only to be performed if there is adequate tumor 
volume left as determined by the investigator. For subjects with adequate tumor volume left 
at the end of Cycle 3 as assessed by the investigator, an additional core needle biopsy will be 
performed only on subjects who agree to participate. Tumor tissue samples will also be 
collected at definitive surgery for subjects who have not achieved pathological complete 
response (pCR) at that time. All tumor tissue samples collected at different time points
during the study will be submitted to the designated central laboratories for translational 
research as described in more detail in Section 7.1.2. 
Breast MRI: Breast MRI will be performed at Screening for more accurate clinical staging 
of the primary tumor and axilla lymphadenopathy. Breast MRI are also performed at the end 
of Cycle 5 following treatment with the first combination regimen (KNp, KNpCb or KTCb), 
and after completion of the second combination regimen (KAC; Cycle 9) but prior to 
surgery. Changes from the baseline will be assessed by the investigator per RECIST 1.1.
Definitive surgery: Definitive surgery will be performed as part of the local standard of care 
(SOC) approximately 3-6 weeks following the completion or early discontinuation of the 
study treatments. A thorough evaluation of breast cancer status, pathological staging per 
American Joint Committee of Cancer (AJCC) Breast Cancer Staging version 7 and 
assessment of surgical margins will be performed by local pathologist on all the tissues 
removed during the surgery. 
Safety will be monitored as outlined in the Trial Flow Chart in Section 6 and described in 
more detail in Section 7.2. An End of Treatment/Early Discontinuation Visit will be 
scheduled 3-6 weeks following discontinuation of treatment and prior to definitive surgery.  
Adverse events (AEs) will be monitored throughout the trial and graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 (See Appendix 12.5).  A Safety Follow-up Visit will be scheduled 
approximately 30 days following definitive surgery. Thereafter, subjects will be followed by 
telephone contact every 12 weeks (±2 weeks) to obtain information regarding subject’s 
disease and survival status. Disease follow-up and anticancer treatment for recurrent or 
metastatic disease will be at the discretion of subject’s treating physician per local SOC.
The 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 is depicted in Figure 1.
 
 
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Figure 1
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective (Cohort A):  To determine the safety and tolerability and to establish an
RP2D for the combination regimen KNp/KAC as a neoadjuvant treatment for 
subjects with locally-advanced TNBC. 
2) Objective (Cohorts B, C, and D):  To determine the safety and tolerability and to 
establish an RP2D for the combination regimen KNpCb/KAC as a neoadjuvant 
treatment for subjects with locally-advanced TNBC. 
3) Objective (Cohorts E and F):  To determine the safety and tolerability and to 
establish an RP2D for the combination regimen KTCb/KAC as a neoadjuvant 
treatment for subjects with locally-advanced TNBC. 
 
 
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Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective:  To evaluate the rate of pCR using the definition of ypT0 ypN0 (i.e. no 
invasive or noninvasive residual in breast or nodes) as assessed by the local 
pathologist at the time of definitive surgery in TNBC subjects treated with KNp/KAC 
(Cohort A), KNpCb/KAC (Cohorts B, C, and D) or KTCb/KAC (Cohorts E and F) as 
a neoadjuvant regimen at RP2D.
2) Objective:  To evaluate the rate of pCR using an alternative definition, ypT0/Tis 
ypN0 (i.e. no invasive residual in breast or nodes; noninvasive breast residuals 
allowed) as assessed by local pathologist at the time of definitive surgery in TNBC 
subjects treated with KNp/KAC (Cohort A), KNpCb/KAC (Cohorts B, C, and D) or 
KTCb/KAC (Cohorts E and F) as a neoadjuvant regimen at RP2D.
3) Objective:  To evaluate the objective response rate (ORR) using RECIST1.1 as 
assessed by site radiology review after completion of the first combination regimen 
(KNp,KNpCb or KTCb), and after completion of the second combination regimen 
(KAC) in Cohorts A, B, C, D, E and F in subjects who started with RP2D. 
4) Objective: To evaluate the 6 month, 12 month and 24 month event free survival 
(EFS) rate from first dose of trial treatment as assessed by investigator per local SOC 
and 6 month, 12 month and 24 month overall survival (OS) rate from first dose of 
trial treatment in TNBC subjects treated with the RP2D KNp/KAC (Cohort A), 
KNpCb/KAC (Cohorts B, C, and D) or KTCb/KAC (Cohorts E and F).
Exploratory Objectives 
3.3
1) Objectives for translational research:

To characterize the tumor microenvironments before treatment, changes after a 
single dose of pembrolizumab and after the combinations, this may include
presence and changes of tumor infiltrating T lymphocytes (TILs), immune-related 
mRNA expression signatures, and PD-L1 expression. 

To perform tumor genetic profiling such as genetic testing for mutational burden
based on tumor samples collected at Screening.
Additional translational research may include T cell clonality, neoantigen expression, 
presence and changes in circulating tumor markers such as ctDNA, and serum 
miRNA and protein changes at Screening and following treatment. 
Correlation of clinical response (pCR and ORR) to tumor/ circulating markers at 
Screening and after treatments may be evaluated. 
2) Objective for pharmacogenetic research: 

To explore the relationship between genetic variation and response to the 
treatment(s) administered.  Variation across the human genome will be analyzed 
for association with clinical data collected in this study.
 
 
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4.0 BACKGROUND & RATIONALE
Background
4.1
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD 1.  Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies.  Keytruda™ (pembrolizumab) is indicated for the treatment of 
patients across a number of indications.  For more details on specific indications refer to the 
Investigator’s brochure.
Pharmaceutical and Therapeutic Background
4.1.1
4.1.1.1
Disease Background
Breast cancer is the most commonly diagnosed malignancy and the second leading cause of 
cancer death in women. In the United States, the estimated number of new cases and death 
from breast cancer in 2014 is approximately 232,670 and 40,000, respectively [1].  TNBC, 
which is phenotypically defined by 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, accounts for approximately 15%-20% of all breast 
cancers [2]. 
Compared to other breast cancer subtypes, TNBC is associated with younger age and more 
advanced tumor stage at diagnosis, African American race/ethnicity, higher tumor grade and 
poorer overall survival; TNBC is also associated with a higher risk of disease recurrence and 
higher recurrence in viscera within 5 years of diagnosis [3, 4].
TNBC is a heterogeneous disease with distinct pathological, genetic and clinical features
among subtypes.  Recent gene expression profiling has identified six distinct TNBC subtypes
including two basal-like, an immunomodulatory, a mesenchymal, a mesenchymal stem-like,
and a luminal androgen receptor subtype. They have different prognosis and sensitivity to 
treatments, for example, basal-like tumors are highly sensitive to platinum treatment [2]. 
Molecular characterization of basal vs. non-basal-like TNBC by Prat et al using two large 
datasets showed that 78.6% TNBC are basal-like while 68.5% basal-like tumors are TNBC, 
indicating a large overlap between the two [5]. Another finding from molecular 
characterization is that the majority of BRCA1 germline mutation carriers, when develop 
breast cancer, will develop basal-like subtype of TNBC; and the prevalence of BRCA1 in 
TNBC is around 10-20% [6, 7].  
4.1.1.2
Current and Emerging Neoadjuvant Treatments for TNBC
Neoadjuvant chemotherapy with anthracycline/taxane-based regimen has been considered an 
important part of treatment strategy for patients with locally advanced TNBC [8, NCCN 
 
 
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guideline for invasive breast cancer version 1.2015]. Early prospective observational studies 
evaluating outcome of neoadjuvant chemotherapy in different breast cancer subtypes 
revealed that TNBC was more chemosensitive compared to non-TNBC, in particular, 
compared to the ER+/Her2- (luminal) subtype , with substantially increased pCR rate and 
clinical response rate. However, patients with TNBC had poorer prognosis as a group with 
significantly higher disease recurrence rate and low survival rate. The poor long term 
outcome in TNBC was found to be driven by those without achieving pCR after neoadjuvant 
chemotherapy. Patients who achieved pCR demonstrated sustained clinical benefit regardless 
of breast cancer subtypes [9, 10]. Recent reports of a large pooled analysis demonstrated 
strong association of pCR, when defined as no tumor in both breast and lymph nodes (ypT0 
ypN0 or ypT0/is yp N0) following neoadjuvant therapy for breast cancer, with improved 
long-term benefit as measured by event-free survival and overall survival. Furthermore, this 
association was found to be strongest in patients with TNBC [11]. These findings have led to 
increased efforts in identifying new drugs and drug combinations that can deliver higher pCR 
in TNBC. Recent studies evaluating carboplatin and nab-paclitaxel in the neoadjuvant TNBC 
setting have shown some interesting results. 
In a randomized Phase III study (GeparSepto) comparing weekly nab-paclitaxel 150mg/m2/
125mg/m2 with weekly paclitaxel 80mg/m2 for 12 weeks with both arms followed by 
epirubicin 90mg/m2 plus cyclophosphamide 600mg/m2 Q3W for 4 cycles as neoadjuvant 
treatment for breast cancer, the pCR (ypT0 ypN0) in the TNBC subgroup was 48.2% in those 
who received nab-paclitaxel compared with 25.7% (p<0.001) in those who received 
paclitaxel [12]. The initial dose of nab-paclitaxel was 150mg/m2 weekly. The dose was
subsequently reduced to 125mg/m2 weekly due to toxicity with 400/1200 enrolled subjects 
received 150mg/m2 dose. The combined data showed that nab-paclitaxel was associated with 
a significantly higher rate of peripheral sensory neuropathy compared to paclitaxel 80mg/m2
(62.3% vs. 42.1% for all grade, 39.6% vs. 31.6% for grade 1, 17% vs. 5.3% for grade 2, 5.7% 
vs. 5.3% for grade 3 (no grade 4 events).  
Two randomized studies have shown significantly increased pCR by adding carboplatin to an
anthracycline/taxane-based neoadjuvant regimen in TNBC. In the GeparSixto trial, a 
randomized Phase II study which enrolled a subset of patients with previously untreated 
stage II/III TNBC, addition of weekly carboplatin (1.5-2AUC) to the triple combination of 
weekly paclitaxel (80mg/m2) plus weekly non-pegylated liposomal doxorubicin (20mg/m2) 
plus Q3W bevacizumab (15mg/kg) for a total of 6 cycles, showed increased pCR (defined as 
ypT0 ypN0) from 36.9% to 53.2% (p = 0.005) [13]. Compared to patients without 
carboplatin, the following AEs were significantly higher in those who received carboplatin: 
grade 3/4 neutropenia (65% vs. 27%), grade 3/4 anemia (15% vs. < 1%), grade 3/4 
thrombocytopenia (14% vs. <1%) and grade 3/4 diarrhea (17% vs. 11%). These 
hematological and non-hematological toxicities reduced when the dose of carboplatin was 
changed from AUC2 to AUC1.5.
In a randomized Phase III study (CALGB 40603) that evaluated the addition of carboplatin
or/and bevacizumab to the standard neoadjuvant treatment for TNBC (paclitaxel 80mg/m2
weekly for 12 weeks followed by doxorubicin plus cyclophosphamide Q2W for 4 cycles), 
addition of carboplatin Q3W at AUC6 to weekly paclitaxel vs. weekly paclitaxel alone 
significantly increased pCR rate for breast (defined as ypT0/is) from 42% to 53%, and pCR 
rate of breast/axilla (defined as ypT0/Tis ypN0) from 39% to 49% [14]. In this study, 
 
 
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addition of Q3W carboplatin at AUC6 showed significantly increased Grade 3/4 neutropenia 
(56% vs. 22%), and Grade 3/4 thrombocytopenia (20% vs. 4%).  In a meta-analysis 
evaluating the value of platinum agents as neoadjuvant treatment for TNBC based on data 
pooled from 6 randomized studies and 22 retrospective studies, the pooled pCR rate in 
patients who received platinum treatments was 45%. Data from the 6 randomized trials 
showed a relative risk of 1.45 (95% CI, 1.25-1.68, p<0.0001) of not having a pCR in those 
who patients who received no platinum treatment [15]. 
4.1.1.3
Targeting PD-1 immune checkpoints for cancer treatment 
It is widely accepted that cancer cells carry tumor-specific or tumor-associated antigens and 
therefore are immunogenic and subject to immune surveillance of the human body [16]. 
However, cancer cells can often escape immune system’s surveillance and control via 
various mechanisms and progress into clinically evident disease, a process called cancer 
immunoediting [17, 18]. The ability of human cancer to evade the immune system’s 
destruction has recently been recognized as an emerging hallmark of cancer [19]. 
In the adaptive immune system, cytotoxic T lymphocytes cells (CTLs, also called CD8+ or 
effector T cells) can recognize foreign antigens presented on the surface of antigen 
presenting cells (APC) via T cell receptor (TCR) and become activated executing the cell 
killing function. TCR-mediated T cell activations are tightly controlled by co-stimulatory and 
co-inhibitory signals or pathways that are triggered by the interactions between T cell surface 
receptors and their ligands. These inhibitory pathways, also called immune checkpoints, are 
crucial for maintaining self-tolerance and minimizing collateral tissue damage in the event of 
immune response to pathogens [20]. Cancer can exploit immune checkpoint pathways as one 
of the key mechanisms to avoid being detected and destroyed. Therefore, restoration of 
endogenous anti-cancer immunity by immune checkpoint blockade has become an attractive 
strategy of cancer immunotherapy [20, 21, 22].
Among many of the agents in clinical development that target immune checkpoint pathways, 
those that target pathways controlled by programmed cell death protein 1 (PD-1) and 
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) are the most advanced and have 
shown unprecedented clinical anticancer activities and durable responses across multiple 
solid tumors [20, 23, 24, 25]. Two immune checkpoint inhibiting agents have been approved 
by the US Food and Drug Administration (FDA) for treating advanced melanoma: 
ipilimumab, a full human anti-CTLA-4 monoclonal antibody (mAb), and pembrolizumab 
(MK-3475), a humanized mAb targeting PD-1 [see details in Yervoy® US label, Keytruda® 
US Label]. In addition, nivolumab, a full human mAb targeting PD-1, has recently been 
approved for treating melanoma and advanced non-small cell lung cancer (NSCLC) [see 
details in Opdivo® US label]. 
PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators. It is a 
transmembrane 
receptor 
including 
an 
extracellular 
domain 
that 
resembles 
the 
immunoglobulin variable region, a transmembrane region, and an intracellular tail that 
contains separate potential phosphorylation sites for signaling. Binding of PD-1 to its ligands 
PD-L1 (also named B7-H1) and/or PD-L2 (also named B7-DC) will trigger downstream 
signaling inside T cells leading to decreased cytokine production such as IL-2, inhibition of 
cell proliferation, reduced T cell effector function and survival [20, 24, 26]. Unlike CTLA-4 
which modulates the early phase of activation of naïve or memory T cells, PD-1 is expressed 
 
 
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on antigen-experienced T cells in the peripheral tissues and therefore regulates the effector 
phase of the T-cell activity [20, 23]. 
4.1.1.4
Targeting PD-1 immune checkpoints for TNBC
Several studies have demonstrated that the presence of TILs correlated with better prognosis 
in TNBC, independent of systemic therapy [27, 28].  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 
[29].  These findings suggest an active role of acquired immunity in concurring TNBC [30]. 
PD-L1, which is not detected in normal breast tissue, has been reported to be expressed in 
about half of all breast cancers, particularly in HR-negative, high grade and proliferative 
tumors [31].  The presence of Treg cells, tumor PD-L1 expression, and PD-1–positive TILs 
has been associated with high histologic grade, ER negativity, and prominent tumor 
lymphocytic infiltration [31]. 
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 [32].  
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 [33].  This evidence demonstrates 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.
Summary of Pembrolizumab Clinical Activities
4.1.2
Pembrolizumab is a potent and highly selective humanized mAb of the IgG4/kappa isotype 
designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
Details regarding preclinical and clinical pharmacology studies can be found in 
pembrolizumab clinical investigator brochure and the US label. 
4.1.2.1
Summary of Pembrolizumab Clinical Activities in solid tumors
As of 06-Jan-2015, approximately 8,000 patients have been treated with pembrolizumab in 
Merck-sponsored clinical trials and the melanoma Expanded Access Program. In addition, 
the worldwide post-marketing distribution of pembrolizumab through 31-Dec-2014 was 
29,312 vials, which equates to approximately 2,840 patients. Pembrolizumab has been 
generally well tolerated, as expected based on preclinical findings and data from other anti-
PD-1 monoclonal antibodies. Pharmacokinetics were as expected, based on pembrolizumab 
being an IgG mAb and based on preclinical data, which support dosing once every 2 or 3 
weeks. Detailed study results are outlined in the Investigator Brochure, version 9 (May 
2015).  
Study KN001 is the first time in human Phase I study evaluating safety, pharmacokinetics 
and clinical activity of pembrolizumab, which is still on-going. The trial has been conducted 
in subjects with advanced melanoma and NSCLC. The cumulative evidence of high anti-
cancer activities and acceptable safety profile has led to the accelerated approval of 
 
 
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pembrolizumab by the FDA for the treatment of patients with unresectable or metastatic 
melanoma and disease progression following ipilimumab and, if BRAF V600 mutation 
positive, a BRAF inhibitor [Keytruda US label]. A dose of 2mg/kg Q3W is the recommended 
dose in the pembrolizumab label. 
In KN001 pembrolizumab monotherapy induced an ORR of 21% in patients with previously-
treated NSCLC based on RECIST 1.1 as assessed by independent radiology review. Similar 
to melanoma, the responses in NSCLC were remarkably durable. Higher levels of PD-L1 
expression in tumors of NSCLC were associated with increased activity (ORR 57% based on 
RECIST v.1.1 as assessed by independent radiology review); however, additional data are 
required to define the optimal PD-L1 cut point. 
In addition, in KN001, in naïve and previously-treated patients with advanced NSCLC, 
pembrolizumab monotherapy, in an analysis of 313 patients from a validation data set for 
tumor PD-L1 expression, showed an ORR of 45.2 percent (95% CI, 33.5-57.3) in patients 
with ≥ 50% of tumor cells positive for PD-L1 expression (n = 73). In the other PD-L1 
subgroups, ORR was 16.5% (95% CI, 9.9-25.1) in patients with 1-49% tumor cells positive 
(n = 103) and an ORR of 10.7% (95% CI, 2.3-28.2) in patients with < 1% tumor cells 
positive (n = 28) for PD-L1 expression. In the total study population, ORR was 19.4 percent 
(95% CI, 16.0-23.2) (N = 495), which was consistent with data previously presented from 
this study.
4.1.2.2
Summary of pembrolizumab clinical activity in metastatic TNBC
In Study KN012, a cohort of 32 female patients with metastatic TNBC, PD-L1 positivity 
(defined as PD-L1 expression in ≥1% tumor cells or in stroma, using a prototype assay and 
the 22C3 antibody) was enrolled and received pembrolizumab 10mg/kg Q2W dose.  Subjects 
with a median age of 51.9 years (range 29-72 years) and PD-L1 (+) metastatic TNBC 
(mTNBC) were enrolled in the study. The currently available prevalence of PD-L1 positivity 
in mTNBC is 58%, as determined by this study KN012. Most of these patients had received 
and progressed on multiple lines of therapy for advanced disease (median number of prior 
treatments for metastatic disease was 3). Based on a data cutoff of 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 
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. At this cutoff, 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. Given that the current 
systemic treatments had little effect in this setting, this result looks very promising.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
It is well known that TNBC has the worst prognosis and is the most difficult to treat among 
the breast cancer subtypes. Due to lack of specific molecular targets, treatment of TNBC has 
 
 
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been relying on chemotherapy, in particular, regimens based on the combination of 
anthracycline and taxanes. The effect of chemotherapy in the metastatic setting has been 
poor. Even though TNBC is considered chemosensitive compared to other breast cancer 
subtypes in the early setting, disease recurrence rate with the current regimen is still high and 
those with recurrent disease have a very poor outcome. Therefore TNBC is a disease with 
high unmet medical need. 
Neoadjuvant treatment is an important part of the treatment strategy for locally advanced 
TNBC due to having established a positive and significant correlation of pCR with long-term 
clinical benefit such as event-free survival and overall survival as shown via large meta-
analysis [11]. Much effort has been made to identify novel agents and new drug 
combinations that can improve pCR rates in this setting, which is the rationale to evaluate 
pembrolizumab, 
a 
novel 
immunotherapeutic 
agent,
in 
combination 
with 
new 
chemotherapeutic regimens. 
Rationale for Dose Selection/Regimen
4.2.2
4.2.2.1
Rationale for Testing Pembrolizumab in combination with the selected TNBC
neoadjuvant regimens
The rationale for testing pembrolizumab in combination with the selected chemotherapy 
regimens are as follows: 
1. Pembrolizumab functions as an immune checkpoint blockade by targeting PD-1, 
which helps to restore the endogenous anti-cancer immunity. Pembrolizumab has 
shown significant clinical anti-cancer activity across multiple tumor types including 
melanoma, NSCLC, Head and Neck cancer, bladder cancer and has gained FDA 
approval for treating advanced melanoma. Preliminary data has also shown promising 
clinical activity of pembrolizumab in metastatic TNBC patients who have failed 
multiple prior treatments. Therefore further testing of pembrolizumab in both the
metastatic and early stage such as a neoadjuvant setting is warranted. 
2. Weekly nab-paclitaxel followed by epirubicin and cyclophosphamide as neoadjuvant 
treatment has shown a significantly improved pCR rate compared with the standard 
weekly paclitaxel followed by epirubicin and cyclophosphamide in the TNBC 
subgroup of the Phase III randomized study, GeparSepto. In this study, 2/3 of the 
TNBC subjects received 125mg/m2 weekly nab-paclitaxel and 1/3 of the TNBC 
subjects received 150mg/m2 weekly nab-paclitaxel [12]. The pCR rate was 48.2% in 
the TNBC subgroup who received nab-paclitaxel compared with 25.7% (p<0.001) in 
those who received paclitaxel (pCR in this trial was defined as ypT0 ypN0). 
Therefore nab-paclitaxel can be a more interesting combination partner. The safety 
profile of weekly nab-paclitaxel at 125mg/m2 is expected to be better than what was 
shown in the GeparSepto study, which has a combined safety profile of all treated 
subjects. Overlapping toxicities of pembrolizumab and nab-paclitaxel are not 
expected. It is worth noting that nab-paclitaxel has not been approved by regulatory 
authorities as a treatment for neoadjuvant TNBC nor has it been recommended as a 
treatment option by the NCCN or ESMO guidelines for the neoadjuvant TNBC 
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3. Carboplatin in combination with weekly paclitaxel at 80mg/m2 versus paclitaxel 
alone followed by the standard anthracycline/cyclophosphamide combination has 
shown increased pCR rates as neoadjuvant treatment for TNBC via 2 randomized 
trials using either weekly carboplatin at AUC 1.5 – 2 [the Phase II GeparSixto trial, 
13] or carboplatin at AUC6 Q3W [the Phase III CALGB 40603 trial, 14]. A meta-
analysis by Petrelli et al to compare TNBC patients who received carboplatin vs. 
those who did not receive carboplatin in the neoadjuvant setting, showed the risk of 
not having a pCR for those without carboplatin was 1.45 (95% CI, 1.25-1.68, 
p<0.0001) [15] compared to those who have received carboplatin. These data provide 
a good rationale for carboplatin to be included as part of the neoadjuvant combination 
regimen. In this study, nab-paclitaxel and carboplatin have been selected as a novel 
combination regimen to be combined with pembrolizumab. This new combination is 
expected to produce a higher pCR rate, if tolerated.  It is worth noting that the 
combination of nab-paclitaxel and carboplatin has neither been evaluated clinically in 
the neoadjuvant nor metastatic setting for TNBC.  
4. Pembrolizumab relies on a functional immune system to exert its anti-tumor effect. 
Theoretically, an even greater tumor cell reduction might be achieved by enhancing 
the antigen presentation via administration of pembrolizumab in combination with 
standard cytotoxic chemotherapy, provided that the immune suppression by some of 
these agents (e.g.
carboplatin and cyclophosphamide) do not significantly 
compromise the anti-tumor effect of pembrolizumab. Optimal supportive care may 
alleviate some of these potential negative impacts. 
4.2.2.2
Rationale of selecting pembrolizumab 200mg Q3W dose
The dose of pembrolizumab planned to be studied in this trial is 200mg Q3W.  A 2mg/kg 
Q3W dose is approved for metastatic melanoma in some countries.  Information on the 
rationale for selecting 200mg Q3W is summarized below.
An open-label Phase I trial (KN001) is being conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab.  The dose escalation portion of this trial evaluated 
three dose levels, 1mg/kg, 3mg/kg, and 10mg/kg, administered every 2 weeks (Q2W) and 
dose expansion cohort evaluated 2mg/kg Q3W and 10mg/kg Q3W in subjects with advanced 
solid tumors.  All dose levels were well tolerated and no dose-limiting toxicities were 
observed.  This first in human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels.  No Maximum 
Tolerated Dose (MTD) has been identified.
In KN001, two randomized cohort evaluations (Cohorts B2 and D) of melanoma subjects 
receiving pembrolizumab at a dose of 2mg/kg Q3W versus 10mg/kg Q3W have been 
completed, and one randomized Cohort (Cohort B3) evaluating 10mg/kg Q3W versus 
10mg/kg Q2W has also been completed.  The clinical efficacy and safety data demonstrate a 
lack of clinically important differences in efficacy or safety profile at these doses.  For 
example, in Cohort B2, advanced melanoma subjects who had received prior ipilimumab 
therapy were randomized to receive pembrolizumab at 2mg/kg Q3W versus 10mg/kg Q3W, 
and the ORR was 28% (22/79) in the 2mg/kg Q3W group and 28% (21/76) in the 10mg/kg 
Q3W group (per RECIST 1.1 by independent central review).  The proportion of subjects 
 
 
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with drug-related AEs, grade 3-5 drug-related AEs, serious drug-related AEs, death or 
discontinuation due to an AE was comparable between groups.  Cohort D, which compared 
2mg/kg Q3W versus 10mg/kg Q3W in advanced melanoma subjects naïve to ipilimumab,
also demonstrated overall similarity in efficacy and safety profiles between two doses.  In 
Cohort B3, advanced melanoma subjects (irrespective of prior ipilimumab therapy) were 
randomized to receive pembrolizumab at 10mg/kg Q2W versus 10 mg/kg Q3W.  The results 
demonstrate that the ORR was 35.0% (41/117) in the 10mg/kg Q2W group and 30.8% 
(33/107) in the 10mg/kg Q3W group (per RECIST 1.1 by independent central review) (cut-
off date of 18-April-2014).  The proportion of subjects with drug-related AEs, Grade 3-5 
drug-related AEs, serious drug related AEs, death or discontinuation due to an AE was 
comparable between groups.
An integrated body of evidence suggests that 200mg Q3W is expected to provide similar 
response to 2mg/kg Q3W, 10mg/kg Q3W and 10mg/kg Q2W.  Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in 
subjects with melanoma in the range of doses between 2mg/kg and 10mg/kg.  Exposures for 
200mg Q3W are expected to lie within this range and will be close to those obtained with 
2mg/kg Q3W dose.  
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 1139 subjects from 
PN001, of which the majority (94.6% [N=1077]) were patients with advanced melanoma. 
The distribution of exposures from the 200 mg fixed dose are predicted to considerably 
overlap those obtained with the 2mg/kg dose and importantly will maintain individual patient 
exposures within the exposure range established in melanoma as associated with maximal 
clinical response. Additionally, this comparison also demonstrates that the 200mg Q3W 
regimen provides no substantive differences in pharmacokinetic variability (range of the 
distribution of individual exposures) as seen with weight-based dosing.  
In translating to other solid tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma can be expected, as the anti-
tumor effect of pembrolizumab is driven through immune system activation rather than 
through a direct interaction with tumor cells, rendering it independent of the specific tumor 
type.  In addition, available pharmacokinetic results in subjects with melanoma, NSCLC, and 
other solid tumor types support a lack of meaningful difference in pharmacokinetic exposures 
obtained at tested doses among tumor types.  Thus, the 200 mg Q3W fixed dose regimen is 
considered an appropriate fixed dose for other solid tumor indications as well.   
Taken together, the choice of 200mg Q3W as an appropriate dose is based on simulations 
performed using the population PK model of pembrolizumab showing that the fixed dose of 
200mg Q3W will provide exposures that 1) are optimally consistent with those obtained with 
2mg/kg dose Q3W; 2) body weight based dosing does not provide an advantage over fixed 
dosing and that both dosing strategies should provide adequate and similar control of PK 
variability; 3) will maintain individual patient exposures in the exposure range established in 
melanoma as associated with maximal efficacy response; 4) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe; and 
 
 
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5) the dynamics of pembrolizumab target engagement would not vary meaningfully with 
tumor type.
A fixed-dose regimen is expected to simplify the dosing regimen (potentially reducing dosing 
errors), as well as be more convenient for physicians.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities, as well as reducing waste.
4.2.2.3
Starting Dose for This Trial
KNp125 followed by KAC (Cohort A Dose Level 1) and KNp100CbAUC6 followed by 
KAC (Cohort B Dose Level 1) have completed enrollment. KNp125CbAUC5 followed by 
KAC (Cohorts C Dose Level 1) and KNp125CbAUC2 followed by KAC (Cohort D Dose 
Level 1) are enrolling.
KT80CbAUC5 followed by KAC (Cohorts E Dose Level 1) and 
KNT80CbAUC2 followed by KAC (Cohort F Dose Level 1) will begin enrollment 
simultaneously upon approval of the Amendment 04.
Rationale for Cohort A starting dose
The GeparSepto trial that evaluated weekly nab-paclitaxel versus weekly standard paclitaxel 
dosing for 12 weeks followed by 4 cycles of epirubicin and cyclophosphamide standard 
combination demonstrated significant improvement in the primary endpoint pCR in the nab-
paclitaxel arm, especially in the subgroup of subjects with TNBC (see Section 4.1 for 
details). The initial nab-paclitaxel dose was 150mg/m2 weekly, which was subsequently 
reduced to 125mg/m2 weekly due to toxicity with 400/1200 enrolled subjects received nab-
paclitaxel at 150mg/m2. In all nab-paclitaxel-treated subjects, the discontinuation rate was 
21% for nab-paclitaxel vs. 14% for paclitaxel. The discontinuation for nab-paclitaxel due to 
AE, progression, patient and investigator’s decision were 17%, 1.7%, 1.2% and 1%, 
respectively; the discontinuation for paclitaxel due to AE, progression, patient and 
investigator’s decision were 6.2%, 5%, 1%, 1.2% and 1 death (0.2%). There was no 
statistically significant difference in Grade 3/4 anemia, neutropenia, febrile neutropenia. The 
most significant Grade 3/4 toxicity of nab-paclitaxel in the combined data versus paclitaxel 
was peripheral sensory neuropathy (10.2% vs. 2.7%). In an analysis that only included the 
patients enrolled after nab-paclitaxel was reduced to 125mg/m2 and have received all 
scheduled cycles of taxane, the Grade 3/4 peripheral sensory neuropathy was reduced (62.3% 
vs. 42.1% for all grade, 39.6% vs. 31.6% for Grade 1, 17% vs. 5.3% for Grade 2, 5.7% vs. 
5.3% for Grade 3 (no Grade 4 events).  Unfortunately, the data did not include those who 
were prematurely discontinued from treatment.
Given that nab-paclitaxel 125mg/m2 (albeit mixed with 33% who received 150mg/m2 dose) 
has been tested in a large Phase III study with significantly improved pCR, in particular in 
the TNBC subgroup, it is reasonable to first target the dose level of nab-paclitaxel that has 
demonstrated improved efficacy. The doses for AC combination are standard for neoadjuvant 
TNBC. Overlapping toxicities between pembrolizumab and these chemotherapy agents are
not expected based on the pembrolizumab toxicity profile in a Phase I/II study (KN021) that 
evaluated pembrolizumab in combination with various chemotherapy regimens in NSCLC 
including carboplatin and paclitaxel. 
 
 
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Rationale for Cohort B starting dose
Cohort B DL1 (KNp100CbAUC6 / KAC) will be the initial dose level tested for Cohort B. 
This initial dose level is selected as the combination regimen nab-paclitaxel 100mg/m2
weekly plus carboplatin AUC6 Q3W, has been tested via Phase III study and is an approved 
chemotherapy regimen for treating advanced NSCLC [Abraxane Label, 34]. It is therefore 
safer to start Cohort B with dose level of nab-paclitaxel plus carboplatin having been tested 
in a large trial. 
Rationale for Cohorts C & D starting dose
DL1 for Cohort C is nab-paclitaxel 125 mg/m2 weekly plus carboplatin AUC5 Q3W.  The 
rationale for the dose of nab-paclitaxel is based on data from GeptoSepto in which the 
tolerability and higher rate of pCR were demonstrated (see Rationale for Cohort A starting 
dose).  The rationale for the dose of carboplatin is based on data from the Phase III CALGB 
40603 study [14].  However, only about 60% of subjects were able to complete the required 
12 paclitaxel doses.  Furthermore, the grade 3-4 neutropenia rate was 56%.  Based on the 
toxicity data, the carboplatin dose for this study will be AUC of 5.  
DL1 for Cohort D is nab-paclitaxel 125 mg/m2 weekly plus weekly carboplatin AUC2.  
Weekly carboplatin (1.5-2AUC) was tested in the GeparSixto trial, a randomized Phase II 
study with the addition of weekly paclitaxel (80mg/m2), weekly non-pegylated liposomal 
doxorubicin (20mg/m2) and Q3W bevacizumab (15mg/kg).  The response rate was 53% 
within the range of Q3W carboplatin, suggesting the equivalency between weekly and every 
3 week dosing of carboplatin.  Moreover, some data suggested that weekly dosing may be 
more tolerable. As such, it has become the preferred carboplatin dosing for some clinicians
[34].
Rationale for Cohorts E & F starting dose
DL1 for Cohort E is paclitaxel 80 mg/m2 weekly plus carboplatin AUC5 Q3W and DL1 for 
Cohort F is paclitaxel 80 mg/m2 weekly plus carboplatin AUC2 weekly.  The rationale for 
the dose of carboplatin with paclitaxel is based on data from the Phase III CALGB 40603 and 
GeparSixto studies as described previously [13, 14]. While the results of the GeparSepto 
showed higher pCR with Nab-paclitaxel when compared to paclitaxel, the ETNA study, 
which compared Nab-paclitaxel 125 mg/m2 day 1, 8, 15 of 4 weeks cycle for 4 cycles to 
paclitaxel 90 mg/m2 with similar scheduled followed by anthracycline-based chemotherapy 
combination Q3W for 4 cycles as neoadjuvant treatment for breast cancer, showed no 
statistically significant difference in pCR between the two TNBC arms (41.3% vs. 
37.3%).[35] Furthermore, the nab-paclitaxel-containing has slightly higher rate of grade ≥ 3 
neutropenia (30.6% vs. 19.7%) and peripheral neuropathy (4.5% vs. 1.8%). Thus, currently, 
there is no clear data supporting higher efficacy with nab-paclitaxel versus solvent-based 
paclitaxel.
4.2.2.4
Maximum Dose/Exposure for This Trial
The maximum and the target dose regimen for Cohort A will be KNp125 / KAC. The 
rationale can be found in Section 4.2.2.3. The maximum and the target dose regimens for
 
 
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each cohort is as follows: Cohort B will be KNp100CbAUC6 / KAC, Cohort C will be 
KNp125CbAUC5 / KAC, Cohort D will be KNp125CbAUC2 / KAC, Cohort E will be 
KT80CbAUC5 / KAC and Cohort F will be KT80CbAUC2.
Two randomized trials have tested carboplatin in combination with weekly paclitaxel 
80mg/m2 followed by standard AC dosing in the neoadjuvant TNBC setting. In both studies, 
addition of carboplatin has demonstrated improved pCR for TNBC. The Phase III CALGB 
40603 study combined carboplatin AUC6 Q3W with weekly paclitaxel [14]; the Phase II 
GeparSixto study combined weekly carboplatin at AUC1.5 or 2 with weekly paclitaxel [13]. 
The weekly carboplatin seems to have greater toxicity than carboplatin AUC6 Q3W, hence, 
carboplatin AUC6 Q3W was selected as the combination regimen in Cohort B. It is worth 
noting that in the CALGB 40603 study the carboplatin AUC6 Q3W plus weekly paclitaxel 
80mg/m2 arm showed statistically significant increase in Grade 3/4 neutropenia (56% vs. 
22%) and Grade 3/4 thrombocytopenia (20% vs. 4%) compared to paclitaxel alone arm. 
Nab-paclitaxel 100mg/m2 weekly in combination with carboplatin AUC6 Q3W versus 
paclitaxel 80mg/m2 weekly in combination with carboplatin AUC6 Q3W  has been tested in 
a phase III study in patients with advanced NSCLC [36]. The nab-paclitaxel/carboplatin 
combination showed statistically significantly higher Grade 3/4 thrombocytopenia and 
anemia but statistically significantly lower neutropenia and sensory neuropathy compared to 
the paclitaxel and carboplatin combination. The target dose level with carboplatin AUC6 is 
selected as the target dose level to retain efficacy but in consideration of the available safety 
data.
4.2.2.5
Rationale for Dose Interval and Trial Design
The standard neoadjuvant treatment is typically 4 cycles of taxane (12 x weekly dosing) 
followed by 4 cycles of anthracycline / cyclophosphamide combination (e.g. doxorubicin 
60mg/m2 Q3W + cyclophosphamide 600mg/m2 Q3W). This trial will test the new 
combination using the same dosing interval and schedule. Prior to starting the combination 
regimen, all subjects will receive one cycle of pembrolizumab alone and will undergo tumor 
core biopsy during the last week of cycle 1 (see Section 2). This allows for assessing early 
changes in tumor microenvironment following exposure to pembrolizumab treatment. 
Rationale for Endpoints
4.2.3
4.2.3.1
Safety Endpoints
The primary goal for the study is to determine the recommended Phase 2 dose level for each 
of the pembrolizumab chemotherapy combinations therefore the safety primary endpoint will 
be DLT rates as observed during the DLT evaluation periods. Other safety parameters such 
as incidence of AE/SAEs (including fatal SAEs), immune-related AEs (irAEs) and laboratory 
abnormalities, rates of dose interruption and discontinuation due to AEs, and events of 
clinical interest (ECI) are important endpoints for safety and tolerability evaluations.
 
 
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4.2.3.2
Efficacy Endpoints
pCR is a key efficacy endpoint for evaluation of neoadjuvant treatment in TNBC and has 
been used as a surrogate efficacy endpoint by regulatory agencies for the approval of new 
TNBC neoadjuvant treatments (http://www.fda.gov/downloads/drugs/guidancecompliance
regulatoryinformation/guidances/ucm305501.pdf). 
Clinical 
response 
(CR/PR) 
per 
RECIST1.1, EFS and OS rates are useful endpoints to evaluate drug efficacy in this setting 
but with limitations in a Phase 1b trial.
4.2.3.3
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
One of the exploratory translational research objectives is to characterize the tumor 
microenvironments before treatment, after a single dose of pembrolizumab and after the 
combination regimens, including presence and changes of TILs, immune-related mRNA 
expression signatures, and PD-L1 expression. 
Pembrolizumab functions to enhance T-cell mediated adaptive immunity of the host by 
releasing PD-1/PD-L1 mediated immune checkpoint blockade, therefore PD-L1 expression 
in tumor cells and possibly stroma may be highly relevant. However, in order for tumor cells 
to be eliminated, tumor cell immunogenicity, presence of cytotoxic TILs (e.g. CD8+ TILs) 
and ratio of the cytotoxic and regulatory TILs (CD8+/FoxP3+ TILs) are critical so as 
immune enhancing and immune inhibitory cytokines. This translational research objective 
will be carried out using immunohistochemistry (IHC) such as IHC to evaluate PD-L1 
expression, proportion of TILs based on markers of T cell phenotype. Baseline and post-
treatment status of immune-related gene expression signatures in tumor microenvironment 
will also be evaluated using mRNA profiling technology in tumor tissues obtained during the 
study. 
T cell clonality, neoantigen expression, presence and changes in circulating tumor markers 
such as ctDNA, plasma proteomic change may also be evaluated using plasma samples. This 
may shed light on whether a combination with chemotherapy will enhance immune-mediated 
anti-tumor activity by pembrolizumab. 
TNBC is a heterogeneous disease with distinct subtypes. Therefore tumor genetic profiling 
using technology such as targeted next generation sequencing, whole exome sequencing 
(genome-wide), genetic testing of tumor mutational burden and identify subpopulations that 
are more responsive to pembrolizumab or pembrolizumab chemotherapy combination is 
critical. 
In addition, understanding the somatic and germline genetic determinants of drug response is 
an important endeavor during medical research. Particular emphasis will be placed on the 
following biological determinants/pathways such as BRCA1/2, PI3K, PTEN, EGFR, MEK, 
 
 
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FGFR, MET, and Notch signaling etc. This translational research will be prioritized based on 
tumor tissue availability.
4.2.3.4
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of 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 and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Female subjects at least 18 years of age with newly diagnosed, locally advanced non-
metastatic TNBC will be enrolled in this trial.
 
 
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Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Be a female subject 18 years of age on day of signing informed consent
2. Have TNBC histologically defined as follows:

ER negative: with <1% of tumor cells positive for ER by IHC irrespective of 
staining intensity; AND

PR negative: with <1% tumor cells positive for PR by IHC irrespective of 
staining intensity; AND

HER2 negative: 

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
3. Have previously untreated locally advanced non-metastatic (M0) TNBC fulfilling the 
following combined primary tumor (T) and regional lymph node (N) staging per 
AJCC for breast cancer staging criteria version 7 as assessed by the investigator based 
on baseline breast MRI and clinical assessment: 
T1c, N1-N2
T2, N0-N2
T3, N0-N2
T4a-c, N0-N2 
Note: ipsilateral multifocal primary tumor is allowed and the tumor with the most 
advanced T stage should be used to assess the eligibility. 
4. Provide 2 separate core needle biopsies from the primary tumor at screening to the 
central laboratory and agree to have a core needle biopsy after single dose 
pembrolizumab treatment if tumor biopsy is feasible as judged by the investigator. 
5. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. 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
Organ System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 cells / L without granulocyte colony-
stimulating factor (G-CSF) support within 2 weeks 
prior to the first dose of study treatment 
Platelet count
≥100,000 / L without transfusion within 2 weeks prior 
to the first dose of study treatment 
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency
Renal
Serum creatinine OR
Calculated creatinine clearance (CrCl)
(calculated per institutional standard)
≤1.5 X upper limit of normal (ULN) OR
≥50 mL/min 
Hepatic
Total bilirubin
≤ 1.5 X ULN OR 
Direct bilirubin ≤ULN for subjects with total bilirubin 
levels >1.5 X ULN
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)
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy
as long as PT or aPTT/PTT is within therapeutic range 
of intended use of anticoagulants
Activated Partial Thromboplastin Time 
(aPTT) or Partial Thromboplastin Time 
(PTT)
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy
as long as PT or aPTT/PTT is within therapeutic range 
of intended use of anticoagulants
7. Have left ventricular ejection fraction (LVEF) of ≥50% or ≥ institution lower limit of 
normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition 
(MUGA) scan performed at screening.
8. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, for 
the course of the study through 12 months after the last dose of study medication for 
subjects who have received cyclophosphamide, and for six months after the last dose 
of study medication for subjects who did not.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
 
 
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9. Must have a negative urine or serum pregnancy test within 72 hours prior to receiving 
the first dose of study treatment for female subjects of childbearing potential.  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. Has evidence of metastatic breast cancer, concurrent bilateral invasive breast cancer, 
or inflammatory breast cancer.
2. Has another malignancy within the last 5 years. Exceptions include basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin that has undergone 
potentially curative surgery, or in situ cervical cancer.
3. Has received prior chemotherapy, targeted therapy, radiation therapy, immunotherapy 
that target immune checkpoints, co-stimulatory or co-inhibitory pathways for T cell 
receptors within the past 12 months.  
Note: subjects entering the trial after undergoing a sentinel lymph node biopsy 
will be eligible if they meet all other criteria.
4. 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 study treatment. 
Note: subject should be excluded he/she received an investigational agent 
with anti-cancer or anti-proliferative intent within the last 12 months.
5. Has received a live vaccine within 30 days of the first dose of study treatment.
a.
Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., 
FluMist®) are live attenuated vaccines, and are not allowed.
6. 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 (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
7. 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.  
8. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
9. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
10. Has evidence of current pneumonitis. 
11. Has a history of non-infectious pneumonitis requiring treatment with steroids or a 
history of interstitial lung disease.
 
 
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12. Has an active infection requiring systemic therapy.
13. Has significant cardiovascular disease, such as :

History of myocardial infarction, acute coronary syndrome or coronary 
angioplasty/stenting/bypass grafting within the last 6 months

Congestive heart failure (CHF) New York Heart Association (NYHA) Class 
II-IV or history of CHF NYHA class III or IV
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
15. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive children within the projected 
duration of the trial, starting with the screening visit through 12 months after the last 
dose of trial treatment for subjects who have received cyclophosphamide, and for six 
months after the last dose of study medication for subjects who have not.
17. Has a known hypersensitivity to the components of the study therapy or its analogs.
Trial Treatment(s)
5.2
The trial treatments to be used in this trial are outlined below in Table 3.  
Table 3
Trial Treatments
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Dosing Time 
of each 3-
week cycle 
Use 
Pembrolizumab
200 mg
Q3W
IV Infusion
Day 1 of 
Cycles 1-9
Experimental
Nab-paclitaxel
125 mg/m2,  or 
100mg/m2
Weekly
IV Infusion
Day 1, 8, 15
of Cycles 2-5
Experimental
Paclitaxel
80 mg/m2,  or 
70mg/m2
Weekly
IV Infusion
Day 1, 8, 15 
of Cycles 2-5
Experimental
Carboplatin
AUC6 or 
AUC5
Q3W
IV Infusion
Day 1 of 
Cycles 2-5
Experimental
AUC2 or 
AUC1.5
Weekly
IV Infusion
Day 1, 8, 15 
of Cycles 2-5
Experimental
Doxorubicin
60 mg/m2
Q3W
IV Injection
Day 1 of 
Cycle 6-9
Standard 
of 
care
Cyclophosphamide
600 mg/m2
Q3W
IV Infusion
Day 1 of 
Cycle 6-9
Standard 
of 
care
Trial treatment should begin on the day of treatment allocation or within 3 days after the 
treatment allocation date.
 
 
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All supplies indicated in Table 3 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 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 the combination regimens and doses to be used in this trial is 
provided in Section 4.2.2, Rationale for Dose Selection /Regimen.
Pembrolizumab will be used at a fixed dose of 200mg Q3W. 
The dose amount required for nab-paclitaxel, paclitaxel, doxorubicin and cyclophosphamide 
will be calculated based on milligrams per square meter of body surface area (mg/m2). 
The dose amount required for carboplatin will be calculated as AUC.
5.2.1.2
Rules for Dose Finding
Part 1
Dose Finding Based on DLT Evaluation Period
DLTs observed during the DLT evaluation period will be used to determine whether a dose 
level is tolerable or not tolerable, and to determine dose level de-escalation. The DLT 
evaluation period is defined from Day 1 Cycle 1 through end of Cycle 3 (i.e. through 2 cycles 
of the first combination regimen) as well as Day 1 Cycle 6 through end of Cycle 7 (i.e. 
through 2 cycles of the second combination regimen). Based on the criteria below for each of 
the combination regimens, a RP2D combining two regimens will be established for Cohort A
through F, separately. 
The study will start with DL1 for all cohorts as described in Section 2.1 and in Table 1. 
In Part 1 at any dose level tested, a maximum of 10 subjects are planned to be enrolled and 
can be enrolling continuously. Decisions regarding regimen dose level de-escalation can be 
made on an on-going basis and when 6 and 10 subjects are evaluable for DLT at a given dose 
level for each combination regimen based on the following rules. 
During the first 
combination regimen, if DLTs are observed in ≥3 out of the first 6 subjects, or ≥ 4 out of 10 
subjects, the dose level will be deemed unacceptably toxic and an additional 10 subjects will 
be enrolled into the next lower dose level for DLT assessment, or the cohort may be stopped. 
Subjects who are enrolled but not fully evaluable for DLT at the current dose level that is 
determined to be intolerable will receive subsequent doses in accordance with the doses in 
the next lower dose level. For example, if the dose DL1 is determined to be intolerable, the 
 
 
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remaining subjects enrolled but not yet evaluable for DLT will receive remaining treatment 
at the dose level DL -1 for Cohorts A, C, D, E and F or will be treated at whatever  DL-1 had 
been for Cohort B (KNp100CbAUC5 / KAC) because we have no dose level -1 in Cohort B.
If the current dose is DL -1, the study or the cohort may be stopped.
Tolerability evaluation for KAC
No formal dose finding will occur during the KAC portion of the treatment as the regimen 
includes a fixed dose for pembrolizumab and the standard AC dose combination as specified 
in Section 2. However, DLTs will be monitored through the first 2 cycles of KAC treatment 
for the first 10 subjects enrolled in Part 1 who received a given KNp or KNpCb dose.  If ≥4 
subjects experience a DLT during the KAC treatment, then the toxicity profile will be 
thoroughly evaluated by the sponsor medical and statistical team in consultation with the 
investigators to determine which component is the major contributor to the toxicity. If 
addition of pembrolizumab is determined to be the major contributor to the DLTs, then 
pembrolizumab will be dropped from the KAC combination and subsequent subjects will be 
dosed with AC only following KNp, KNpCb or KTCb treatment. If the DLTs are determined 
to be related to AC, a dose reduction may be considered after consultation between the 
sponsor medical monitor and investigator.  If the DLTs that occurred during the KAC 
treatment period are primarily due to cumulative toxicities of chemotherapies and the dose 
levels assessed for KNp,KNpCb or KTCb are already at DL -1 as listed in Table 1, then the 
regimen may be considered as unacceptable. If the dose levels assessed for KNp, KNpCb or 
KTCb are at DL1 for Cohorts A, C, D, E and F when KAC reaches DLT, then the regimen at 
the next lower dose level will be evaluated. 
Part 2
Once a target RP2D has been identified for Cohorts C, D, E and F the cohort(s) may be 
expanded by enrolling an additional 10 subjects at the recommended dose level.  Should no 
RP2D be identified for Cohorts C, D, E or F then the study will end.
5.2.1.3
Definition of Dose-Limiting Toxicities
All toxicities will be graded using National Cancer Institute Common Toxicity Criteria for 
Adverse Events version 4.0 (NCI-CTCAE v4.0). 
An AE is considered to be a DLT if it is considered by the investigator to be clinically 
relevant and attributed (definitely, probably, or possibly) to a component of the regimen 
evaluated during the DLT evaluation period for that particular regimen and meet the criteria 
in Table 4. Subjects who experience a DLT in Part 1 which cannot be managed by a dose 
decrease should be discontinued from the trial unless the investigator considers it in the best 
interest of the subject to continue on the trial. The investigator should discuss with the 
Sponsor medical monitor before resuming study treatment for the subject. 
 
 
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Table 4
Dose-Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Grade 4 neutropenia lasting ≥ 8 days

Febrile neutropenia Grade 3 or Grade 4

Grade 4 thrombocytopenia that requires platelet transfusion, or Grade 3 
thrombocytopenia with bleeding
Non-hematologic

Grade 4 toxicity

Grade ≥3 symptomatic hepatic toxicities lasting for >48 hours, or Grade 
≥3 asymptomatic hepatic toxicities lasting for ≥ 7 days

Grade ≥3 non-hematologic, non-hepatic organ toxicity, excluding the 
following
o
Grade 3 nausea, vomiting or diarrhea that resolves to Grade ≤1 
within 7 days of appropriate supportive therapy
o
Grade 3 asymptomatic or mildly symptomatic rash that can be 
adequately managed with supportive care, or resolves to 
asymptomatic and/or Grade ≤2 within 7 days with appropriate 
supportive therapy
o
Grade 3 fatigue that resolves to Grade ≤2 within 7 days
o
Grade 3 fever (in the absence of any clinically significant 
source of fever) that resolves to Grade ≤2 within 7 days with 
supportive care
o
Grade 3 laboratory abnormality that is asymptomatic and 
deemed by the investigator not to be clinically significant
o
Grade 3 autoimmune thyroiditis or other endocrine abnormality 
that can be managed by endocrine therapy that would not 
necessitate initiation of systemic corticosteroids
o
Grade 3 tumor flare, defined as local pain, irritation, or rash 
localized at sites of known or suspected tumor
o
hypersensitivity/infusion reactions lasting ≤2 days
Other

Any treatment delays for ≥14 days due to unresolved toxicity

Grade 5 treatment-related AE

A dose reduction of the study treatment during the DLT evaluation 
period
5.2.1.4
Replacement of Subjects in Part 1
In order to be included for safety evaluation in Part 1, a subject must be evaluable. Subjects 
are considered non-evaluable and will be replaced if:

they are enrolled but not treated;

they discontinue from the trial prior to completing all safety evaluations due to 
reasons other than drug-related adverse events;

they received <90% of the total infusion in Cycle 1 or Cycle 2 (e.g., because the 
infusion had to be discontinued due to an infusion reaction) and did not experience a 
drug-related event.
Non-evaluable subjects will not be counted toward the cohort total for DLT evaluation. 
 
 
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5.2.1.5
Dose Modification
5.2.1.5.1 Dose Modification and Toxicity Management Guidelines for Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 5. 
 
 
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Table 5
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 must be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and 
symptoms of pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus).

Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for participants with 
T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 6. 
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of _____ with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.
5.2.1.5.2 Dose modification / Discontinuation Guidelines for Nab-paclitaxel, Paclitaxel,
Carboplatin, Doxorubicin and Cyclophosphamide 
This 
section 
provides
dose 
modification/discontinuation 
guidelines 
for 
the 
4 
chemotherapeutic agents administered as the study treatments.  During the combination 
treatment period, the investigator should use their clinical judgment to determine which 
compound(s) contributed to the toxicity in order to apply dose modifications. 
In Table 7, levels of dose reduction are provided for each chemotherapy agent based on the 
starting dose level. Detailed dose modifications/reductions guidelines are provided in Table 8
and Table 9. Specific guidance for options following discontinuation of one or more 
chemotherapeutic agents and handling of missing doses are also provided. 
 
 
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Table 7
Levels of dose reduction
Chemotherapy and 
starting dose
Dose reduction to:
Reference
Nab-paclitaxel 
125mg/m2
100 mg/m2
Abraxane label for pancreatic cancer 
and NSCLC
Nab-paclitaxel 
100mg/m2
75 mg/m2
Paclitaxel 80mg/m2
70 mg/m2
Carboplatin AUC6 
AUC5
Carboplatin AUC5 
AUC4 
Doxorubicin 
60mg/m2
Reduced by 20%, i.e. 48mg/m2
for 
doxorubicin
NCCN guideline 
cyclophosphamide 
600mg/m2
Reduced by 20%, i.e. 480mg/m2 for 
cyclophosphamide
NCCN guideline 
Instruction on discontinuation of a component or entire regimen  
During the first part of the combination therapy (KNp for Cohort A or KNpCb for Cohorts B, 
C and D or KTCb for Cohorts E and F), if one or more than one component must be 
discontinued due to toxicity, the investigator can select one of the following options at 
his/her own discretion for the subject:

If nab-paclitaxel or paclitaxel is discontinued,  
o
Start and complete the KAC regimen as planned per protocol, then followed by 
surgery 

If only carboplatin is discontinued (applies to Cohorts B, C,D, E and F), 
o
Continue with KNp or KT followed by KAC as planned per protocol, then 
followed by surgery

If only pembrolizumab is discontinued,
o
Continue with chemotherapy regimen alone (Np / NpCb / TCb followed by AC)
as planned per protocol, then followed by surgery
During the second part of the combination therapy (KAC), if one or more than one 
component should be discontinued, the investigator can select one of the following options at 
his/her own discretion for the subject:

If doxorubicin and/or cyclophosphamide are discontinued, 
o
Discontinue all study treatment including pembrolizumab and proceed with 
surgery

If only pembrolizumab is discontinued
o
Continue doxorubicin and cyclophosphamide for the remaining cycles as planned 
per protocol and followed by surgery
Subjects who are discontinued from the study treatment and continue with other neoadjuvant 
treatment prior to the definitive surgery will be inevaluable for pCR and/or imaging 
assessments.
 
 
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Instruction on making up missed doses: 
If a dose delay does not require discontinuation of chemotherapy, subjects may resume 
treatment with the next scheduled dose in the regimen and continue on treatment to complete 
the full number of cycles per protocol.
Table 8
Dose modification guideline for nab-paclitaxel, paclitaxel and carboplatin
Toxicities
Grade or actual 
value
Nab-paclitaxel or paclitaxel alone or with carboplatin
Hematological
Neutropenia
≥1000/mm3
G2/G1
No change to Nab-paclitaxel
or paclitaxel  and 
carboplatin

For ANC ≤1500/mm3, prophylactic myeloid growth 
factors (filgrastim) use at the discretion of the 
investigator,
o Should not be given on the same day as 
chemotherapy.
o Pegfilgrastim may not be used with nab-
paclitaxel due to its weekly dosing schedule
<1000/mm3
G3/G4
Hold Nab-paclitaxel or paclitaxel 
and/or carboplatin 
until ANC≥1000/mm3.  
G-CSF may be used between days 2–6 at discretion of the 
investigator. Pegfilgrastim may not be used with nab-
paclitaxel due to its weekly dosing schedule. Resume 
Nab-paclitaxel and/or carboplatin based on timing of 
recovery:

≤1 week: No change to Nab-paclitaxel, or paclitaxel 
and carboplatin

>1 but <3 weeks: Dose-reduce nab-paclitaxel to 
100mg/m2 or 75mg/m2, and paclitaxel to 70 mg/m2 
and/ or carboplatin to AUC 5 or AUC 4 for all 
subsequent cycles. 

≥3 weeks: Stop nab-paclitaxel, paclitaxel and /or 
carboplatin (see general instruction at the beginning 
of the section)
Febrile neutropenia
ANC≤1000/mm3, 
fever≥38.5°
CG3 and G4
Hold nab-paclitaxel or paclitaxel and / or carboplatin 
until resolved (ANC>1000/mm3, fever <38.5°C, and 
resolution of any signs of infection). G-CSF may be used 
between days 2–6 at discretion of the investigator. 
Pegfilgrastim may not be used with nab-paclitaxel or 
paclitaxel due to its weekly dosing schedule.
Resume Nab-paclitaxel or paclitaxel and or carboplatin 
according to number of episodes:

First episode: no change to nab-paclitaxel or
paclitaxel and carboplatin. Consider adding 
prophylactic GCSF for subsequent cycles.

Second episode: Reduce Nab-paclitaxel to 100mg/m2
or 75mg/m2, and paclitaxel to 70 mg/m2 and/ or 
carboplatin to AUC 5 or AUC 4 for all subsequent 
doses. 

Third episode: Discontinue nab-paclitaxel or 
paclitaxel,  and /or carboplatin (see general 
instruction at the beginning of the section)
 
 
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Toxicities
Grade or actual 
value
Nab-paclitaxel or paclitaxel alone or with carboplatin
Thrombocytopenia
75–<100,000/mm3
G1
Hold nab-paciltaxel or paclitaxel  and / or carboplatin 
until ≥100,000/mm3, resume treatment based on timing of 
recovery:

≤1 week—no change to nab-paclitaxel, paclitaxel 
and carboplatin.

>1 but <3 weeks— Reduce Nab-paclitaxel to 
100mg/m2 or 75mg/m2, ,and paclitaxel to 70 mg/m2 
and/ or carboplatin to AUC 5 or AUC 4 for all 
subsequent doses. 

≥3 weeks: Discontinue nab-paclitaxel or  paclitaxel  
and /or carboplatin (see general instruction at the 
beginning of the section)
<75,000/mm3
≥G2
Hold nab-paclitaxel, paclitaxel and/or carboplatin until 
≥100,000/mm3.  

Reduce Nab-paclitaxel to 100mg/m2 or 75mg/m2, , 
and paclitaxel to 70 mg/m2 and/ or carboplatin to 
AUC 5 or AUC 4 for all subsequent doses. 

Stop nab-paclitaxel or paclitaxel  and/or carboplatin 
if held for ≥ 3 weeks in a row, (see general 
instruction at the beginning of the section)
Anemia 
All grades
No change to nab-paclitaxel or paciltaxel and carboplatin

Iron studies should be done and iron should be 
replaced as indicated.

Red blood cell transfusions can be given at the 
investigators discretion. 
Nausea/Vomiting
Grade 1 or 2
No change to Nab-paclitaxel or paclitaxel and carboplatin
≥ Grade 3
Hold Nab-paclitaxel or paclitaxel and/or carboplatin until 
resolved to ≤grade 1. 

Resume nab-paclitaxel or paclitaxel and/or 
carboplatin at previous dose with modification of 
premedication

Second episode ≥ Grade 3 despite with maximum 
supportive care, reduce Nab-paclitaxel to 100mg/m2
or 75mg/m2 , and paclitaxel to 70 mg/m2and/ or 
carboplatin to AUC 5 or AUC 4 for all subsequent 
cycles 
Mucositis/Stomatitis
Grade 1 or 2
No change to Nab-paclitaxel or paclitaxel and carboplatin
≥ Grade 3
Hold Nab-paclitaxel or paclitaxel until resolved to ≤grade 
1. 

Resume nab-paclitaxel  or paclitaxel and /or 
carboplatin at previous dose with modification of 
premedication

Second episode ≥ Grade 3 despite with maximum 
supportive care, reduce Nab-paclitaxel to 100mg/m2
or 75mg/m2 , and paclitaxel to 70 mg/m2 and/ or 
carboplatin to AUC 5 or AUC 4 for all subsequent 
cycles 
 
 
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Toxicities
Grade or actual 
value
Nab-paclitaxel or paclitaxel alone or with carboplatin
Neurotoxicity
Grade 1–2
No change to nab-paclitaxel or paclitaxel  and carboplatin
Grade 3
Hold nab-paclitaxel or paclitaxel and /or carboplatin until 
neuropathy improves to ≤grade 2.

Resume nab-paclitaxel dose reduced to 100mg/m2 or 
75mg/m2 , and paclitaxel to 70 mg/m2 and/ or 
carboplatin to AUC 5 or AUC 4for all subsequent 
doses.

Discontinue nab-paclitaxel or paclitaxel and/ or 
carboplatin if held for ≥3 weeks in a row, (see 
general instruction at the beginning of the section)
Grade 4

Discontinue  nab-paclitaxel or paclitaxel and/or 
carboplatin if held for ≥3 weeks in a row, (see 
general instruction at the beginning of the section)
Hepatic
Grade 1

No change to nab-paclitaxel or paclitaxel and/or 
carboplatin
≥ Grade 2 or 3

Bilirubin fractionation should be performed if total 
bilirubin > 1.5xULN. Dose may continue if isolated 
bilirubinemia is mostly indirect such as in subject 
with Gilbert 

Hold  nab-paclitaxel or paclitaxel and/or carboplatin 
until resolve to Grade 1 and resume the dose at 
previous level

Discontinue  nab-paclitaxel or paclitaxel and/or 
carboplatin  if held for ≥ 3 weeks in a row, (see 
general instruction at the beginning of the section)
Grade 4

Discontinue  nab-paclitaxel or paclitaxel and/or 
carboplatin  (see general instruction at the beginning 
of the section)
Note all concurrent ALT/AST >3xULN and Total 
bilirubin > 2xULN should be discontinued and 
evaluated for potential Hy’s law
Anaphylaxis 
/hypersensitivity
severe

Stop infusion immediately and discontinue treatment 
(see general instruction at the beginning of the 
section)
Other significant 
toxicities excluding 
fatigue, alopecia and 
leukopenia at discretion 
of the investigators
Grade 2

Hold nab-paclitaxel or paclitaxel and/or carboplatin 
until resolve to ≤Grade 1

Resume at the previous dose and increase supportive 
care measure, if available
≥ Grade 3

Hold nab-paclitaxel or paclitaxel and/or carboplatin, 
and discuss with sponsor medical monitor for further 
instructions

If ≥ Grade 3 toxicity recurs upon rechallenge, 
discontinue treatment permanently
 
 
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Table 9
Dose Modification Guidelines for Doxorubicin and Cyclophosphamide (AC) 
Toxicities
Grade 
or 
actual 
value
Doxorubicin and cyclophosphamide
Hematological
Neutropenia
≥1000/mm3
(G2/G1)
No change to AC 
<1000/mm3
G3/G4
Hold AC until ANC≥1000/mm3.  
Resume AC based on timing of recovery:

≤1 week: No change to  AC

≥1 but <3 weeks: Reduce AC by 20% for all 
subsequent cycles. 

≥3 weeks: discontinue AC (see general instruction at 
the beginning of the section)
Febrile neutropenia
ANC≤1000/mm3, 
fever≥38.5°C
G3 and G4
Hold AC until resolved (ANC>1000/mm3, fever <38.5°C, 
and resolution of any signs of infection
Resume AC according to number of episodes:

First episode: no change to AC.

Second episode: Reduce AC by 20% for all 
subsequent cycles 

Third episode:  Discontinue AC (see general 
instruction at the beginning of the section)
Thrombocytopenia
75–<100,000/mm3
Grade 1
Hold AC until ≥100,000/mm3, resume paclitaxel based 
on timing of recovery:

≤1 week—no change to AC.

>1 but <3 weeks—  Reduce AC by 20% for all 
subsequent cycles

≥3 weeks:  Discontinue AC (see general instruction 
at the beginning of the section)
<75,000/mm3
≥ Grade 2
Hold AC until ≥100,000/mm3.  

Reduce AC by 20% for all subsequent cycles

Discontinue AC if held for ≥ 3 weeks in a row, (see 
general instruction at the beginning of the section)
Anemia 
All grades
No change to AC

Iron studies should be done and iron should be 
replaced as indicated.

Red blood cell transfusions can be given at the 
investigators discretion. 
Nausea/Vomiting
Grade 1 or 2
No change to AC 
≥ Grade 3
Hold AC until resolved to ≤grade 1. 

Resume AC at previous dose with modification of 
premedication

Second episode ≥ Grade 3 despite with maximum 
supportive care, reduce AC by 20% for all 
subsequent cycles 
Mucositis/Stomatitis
Grade 1 or 2
No change to AC 
≥ Grade 3
Hold AC until resolved to ≤grade 1. 

Resume AC at previous dose with modification of 
premedication

Second episode ≥ Grade 3 despite with maximum 
supportive care, reduce AC by 20% for all 
subsequent cycles 
 
 
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Toxicities
Grade 
or 
actual 
value
Doxorubicin and cyclophosphamide
Hepatic
Grade 1

No change to AC
≥ Grade 2 or 3

Hold AC until resolve to Grade 1 and resume the 
dose at previous level

Discontinue AC if held for ≥ 3 weeks in a row, (see 
general instruction at the beginning of the section)
Grade 4 

Discontinue  AC  (see general instruction at the 
beginning of the section)
Note all concurrent ALT/AST >3xULN and Total 
bilirubin >2xULN should be discontinued and 
evaluated for potential Hy’s law
Cardiac toxicity 
Grade 1 or 2

No change to AC 
≥ Grade 3

Discontinue doxorubicin (see general instruction at 
the beginning of the section)
Anaphylaxis/ 
hypersensitivity
Mild 

Complete AC infusion, observe until symptom 
resolved
moderate

Stop infusion and treat per standard practice

Resume infusion at half of the infusion speed if 
symptom resolve

Stop if symptom recurs
severe

Stop infusion immediately and discontinue treatment 
(see general instruction at the beginning of the 
section)
Other significant 
toxicities excluding 
fatigue, alopecia and 
leukopenia at discretion 
of the investigators
Grade 2

Hold AC until resolve to ≤ Grade 1

Resume at the previous dose and increase supportive 
care measure, if available
≥ Grade 3

Hold AC and discuss with sponsor medical monitor 
for further instructions

If ≥ Grade 3 toxicity recurs upon rechallenge, 
discontinue treatment permanently
Timing of Dose Administration
5.2.2
On each trial treatment dosing day, trial treatments should be administered after all 
procedures/ assessments have been completed as listed in the Trial Flow Chart (Section 6). 
Refer to the product label for detailed instructions on preparation and administration 
precautions on combination chemotherapy agents included in the trial: nab-paclitaxel, 
carboplatin, doxorubicin and cyclophosphamide. 
5.2.2.1
Pembrolizumab
Pembrolizumab will be administered on Cycle 1 Day 1 (with a window of +3 days) as the 
first trial treatment.  For Cycle 2-9, trial treatments should be administered in accordance 
with the schedules provided in Table 3 (Section 5.2) with a window of +/- 2 days for Cycle 
2-5 and a window of +/- 3 days for Cycle 6-9. 
At each treatment, a fixed dose of 200 mg pembrolizumab will be administered as a 
30 minute IV infusion. 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, 
 
 
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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 reconstitution,
preparation of the infusion fluid, and administration.
When pembrolizumab is administered on the same day with chemotherapy agents, 
pembrolizumab should be administered prior to chemotherapy agents. 
5.2.2.2
Nab-paclitaxel 
Nab-paclitaxel, at a dose level of 125mg/m2 or 100mg/m2, will be administered on Days 1, 8, 
and 15 during Cycle 2-5 as IV infusion administered per institutional guidelines. . 
For Cohort A, when nab-paclitaxel is administered on the same day with pembrolizumab 
during Cycle 2-5, nab-paclitaxel should be administered after pembrolizumab.
For Cohorts B, C, and D, when nab-paclitaxel is administered on the same day together with 
pembrolizumab and carboplatin, nab-paclitaxel should be administered after pembrolizumab 
but prior to the administration of carboplatin. 
Premedication to prevent hypersensitivity reactions is generally not required for 
nab-paclitaxel per product label. 
5.2.2.3
Paclitaxel
Paclitaxel, at a dose level of 80mg/m2  will be administered on Days 1, 8, and 15 during 
Cycle 2-5 as IV infusion administered per institutional guidelines. 
For Cohorts E, and F, when paclitaxel is administered on the same day together with 
pembrolizumab and carboplatin, paclitaxel should be administered after pembrolizumab but 
prior to the administration of carboplatin. 
Additional premedication should be administered as per standard practice.
5.2.2.4
Carboplatin
Carboplatin at AUC 6 or 5, will be administered on Day 1 of Cycles 2-5 and carboplatin at 
AUC 2 or 1.5 will be administered on Day 1, 8, 15 of Cycles 2-5 as an IV infusion 
administered per institutional guidelines immediately following the administration of nab-
paclitaxel. Additional premedication should be administered as per standard practice.  
5.2.2.5
Cyclophosphamide 
Cyclophosphamide should be administered intravenously per institutional guidelines on Day 
1 of Cycle 6-9 following the administration of pembrolizumab. Additional premedication
should be administered as per standard practice. 
5.2.2.6
Doxorubicin
Doxorubicin should be administered IV push on Day 1 of Cycle 6-9 following the 
administration of pembrolizumab. Additional premedication should be administered as per 
standard practice. 
 
 
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Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
At any time during Part 1 or Part 2 of the study, if more than one cohort is open for 
enrollment, eligible subjects will be randomly assigned to a cohort; otherwise, subjects will 
be enrolled to the cohort that is open for enrollment.
Treatment allocation will occur centrally using an interactive voice response/integrated web 
response system (IVRS/IWRS).   
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
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.
Supportive care is permitted for managing drug-related toxicities. See guidelines in Section 
5.6 for more details. 
All concomitant medications received within 28 days before the first dose of trial treatment 
through the safety follow-up visit should be recorded.  After the safety follow-up visit, record 
all medications administered for the treatment of SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medications
5.5.2
Subjects are prohibited from receiving the following therapies from the time of screening
until after definitive surgery:

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol
 
 
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
Investigational agents not specified in this protocol

Radiation therapy

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella, zoster, yellow fever, intranasal 
influenza, rabies, BCG, and typhoid vaccine.
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.

Glucocorticoids for any purpose other than to modulate symptoms from an irAE of 
suspected immunologic etiology or for use as a pre-medication for chemotherapeutic 
agents specified in the protocol. 
o
Note: Inhaled steroids are allowed for management of asthma.
o
Note:  Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to
IV contrast dye) is permitted.
Subjects who are discontinued from the study treatment and continue with other neoadjuvant 
treatment prior to the definitive surgery will be inevaluable for pCR and/or imaging 
evaluations. Details are described in Section 8.4. The anti-cancer treatment received will be 
recorded in the CRF. Subjects may receive other medications that the investigator deems to 
be medically necessary.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy may be required.
Following the definitive surgery, subjects can receive adjuvant treatment or metastatic 
treatments based on subject’s disease status, with the regimen at the discretion of the 
subject’s physician. 
The Exclusion Criteria describes other prior medications prohibited for trial enrollment.
Site staff should refer to the local product label for permitted and prohibited medications, as 
well as, drug interactions for each chemotherapy agent used as trial treatment.
Rescue Medications & Supportive Care
5.6
Supportive Care Guidelines for Pembrolizumab
5.6.1
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.1.5.1, [Table 5]. Where appropriate, these guidelines include the use of oral or 
IV treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms 
do not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
 
 
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guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance. Refer to [Table 6] in Section 
5.2.1.5.1 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
Supportive Care Guidelines for Chemotherapy Agents
5.6.2
Instructions regarding supportive care for the chemotherapeutic agents administered in this 
study can be found in the local product label for each agent.  Infusion reactions and injection 
site reactions will be managed by the investigators according to the local product labels.
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Contraception
5.7.2
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.  
Female subjects will be considered of non-reproductive potential if they are either: 
1. postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
2. have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
3. has a congenital or acquired condition that prevents childbearing.
Female subjects of reproductive potential must agree to avoid becoming pregnant while 
receiving study drug and for 12 months after the last dose of study drug for subjects who 
have received cyclophosphamide, and for six months after the last dose of study medication 
for subjects who have not, by complying with one of the following:  
1. practice abstinence† from heterosexual activity; 
OR 
2. use (or have their partner use) acceptable contraception during heterosexual activity.  
 
 
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Acceptable methods of contraception are‡:
1. Single method (one of the following is acceptable):

intrauterine device (IUD)

vasectomy of a female subject’s male partner 

contraceptive rod implanted into the skin
2. Combination method (requires use of two of the following):

diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

cervical cap with spermicide (nulliparous women only)  

contraceptive sponge (nulliparous women only) 

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
† Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡ If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Subjects should be informed that taking the 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 subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 12 
months after the last dose of trial therapy for subjects who have received cyclophosphamide, 
and for six months after the last dose of study medication for subjects who have not.  If there 
is any question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study.
Pregnancy
5.7.3
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from study treatment.  The site will contact the subject 
at least monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
 
 
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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.   
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

Unacceptable adverse experiences as described in Section 5.2.1.5.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject from study treatment due to disease 
progression or other reasons. See Section 7.1.2.10 for details on disease progression 
evaluation. 

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

Administrative reasons
The End of Treatment/Early Discontinuation and Follow-up visit procedures are listed in 
Section 6 (Protocol Flow Chart) and Section 7.1.5 (Visit Requirements). Following 
definitive surgery, each subject will be followed for 30 days for any adverse events
(serious adverse events will be collected for 90 days after definitive surgery or 30 days 
 
 
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following definitive surgery if the subject initiates new anticancer therapy, whichever is 
earlier, as described in Section 7.2.3.1).  
Subject Replacement Strategy
5.9
Refer to Section 5.2.1.4 for replacement of subjects in Part 1 of the trial. A subject who 
discontinues from Part 2 of the trial will not be replaced.
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).
Clinical Criteria for Early Trial Termination
5.11
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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
Trial Period:
Screening 
Phase
Treatment Phasea
End of 
Treatment
or early 
disconb.
Surgery
Post-Surgery
Treatment Cycle:
Screening 
C1
D1
C2
D1
C2
D8
C2
D15
C3
D1
C3
D8
C3
D15
C4
D1
C4
D8
C4
D15
C5
D1
C5
D8
C5
D15
C6
D1
C7
D1
C8
D1
C9
D1
Safety 
Follow-
up Visit
Survival 
Follow 
Upc
Scheduling Window 
(Days)d:
-28 to -1
+3
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 3
± 3
± 3
± 3
3-6 weeks   
post 
treatment 
but prior to 
surgery
3-6 
wks.   
post 
trmt.
30 days 
post 
surgery
(± 3 
days)
Every 12 
weeks
(±2
weeks)
Administrative Procedures
Informed Consente
X
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
X
X
X
X
X
X
X
X
X
X
X
Treatment allocation
via IVRS/IWRS
X
End of 
Treatment/Post-study 
Anticancer Therapy 
Status
X
X
Survival Status 
X
Administration of Trial Treatment
Pembrolizumab
X
X
X
X
X
X
X
X
X
Nab-paclitaxel 
X
X
X
X
X
X
X
X
X
X
X
X
Paclitaxel
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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Trial Period:
Screening 
Phase
Treatment Phasea
End of 
Treatment
or early 
disconb.
Surgery
Post-Surgery
Treatment Cycle:
Screening 
C1
D1
C2
D1
C2
D8
C2
D15
C3
D1
C3
D8
C3
D15
C4
D1
C4
D8
C4
D15
C5
D1
C5
D8
C5
D15
C6
D1
C7
D1
C8
D1
C9
D1
Safety 
Follow-
up Visit
Survival 
Follow 
Upc
Scheduling Window 
(Days)d:
-28 to -1
+3
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 3
± 3
± 3
± 3
3-6 weeks   
post 
treatment 
but prior to 
surgery
3-6 
wks.   
post 
trmt.
30 days 
post 
surgery
(± 3 
days)
Every 12 
weeks
(±2
weeks)
Carboplatin
(Cohorts B C & E)
X
X
X
X
Carboplatin
(Cohorts D & F)
X
X
X
X
X
X
X
X
X
X
X
X
Doxorubicin 
X
X
X
X
Cyclophosphamide
X
X
X
X
Clinical Safety Assessments
Review Adverse 
Eventsh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
Xi
12-Lead ECG 
(Locally performed)
X
X
X
MUGA or ECHO for 
LVEF Assessment
X
Full Physical 
Examination
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
Vital Signs, Height 
and Weightj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Statusk
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests/ analysis by a LOCAL laboratory
Pregnancy Test –
Urine or Serum -
HCGl
X
Blood for 
menopausal status (if 
applicable)m
X
 
 
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Trial Period:
Screening 
Phase
Treatment Phasea
End of 
Treatment
or early 
disconb.
Surgery
Post-Surgery
Treatment Cycle:
Screening 
C1
D1
C2
D1
C2
D8
C2
D15
C3
D1
C3
D8
C3
D15
C4
D1
C4
D8
C4
D15
C5
D1
C5
D8
C5
D15
C6
D1
C7
D1
C8
D1
C9
D1
Safety 
Follow-
up Visit
Survival 
Follow 
Upc
Scheduling Window 
(Days)d:
-28 to -1
+3
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 3
± 3
± 3
± 3
3-6 weeks   
post 
treatment 
but prior to 
surgery
3-6 
wks.   
post 
trmt.
30 days 
post 
surgery
(± 3 
days)
Every 12 
weeks
(±2
weeks)
PT/INR and 
aPTT/PTTn
X
CBC with 
Differentialp
Xo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xq
Chemistry Panelp
Xo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xq
Urinalysisp
Xo
X
X
X
X
X
X
X
X
X
Xq
T3, FT4 and TSHp
Xo
X
X
X
Laboratory tests/ analysis by a CENTRAL laboratory
Blood for 
Exploratory 
Biomarkers (Plasma, 
Serum) r
X
X
X
X
X
Correlative Blood 
Samples (DNA, 
RNA)s
X
X
X
X
X
Blood for Geneticst
X
Efficacy Measurements
Breast MRI and 
clinical tumor staging
X
Xu
Xu
pCR assessment  
X
Tumor Tissue sample collection
Core tumor tissue 
biopsy for 
translational research
X
Xu
Xv
Definitive surgery
Xw
FFPE tissue or slides 
for TNBC  statusx
X
 
 
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a. In general, assessments/procedures are performed on Day 1 of each cycle prior to dosing of any study treatment (or prior to weekly dosing of nab-paclitaxel) unless otherwise 
specified.  Each treatment cycle is 3 weeks (21 days); If treatment is delayed, all procedures should be performed based on the new dosing schedule. 
b. The End of Treatment/Discontinuation Visit should be conducted 3-6 weeks post treatment discontinuation and before definitive surgery. 
c. After the completion of definitive surgery, the subject should be contacted by telephone every 12 weeks (± 2weeks) to assess for survival or disease recurrence status.
d. Site personnel will access the IVRS prior to dosing on Cycle 1, Day 1 to obtain the subject’s allocation number. Cycle 1 treatment must be given within 3 days following 
allocation (+ 3 days). The window for each visit during Cycle 2 through Cycle 5 is ±2 days and the window for each visit during Cycle 6 through Cycle 9 is ± 3 days.  
e. Written consent must be obtained prior to performing any protocol specified procedure.  Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial treatment).  Screening number 
will be assigned when the trial informed consent is signed.
f. Signing the informed consent for future biomedical research (FBR) sample is optional.  Detailed instructions for the collection and management of specimens for FBR are 
provided in the Procedures Manual and Section 12.2.  
g. Prior medications – Record all medications taken within 30 days prior to the screening visit. Concomitant medications – Enter new medications started during the screening 
period through the Safety Follow-up visit.  Record all medications taken for AEs as defined in Section 7.2.
h. AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.  
i. Report all AEs occurring up until 30 days following definitive surgery and all SAEs occurring up until 90 days following definitive surgery, or 30 days following definitive  
surgery if the subject initiates new anticancer therapy, whichever is earlier.  
j. Vital signs to include temperature, pulse, respiratory rate and blood pressure. Height will be measured at Screening only; weight will be measured at baseline and at each cycle. 
Vital signs will be collected weekly during Cycle 2 through Cycle 5.
k. ECOG PS at Screening to be performed within  10 days prior to of the first dose of trial treatment. ECOG performance status will also be performed prior to the administration 
of each dose of trial treatment at every cycle, at treatment discontinuation, and at follow-up.
l. For women of childbearing potential, a serum or urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results are 
positive or cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should 
be repeated if required by local guidelines.
m. 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/PTT) should be tested for all subjects at baseline and monitored closely in subjects receiving anticoagulant therapy during treatment and 
safety follow-up period.
o. See Section 7.1.3 for details regarding laboratory parameters to be included.
p. After Cycle 1, predose lab samples can be collected up to 72 hours prior to the scheduled time point.  
q. Unresolved abnormal labs that are drug-related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
r. Blood for exploratory biomarkers (plasma, serum) is to be collected at screening, predose on Day 1 of Cycles 2, 3, and 6, and at End of Treatment/Early Discontinuation. See 
Procedures Manual. Any leftover samples from the blood studies will be stored for future biomedical research if the subject signs the FBR consent.
s. Correlative blood samples for RNA/DNA should be collected at predose on Day 1 of Cycles 1, 2, 3, and 6, and at End of Treatment/Early Discontinuation. See Procedures 
Manual. Any leftover samples from the blood studies will be stored for future biomedical research if the subject signs the FBR consent.
t. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.  
u. Biopsy and MRI should be conducted between Day 15 through Day 21 of the designated cycle. Leftover tumor tissue will also be stored for FBR if the subject consents. Post-
treatment MRI should be conducted within 3-6 weeks following discontinuation of trial treatment and prior to definitive surgery. 
v. For subjects with adequate tumor volume left at the end of Cycle 3 as assessed by the investigator, an additional core needle biopsy will be performed only on subjects who are 
willing to participate.
 
 
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w. Any remaining tumor tissue collected at definitive surgery will be stored for FBR if the subject consents. 
x. FFPE tissue or slides from the subject’s initial diagnosis of TNBC should be provided at screening and will be sent to a central pathology laboratory for retrospective 
confirmation of TNBC diagnosis at the end of the study or at a time point designated by the Sponsor.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
 
 
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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
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Any autoimmune disorders, 
regardless of onset date, should be recorded. Details regarding the subject’s TNBC will be 
recorded under medical history CRF, see Section 7.1.1.4.1 for further instructions.  
7.1.1.4.1 Disease Details
Details regarding subject’s TNBC history and status at baseline must be thoroughly evaluated 
by the investigator or qualified designee and recorded in the appropriate eCRF including:
date of initial diagnosis, stage at diagnosis, tumor grade, primary tumor location and type 
(i.e. single lesion, multicentric, multifocal), TNM staging at baseline, sentinel lymph node 
biopsies and results, etc. Refer to Section 5.1 to ensure subject’s disease status meets the 
relevant inclusion and exclusion criteria for study entry. 
7.1.1.4.2 Menopausal Status
The investigator or qualified designee will obtain details regarding the subject’s menopausal 
status as specified (or defined) in Section 7.1.3.2.  
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days prior to the screening visit.
 
 
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7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
starting at the screening visit through the Safety Follow-up Visit.  All medications related to 
reportable AEs, SAEs and ECIs, including AEs and SAEs following definitive surgery 
should be recorded as defined in Section 7.2.
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 treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will receive a treatment number. The treatment number identifies the 
subject for all procedures occurring after treatment allocation. Once a treatment number is 
assigned to a subject, it can never be re-assigned to another subject. A single subject cannot 
be assigned more than 1 treatment number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment for greater than 6 weeks between 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 pembrolizumab or combination product infused will be compared to the 
total volume prepared to determine compliance with each dose of pembrolizumab or 
combination product administered. The instructions for preparing and administering 
pembrolizumab will be provided in the Pharmacy Manual.  Refer to the product label for 
instructions on preparation and administration precautions on combination chemotherapy 
agents included in the trial: nab-paclitaxel, carboplatin, doxorubicin and cyclophosphamide.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Adverse Event 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 Section 12.5).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
 
 
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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 
ECI of a potentially immunologic etiology (termed immune-related adverse events, or 
irAEs).  
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
7.1.2.2
12-Lead Electrocardiogram (ECG)
A 12-lead ECG will be performed using local standard procedures at the time points 
specified in Section 6.0 – Trial Flow Chart.  Clinically significant abnormal findings should 
be recorded as medical history. Additional assessments may be performed as clinically 
necessary.
7.1.2.3
Echocardiography (ECHO) or Multigated Acquisition (MUGA) Scan 
An ECHO or MUGA scan will be required at screening for all subjects to determine study 
eligibility.  The assessment method will be at the investigators discretion and per the local 
SOC.  Additional assessments may be performed as clinically necessary.
7.1.2.4
Physical Exam
7.1.2.4.1 Full Physical Exam
The investigator or qualified clinical designee will perform a complete physical exam during 
the screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  After study enrollment new clinically significant abnormal findings should be 
recorded as AEs.
7.1.2.4.2 Directed Physical Exam
The investigator or qualified clinical designee will perform directed physical exams to assess 
subject’s TNBC status according to the time points as specified in the Trial Flow Chart or as 
needed according to subject’s signs and symptoms.  New clinically significant abnormal 
findings should be recorded as AEs
7.1.2.5
Vital Signs
The investigator or qualified clinical designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment, at treatment discontinuation, and at the 
Follow-up Visit 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. Vital signs should be taken prior to treatment administration.
7.1.2.6
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified clinical designee will assess ECOG status (Section 12.4) at 
screening, prior to dosing on Day 1 of each treatment cycle, at discontinuation of trial 
treatment and at the Follow-up Visit as specified in the Trial Flow Chart.
 
 
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7.1.2.7
Tumor Tissue Biopsy and Sample Collection
In accordance with the study inclusion criteria, subjects are required to have 2 core needle 
biopsies (fine needle aspirate not adequate) performed during the Screening Period and agree 
to have a core needle biopsy performed at the end of Cycle 1 (Days 15-21) if clinically 
feasible as judged by the investigator (See Section 6.0 – Trial Flow Chart). For subjects with 
adequate tumor volume left at the end of Cycle 3 as assessed by the investigator, an 
additional core needle biopsy will be performed only on subjects who agree to participate.
Tumor tissue samples obtained from these biopsies will be used for translational research as 
specified in Section 4.2.3.3. 
The Screening biopsy should be performed preferably after subject has met all other 
eligibility criteria. At least two core biopsies should be obtained and prepared according to 
the instructions outlined in the Procedures Manual for this trial. If feasible, two core biopsies 
should be obtained at each of the additional time points. These tumor tissues will be 
submitted to the designated central laboratory. 
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 as 
specified in Section 4.2.3.4.  
Additionally, archived tumor tissue specimens obtained during subject’s initial diagnosis will 
be collected at Screening for retrospective confirmation of TNBC status by a central 
pathology vendor.    
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
7.1.2.8
Imaging Disease Assessment
Subjects must have evidence of non-metastatic disease (M0) based on the assessments from 
their initial diagnosis. In the event of suspected regional or distant metastasis during 
Screening, subjects should be thoroughly evaluated as clinically indicated; and those with 
metastatic disease should be excluded. At Screening, breast MRI will be performed in all 
subjects for more accurate clinical staging of the primary tumor and axilla lymphadenopathy 
and to ensure the primary tumor and regional lymph node staging fulfill protocol required 
criteria (see Section 5.1.2, Inclusion Criteria). Breast MRI performed as part of routine 
clinical management are acceptable for use as the screening tumor imaging if they are of 
diagnostic quality and were performed within 28 days prior to the first dose of trial treatment.
After treatment allocation, breast MRI is scheduled at end of Cycle 5 (between Days 15-21) 
following treatment with the first combination regimen (KNp or KNpCb), and at end of 
Cycle 9 (between Days 15-21) after completion of the second combination regimen (KAC) 
but prior to surgery. Additional images will be ordered as clinically indicated, for example 
with suspected disease progression or metastasis. 
7.1.2.9
Definitive Surgery
Approximately 3-6 weeks following discontinuation or completion of study treatments, 
subjects will undergo definitive surgery per local standard of care.  Details regarding date of 
surgery, type of surgery, tumor resectability, etc., should be recorded in the appropriate 
 
 
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eCRF. Detailed pathological staging per AJCC and assessment of surgical margins will be 
performed by local pathologist on all the tissues removed during the surgery and recorded in 
the appropriate eCRF.  
For subjects who did not achieve a pCR, tumor tissue samples should be collected and 
submitted to the designated central laboratory for translational research as specified in 
Section 4.2.3.3.  Any leftover tissue will be archived for FBR if the subject has signed the 
optional informed consent for FBR as specified in Section 4.2.3.4.  
7.1.2.10 Determination of Disease progression
Measurement of the baseline lesions, changes from the baseline, and overall response will be 
assessed by the investigator per RECIST 1.1. Due to observed pseudoprogression in a small 
percentage of subjects treated with pembrolizumab in other cancer indications, irRECIST has 
been developed to address this issue. 
7.1.2.10.1 irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs. irRECIST will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions. 
When feasible, subjects should not be discontinued from study treatment until progression is 
confirmed by the investigator/local radiology assessment.  This allowance to continue 
treatment despite initial radiologic progressive disease (PD) takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, and then experience subsequent disease response.  The following 
may present as tumor flare:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
In subjects who have shown initial evidence of radiological PD by RECIST 1.1, the 
investigator needs to decide whether to continue a subject on study treatment until repeat 
imaging is obtained (see Table 10), which should be based on assessing subject’s overall 
clinical condition including performance status, clinical symptoms, and laboratory data.  If 
the subject is clinically stable and can continue on study treatment, repeat scan should be 
performed in ≥4 weeks later to confirm PD.  Clinical stable status is defined as the following: 
1) Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values
2) No decline in ECOG performance status 
3) Absence of rapid progression of disease 
4) Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention  
 
 
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Any subject deemed clinically unstable should be discontinued from trial treatment at site-
assessed 1st radiologic evidence of PD and is not required to have repeat imaging for PD 
confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the investigator should consider all target and non-target lesions as well as any incremental 
new lesion(s).
Per irRECIST, PD is considered Not Confirmed at repeat imaging if ALL of the following 
occur:

Target lesion sum of diameters is < 20 % or < 5 mm absolute increase compared to 
nadir

Non-target lesion(s) resulting in initial PD is qualitatively stable or improved

New lesion(s) resulting in initial PD is qualitatively stable or improved

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the investigator and the 
subject continues to be clinically stable, study treatment and tumor imaging assessment may 
continue per study schedule. 
Per irRECIST, PD is considered Confirmed at repeat imaging if ANY of the following 
occurs:

Target lesion sum of diameters remains ≥ 20% and at least 5 mm absolute increase 
compared to nadir

Non-target lesion(s) resulting in initial PD is qualitatively worse

New lesion(s) resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy.
Additional details about irRECIST are referenced in Merck TIP Sheet for RECIST 1.1 and 
irRECIST.
 
 
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Table 10
Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD by 
RECIST 1.1
Repeat imaging at >4 
weeks at site to 
confirm PD
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting confirmatory 
scan by site
Repeat imaging at >4 
weeks to confirm PD 
per physician 
discretion only
Discontinue treatment
Repeat scan confirms 
PD by irRECIST at 
the local site 
No additional imaging 
required
Discontinue treatment 
No additional imaging 
required
N/A
Repeat scan shows 
SD, PR or CR 
compared to baseline 
scan as per RECIST 
1.1
Continue regularly 
scheduled imaging 
assessments 
Continue study 
treatment at the 
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s 
discretion.  Next 
tumor imaging should 
occur according to the 
regular imaging 
schedule outlined in 
the protocol
*: SD, PR and CR for irRECIST are identical to RECIST 1.1 
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 Procedure 
Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 11.
 
 
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Table 11
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/PTT 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
Glucose
Lactate Dehydrogenase
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/PTT) 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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In cases where a site is not able to obtain the thyroid function testing (T3, FT4, and TSH) 
results prior to scheduled dosing, review of the thyroid function test results after dosing is 
acceptable and poses no additional immediate safety risk to subjects.
7.1.3.2
Menopausal Status
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.
7.1.3.3
Pregnancy Test
For women of reproductive potential, a serum or urine pregnancy test should be performed 
within 72 hours prior to treatment allocation. If urine pregnancy results are positive or cannot 
be confirmed as negative, a serum pregnancy test performed by the local study site laboratory 
will be required. Pregnancy tests should be repeated if required by local guidelines.
7.1.3.4
Correlative Blood Collections – Samples for Correlative, Genetic, and 
Exploratory Biomarker Analyses
Details regarding time points for blood collection to support analysis of exploratory 
biomarkers presented in Section 4.2.3.3 are outlined in the Study Flow Chart – Section 6.0.
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.  
 
 
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Detailed instructions for sample collection, processing and shipment are provided in the 
Procedures Manual.
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual.
7.1.3.5
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research if the 
subject signs the FBR consent:

Leftover DNA for future research

Leftover tumor tissue

Leftover DNA and RNA from correlative studies

Leftover plasma and serum from exploratory biomarker studies
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the End of Treatment/Early Discontinuation 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.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
 
 
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7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
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, and 
Pharmacy 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
Approximately 28 days prior to treatment allocation, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1.  Screening 
procedures may be repeated after consultation with the Sponsor.
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame.  
Screening procedures are to be completed within 28 days prior to treatment allocation except 
for the following:

Laboratory tests and ECOG PS are to be performed within 10 days prior to treatment 
allocation.

For women of reproductive potential, a urine and/or serum pregnancy test will be 
performed within 72 hours prior to treatment allocation.  
Subjects may be rescreened twice after initially failing to meet the inclusion/exclusion 
criteria.  Results from assessments performed during the initial screening period are 
 
 
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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 timing requirements during the treatment period are as follows:

Assessments/procedures should be performed on Day 1 for each cycle unless 
otherwise specified in the flow chart.

During Cycles 2-5 where nab-paclitaxel or paclitaxel is administered weekly, 
assessments/procedures should be performed on Day 1, Day 8, and Day 15.

Treatment cycles are 3 weeks (21 days).  

The window for each visit is ± 2 days for Cycles 2-5 and ± 3 days for Cycles 6-9 
unless otherwise noted.  Cycle 1 treatment should be no more than 3 days after 
treatment allocation.  

Biopsies and imaging are performed between Days 15-21 of each specified treatment 
cycle.
For the full list of all visit assessments/procedures please see Section 6.0 – Trial Flow Chart.  
Specific procedure-related details are provided above in Section 7.1 – Trial Procedures. 
7.1.5.3
Definitive Surgery
Definitive surgery will be performed per local standard of care approximately 3-6 weeks 
following discontinuation or completion of study treatment.
7.1.5.4
Post-Treatment Visits
7.1.5.4.1 End of Treatment or Early Discontinuation Visit
The End of Treatment or Early Discontinuation visit should occur at any time study treatment 
is discontinued for any reason.  This visit should be conducted between 3-6 weeks following 
treatment discontinuation but prior to definitive surgery or new therapy.  Visit requirements 
are outlined in Section 6.0 – Trial Flow Chart.  Specific procedure-related details are 
provided in Section 7.1 – Trial Procedures.  Additional details regarding subject withdrawal 
and discontinuation are outlined in Section 5.8.
7.1.5.4.2 Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days following 
definitive surgery.  All AEs that occur prior to the Safety Follow-up Visit should be 
recorded.  Subjects with an AE of Grade >1 will be followed until resolution of the AE to 
Grade 0-1.  Serious AEs that occur within 90 days following definitive surgery (or 30 days 
following definitive surgery if the subject initiates new anticancer therapy, whichever is 
earlier) should also be followed and recorded. 
 
 
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7.1.5.4.3 Follow-up for Disease Status and Survival
After completion of the Safety Follow-up Visit, the subject will be contacted by telephone 
every 12 weeks to assess for disease and survival status for 24 months following surgery or 
until death, withdrawal of consent whichever comes first. Time of disease recurrence, 
progression, start and stop dates of subsequent anticancer treatments, and reasons for 
treatments should be recorded in the appropriate eCRF. For a subject who dies during the 
follow up period, date and cause of death should be recorded in the appropriate eCRF.
The Sponsor may request survival status be assessed at additional time points during the 
course of the study.  For example, these additional time points may be requested prior to: an 
eDMC safety review, efficacy interim analysis, and/or final analysis.  All subjects who are 
not known to have died prior to the request for these additional survival status time points 
will be contacted at that time.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during 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
definitive surgery, all adverse events must be reported by the investigator. Such events will 
be recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in 
 
 
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section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
For this trial, an overdose will be defined as ≥1000 mg (5 times the dose) of pembrolizumab 
and as any dose ≥20% over the prescribed dose for the chemotherapies used in the study. No 
specific information is available on the treatment of overdose of pembrolizumab. In the event 
of overdose, pembrolizumab should be discontinued and the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
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 12 months after the last dose of study medication for 
subjects who have received cyclophosphamide, and for six months after the last dose of study 
medication for subjects who did not, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
 
 
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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;
●
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 12 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following definitive surgery, or 30 days following definitive surgery 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).
 
 
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Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor. 
All subjects with serious adverse events must be followed up for outcome.
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, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
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).
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 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
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Table 12
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
Communication of Cohort Dose Level Adjustment
7.3.1
After 6 and 10 subjects have completed DLT evaluation period for a given dose level in Part 
1 of the study, an assessment of DLTs will be conducted according to the rules outlined in 
Section 5.2.1.2.  A meeting (via teleconference or WebEx) will be scheduled between the 
Sponsor, Principal Investigator and other relevant study personnel to determine the dose level 
adjustment (if any) that is needed based on the dose finding rules.  The results of this 
evaluation will be communicated to all investigative sites and study personnel and enrollment 
in each cohort using the new dose level will begin immediately and as applicable.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to conduct of the final 
analysis, will be documented in the Clinical Study Report (CSR) for the study.  Post hoc 
exploratory analyses will be clearly identified in the CSR.  For this Phase 1b protocol, no 
separate statistical analysis plan will be issued for this study, with the exception of an 
analysis plan for the pharmacokinetics analyses.
Statistical Analysis Plan Summary
8.1
Study Design Overview
A Phase 1b Open-Label Study to Evaluate Pembrolizumab plus 
Chemotherapy as Neoadjuvant Treatment for Triple Negative Breast 
Cancer (TNBC)
Analysis Populations
Safety: All Subjects as Treated (ASaT)
Efficacy (secondary): Full Analysis Set (FAS)   
Primary Endpoint(s)
Safety: DLT   
Key Secondary Endpoints
pCR (defined as ypT0 ypN0) Rate
pCR (defined as ypT0/Tis ypN0) Rate
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Counts and percentages will be provided for pCR rate separately for each 
cohort for subjects who are treated with RP2D.  
An exact (Clopper-Pearson) 90% CI will be provided for the pCR rate in 
each cohort.
 
 
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Treatment Assignment
Subjects are allocated to the following cohorts:
Cohort A (KNp/ KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + nab-paclitaxel (Np) weekly] x 4 cycles (1 
cycle = 21 days), followed by KAC Q3W x 4 cycles
Cohort B (KNpCb/ KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + nab-paclitaxel (Np) weekly + carboplatin 
(Cb) Q3W] x 4 cycles, followed by KAC Q3W x 4 cycles
Cohort C (KNpCb / KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + nab-paclitaxel (Np) weekly + carboplatin 
(Cb) Q3W] x 4 cycles, followed by KAC Q3W x 4 cycles.
Cohort D (KNpCb / KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + nab-paclitaxel (Np) weekly + carboplatin 
(Cb) weekly] x 4 cycles, followed by KAC Q3W x 4 cycles.
Cohorts E (KTCb / KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + paclitaxel (T) weekly + carboplatin (Cb) 
Q3W] x 4 cycles, followed by pembrolizumab + doxorubicin + 
cyclophosphamide (KAC) Q3W x 4 cycles. 
Cohort F (KTCb / KAC): Single dose pembrolizumab (K), followed by 
[pembrolizumab (K) Q3W + paclitaxel (T) weekly + carboplatin (Cb) 
weekly] x 4 cycles, followed by pembrolizumab + doxorubicin + 
cyclophosphamide (KAC) Q3W x 4 cycles.
If more than one cohort is open for enrollment simultaneously, allocation 
to a cohort will be made randomly.  
Statistical Methods for Key 
Safety Analyses
Summary statistics (counts, percentage, mean, standard deviation, etc.) 
will be provided for the safety endpoints as appropriate
Interim Analyses
Two interim analyses are planned in this study. Details are provided in 
Section 8.7.

First Interim Analysis
o
Timing: after all subjects either have the safety follow up 
visit (30 days following definitive surgery) or have 
discontinued the study prior to the safety follow-up visit. 
o
Purpose: primary analysis for DLT rate and interim 
efficacy analysis for ORR.

Second Interim Analysis 
o
Timing: after the last subject is followed for 6 months after
definitive surgery, has died, or is lost to follow up, 
whichever comes first. 
o
Purpose: safety analysis and interim efficacy analysis for 
EFS and OS.

Final Analysis
o
Timing: after the last subject is followed for 24 months 
after surgery for events, has died, or is lost to follow up, 
whichever occurs earlier.
o
Purpose: final efficacy analysis for long-term EFS and OS. 
o
Multiplicity
No multiplicity adjustment is planned in this Phase 1b study.
Sample Size and Power 
There will be no more than 20 subjects for each dose level, but up to 30 
subjects per cohort.   
 
 
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Responsibility for Analyses/In-House Blinding
8.2
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 conducted as an open-label trial, i.e., subjects, investigators, and SPONSOR 
personnel will be aware of subject treatment assignments after each subject is enrolled and 
treatment is assigned. If more than one cohort is open for enrollment at the same time, 
allocation to treatment will be randomly assigned.
Planned interim and final analyses are described in Section 8.7.
Hypotheses/Estimation
8.3
Objectives of the study are stated in Section 3.0.
Analysis Endpoints
8.4
Efficacy and safety endpoints are listed below, followed by the descriptions of the 
derivations of selected endpoints.
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
8.4.1
Efficacy endpoints and their definitions are presented in Section 8.4.3.
Safety Endpoints
8.4.2
The primary safety endpoint is DLT.  Safety will be monitored by cumulative data reviews 
throughout the trial.  The toxicities and grades experienced by subjects who have received 
study treatment, including AEs, SAEs and ECIs will be summarized.  Other safety measures 
evaluated in all parts of the study include laboratory safety assessments, ECGs, vital signs, 
and physical examinations.
Derivations of Efficacy/Immunogenicity/Pharmacokinetics Endpoints
8.4.3
Secondary efficacy endpoints and their definitions are presented below. 
Pathological complete response (pCR) Rate (ypT0 ypN0):  is defined as the rate of 
absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation of the 
complete resected breast specimen and all sampled regional lymph nodes following 
completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed 
by local pathologist at the time of definitive surgery.
Pathological complete response (pCR) Rate (ypT0/Tis ypN0): is defined as the rate of 
absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete 
resected breast specimen and all sampled regional lymph nodes following completion of 
neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by local 
pathologist at the time of definitive surgery.
For subjects who are discontinued from the study treatment and continue with other 
neoadjuvant treatment not specified by the study prior to the definitive surgery will be 
classified as not having a pCR in the efficacy analyses, regardless of the results obtained 
from the surgery.
 
 
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Objective Response Rate (ORR): is defined as the percentage of subjects who have 
achieved complete response (CR) or partial response (PR) according to RECIST 1.1 by site 
radiology review. Because imaging will be assessed prior to surgery, a confirmation 
assessment of CR or PR will not be obtained.  Subjects with missing outcome for objective 
response will be considered non-responders.
Event Free Survival (EFS):  is the time from the first dose date of study treatment to any of 
the following events: progression of disease that precludes definitive surgery, disease 
recurrence (for subjects with complete surgical resection), progression (for subjects with 
incomplete surgical resection), or death due to any cause. Subjects without documented 
events will be censored at the date of the last disease status assessment.
Overall Survival (OS): is the time from the first dose date of study treatment to death due to 
any cause. Subjects without documented death at the time of the analysis will be censored at 
the date of the last follow-up.
Derivations of Safety Endpoints
8.4.4
Description of safety measures is provided in Section 7.2.
Analysis Populations
8.5
Safety Analysis Populations
8.5.1
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all subjects who received at least one dose of 
study treatment.  In case of treatment administration errors, subjects will be analyzed 
according to the treatment they actually received. 
The DLT evaluation period consists of Day 1 Cycle 1 through end of Cycle 3 (i.e. through 2 
cycles of the first combination regimen) as well as Day 1 Cycle 6 through end of Cycle 7 (i.e. 
through 2 cycles of the second combination regimen).
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.
Efficacy Analysis Populations
8.5.2
The full analysis set (FAS) is defined as all subjects with a baseline evaluable disease by 
investigator assessment who started with RP2D, regardless of dose modification during the 
course of the study. The FAS will be the primary population for secondary analyses of 
efficacy. The subjects with evaluable disease include those who met inclusion criteria 3 and 4 
in Section 5.1.2, i.e. subjects with locally advanced non-metastatic TNBC.  
 
 
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Statistical Methods
8.6
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the secondary efficacy objectives.  
Efficacy assessments will be provided separately for subjects in each cohort.  The primary 
analyses of the efficacy endpoints will be based on FAS subjects in Part 1 and Part 2. 
Additional supporting analyses using ASaT subjects will also be carried out. 
The key efficacy endpoints are pCR rate (ypT0/Tis ypN0) and pCR rate (ypT0 ypN0). Point 
estimates for each pCR rate and the corresponding exact 90% confidence intervals based on 
the Clopper-Pearson method will be provided. The 90% CI will be interpreted in the context 
of a historical pCR rate of 50%. The 50% pCR rate is based on the Phase III study 
(GeparSepto), in which the pCR (ypT0 ypN0) in the TNBC subgroup was 48.2% in those 
who received nab-paclitaxel compared with 25.7% in those who received paclitaxel. Another 
randomized Phase II study (GeparSixto) showed pCR (ypT0 ypN0) rate of 53.2% in those 
who received addition of weekly carboplatin compared with 36.9% in those who did not. 
Additional details of these two studies can be found in Section 4.1.1.2 Current and Emerging 
Neoadjuvant Treatments for TNBC.
The subject’s TNBC status used in the primary analysis of pCR rate will be based on the 
evaluation by the local pathologist. The agreement on the TNBC status evaluated by the local 
pathologist and retrospectively confirmed by central laboratory will be assessed and if one 
cohort has more than 10% subjects showing different TNBC status, the primary pCR 
analyses will be re-done using the central laboratory confirmed result. 
Additional efficacy endpoints include ORR, EFS, and OS:
Estimates of ORR and the corresponding exact 90% confidence intervals after completion of 
the first combination regimen (KNp, KNpCb, or KTCb) and after completion of the second 
combination regimen (KAC) will be provided using the same approach as pCR rate.
Kaplan-Meier estimates and the corresponding 90% confidence intervals at month 6, month 
12, and month 24 following treatment start will be provided for EFS and OS.
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements and physical examinations.
DLTs will be listed.  DLTs and adverse experiences will be summarized as counts and 
frequencies by cohort for each dose level for which at least 3 subjects are treated and listed 
for other dose levels.  Laboratory assessments, vital signs, and other safety endpoints will be 
summarized as appropriate.
Immune-related ECIs (irECIs) that are designated as AEs of special interest will be 
summarized in separate tables from other AEs.  Any AE of unknown etiology associated the 
combination exposure will be evaluated to determine if it is possibly an ECI of a potentially 
immunologic etiology (irECI) (see Section 7.2.3.2).  
 
 
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In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, a drug related AE, a serious AE, an AE which is both drug-related and 
serious, and who discontinued due to an AE will be summarized for dose levels with at least 
3 subjects treated and listed for other doses.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
8.6.3.1
Demographic and Baseline Characteristics
The number and percentage of subjects screened, randomized/allocated, the primary reasons 
for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized either by descriptive statistics or categorical 
tables for ASaT population (by Dose Level and Cohort).
Interim Analyses
8.7
Safety will be evaluated continuously and the number of subjects with a DLT will be 
assessed for dosing decisions following the time that 6 and 10 subjects are evaluable for DLT
of each cohort, however, if dosing decisions can be made according to the pre-specified rules 
prior to the time that the 6th or 10th subjects are evaluable, the study may proceed according
to decisions outlined in Section 5.2.1.2.
First analyses of the primary endpoint (DLT) and two of the secondary efficacy endpoints 
(pCR rate and ORR) will be evaluated following the time that all subjects either (1) have the 
safety follow up visit (30 days following definitive surgery) or (2) have discontinued the 
study prior to the safety follow-up visit. This is expected to happen about 6 months after the 
last subject is enrolled.  
Another analysis of safety and efficacy endpoints (EFS and OS) will be evaluated after the 
last subject is followed for approximately 6 months after definitive surgery for events, has 
died, or is lost to follow up, whichever comes first. 
Final analysis of long term EFS and OS will be performed after the last subject is followed 
for approximately 24 months after surgery for events, has died, or is lost to follow up, 
whichever occurs earlier, to show the long-term clinical benefit.
Multiplicity
8.8
There will be no multiplicity control in this Phase 1b study.
Sample Size and Power Calculations
8.9
The primary purpose of the trial is to investigate the safety and tolerability of neoadjuvant 
KNp/KAC (Cohort A), KNpCb/KAC (Cohorts B, C, and D), and KTCb/KAC (Cohorts E and 
F) in adult subjects with locally-advanced TNBC to establish a dose for each combination for 
further study.  The total sample size is based on clinical considerations and not statistical 
considerations.
Up to 150 subjects will be enrolled, with a maximum of 20 subjects in Cohort A, 10 subjects 
in Cohort B, and 30 subjects in Cohorts C, D, E or F. As defined in Section 3.2, the efficacy 
 
 
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analyses will include subjects who started with RP2D. Once the RP2D is established for 
Cohorts C, D, E, and F, additional subjects may be enrolled at the RP2D up to 20 subjects.
Table 13 provides information on the sample size and power calculation based on several 
hypothetical scenarios. Given this is primarily a dose-finding safety study, the secondary 
efficacy analyses are exploratory in nature and the power calculations are provided only as 
examples.
Table 13
Sample Size and Power Calculation with Various Scenarios
pCR Rate Under 
Null Hypothesis
pCR Rate Under 
Alternative Hypothesis
Sample Size
Power1
40%
60%
20
42%
40%
70%
20
77%
50%
60%
20
13%
50%
70%
20
42%
1: Based on one-sided alpha level of 0.05.
As described in Section 5.2.1.2, the decisions regarding dose de-escalation will be made in 
the first 3 Cycles as well as in Cycle 6 and 7 after 6 and 10 subjects are evaluable for DLT at 
a given dose level. If DLTs are observed in ≥3 out of the first 6 subjects who are evaluable 
for DLT, or ≥ 4 out of the first 10 subjects who are evaluable for DLT, the dose level will be 
deemed unacceptably toxic. Table 14 provides the probabilities of observing the above 
criteria given various assumed true DLT rates in the first 3 Cycles of each combination.
Table 14
Probability of Observing DLTs at the Time of DLT Assessment in the first 3 
Cycles
Probability1 of Declaring Dose Unacceptably Toxic
DLT Rate in the First 3 Cycles
After 6 subjects
(≥3/6 with DLT)
After 10 subjects
(≥4/10 with DLT if <3/6 have DLT) 
10%
1.6%
2.2%
15%
4.7%
7.2%
20%
9.9%
15.4%
25%
16.9%
26.6%
30%
25.6%
39.5%
40%
45.6%
65.4%
50%
65.6%
84.8%
1: Based on Binomial distribution of 6 and 10 subjects given the DLT rate in each row.
Subgroup Analyses and Effect of Baseline Factors
8.10
No subgroup analyses will be performed.
 
 
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Compliance (Medication Adherence)
8.11
Drug accountability data for trial treatment will be collected during the study.  Percent 
compliance with drug administration will be calculated for each subject for pembrolizumab
(K), nab-paclitaxel
(Nb),
paclitaxel (T),
carboplatin
(Cb),
doxorubicin (A) and 
cyclophosphamide (C) separately.
For all doses, percent compliance will be calculated as following: 
For nab-paclitaxel, paclitaxel, and carboplatin with weekly dose, “Number of Doses that 
Should have been Taken” will be calculated as 1 plus the number (integer) of 1-week 
intervals that fit between the date of the first dose and the date of the last dose of nab-
paclitaxel.
For pembrolizumab, carboplatin Q3W, doxorubicin, and cyclophosphamide, “Number of 
Doses that Should have been Taken” will be calculated as 1 plus the number (integer) of 3-
week intervals that fit between the date of the first dose and the date of the last dose of the 
respective study medication.
Extent of Exposure
8.12
A subject’s extent of exposure to study medication is defined as the total number of doses of 
combination therapy the subject received.  
Extent of Exposure will be summarized for each KNp/KAC, KNpCb/KAC, and KTCb/KAC
dose levels with at least 3 subjects enrolled and listed for other dose levels.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 15.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
 
 
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Table 15
Product Descriptions
Product Name & 
Potency
Dosage Form
Source
Pembrolizumab (MK-
3475), 50mg
Powder for 
Infusion
Provided centrally by the Sponsor
Nab-Paclitaxel, 100mg
Powder for 
Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee
Nab-Paclitaxel, 250mg
Powder for 
Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee
Paclitaxel 6 mg/mL, 
16.7 mL
Solution for 
Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee
Carboplatin 10mg/mL, 
60mL
Solution for 
Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee
Doxorubicin 2mg /mL, 
100mL
Solution for 
Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee
Cyclophosphamide, 1g
Powder for 
Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee
All supplies indicated in Table 15 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 15 will be provided by the trial 
site, subsidiary or designee.
Every attempt should be made to source these supplies from a single lot/batch number. The 
trial site is responsible for recording the lot number, manufacturer, and expiry date for any 
locally purchased product as per local guidelines unless otherwise instructed by the Sponsor.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
All supplies will be provided open label. Pembrolizumab (MK-3475) will be provided as
non-kitted single vials or as single vials in a kit box. The other products will be provided as a 
kit with a single vial.
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.
 
 
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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 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0
ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
 
 
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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 identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1.
name, address, telephone number and e-mail address;
2.
hospital or clinic address and telephone number;
3.
curriculum vitae or other summary of qualifications and credentials; and
4.
other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
 
 
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The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
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.
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 
 
 
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approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialsregister.eu 
 
 
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or other local registries. Merck, as Sponsor of this trial, will review this protocol and submit 
the information necessary to fulfill these requirements. Merck entries are not limited to 
FDAAA or the EMA clinical trial directive mandated trials. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
 
 
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agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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7. Fostira F, Tsitlaidou M, Papadimitriou C, et al. Prevalence of BRCA1 mutations 
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8. Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus 
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11. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term 
clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014; 384: 
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12. Untch M, Jackisch C, Schneeweiss A, et al. A randomized phase III trial comparing 
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14. Sikov WM, Berry DA, Perou CM, et al.  Impact of the addition of carboplatin and/or 
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in breast cancer. J Clin Oncol. 2011; 29(15): 1949-55.
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31. Ghebeh H, et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed 
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Increased TILs and Better Outcome in Breast Carcinomas. Clin Cancer Res. 2014;
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Immunol Res. 2014; 2(4): 361-70.
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versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a 
randomised, multicentre, open-label, phase 3 trial. Lancet. 2014; 15: 396-405.
35. Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, et al. ETNA 
(Evaluating Treatment with Neoadjuvant Abraxane) randomized phase III study 
comparing neoadjuvant nab-paclitaxel (nab-P) versus paclitaxel (P) both followed by 
anthracycline regimens in women with HER2-negative high-risk breast cancer: A 
MICHELANGO study [abstract]. Abstracts of the 2016 ASCO Annual Meeting; 2016 
Jun 3-7; Chicago, IL: ASCO; 2016. p. 2.
36. Socinski MA, Bonadarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in 
combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-
line therapy in patients with advanced non-small-cell lung cancer: final results of a 
Phase III trial. J Clin Onc. 2012; 30(17): 2055-2062.
 
 
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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 7.1.3.5 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in 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.  
 
 
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A template of each trial site’s approved informed consent will be stored in the
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
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mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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ECOG Performance Scale
12.4
Grade
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house 
work, office work
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 
50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined 
to bed or chair
5
Dead
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
 
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
12.5
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).
 
 
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
12.6
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. MRI
should be utilized, as per RECIST 1.1, as the preferred imaging technique in this study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
 
 
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Abbreviations 
12.7
Abbreviation/Term
Definition
AC
Doxorubicin + Cyclophosphamide
AE
Adverse Event
AJCC
American Joint Committee on Cancer
ALT
Alanine Aminotransferase
ASaT
All Subjects as Treated
AST
Aspartate Aminotransferase
β-hCG
β-human Chorionic Gonadotropin
BRCA
Breast Cancer 1
Cb
Carboplatin
CBC
Complete Blood Count
CD8+
Cluster of Differentiation 8 positive
CHF
Congestive Heart Failure
CI
Confidence Interval
CR
Complete Response
CRF
Case Report Form
CSR
Clinical Study Report
CTCs
Circulating Tumor Cells
CTCAE
Common Toxicity Criteria for Adverse Events
CTL
Circulating T Lymphocytes
DL
Dose Level
DLT
Dose-limiting Toxicity
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
eCRFs
Electronic Case Report Forms
EFS
Event-free Survival
EGFR
Epidermal Growth Factor Receptor
ER
Estrogen Receptor
ERC
Ethics Review Committee
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization 
Act
FFPE
Formalin-fixed Paraffin  Embedded
FTIH
First Time in Humans
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HER2
Human Epidermal Growth Factor Receptor 2
HGFR
Hepatocyte Growth Factor Receptor
HIV
Human Immunodeficiency Virus
HR
Hormone Receptor
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IgG4
Immunoglobulin G4
IHC
Immunohistochemistry
 
 
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Abbreviation/Term
Definition
INR
International Normalized Ratio
irAEs
Immune-related Adverse Events
IRB
Institutional Review Board
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
K
Pembrolizumab
KM
Kaplan-Meier
KN
KEYNOTE
LMP
Last Menstrual Period
mAb
Monoclonal Antibody
mg
Milligram
mg/m2
Milligram per meter squared
mL
Milliliter
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
MSD
Merck Sharp & Dohme Corp., a subsidiary of 
Merck & Co., Inc.
mTNBC
Metastatic Triple-negative Breast Cancer
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NKC
Natural Killer Cell
NMR
Nuclear Magnetic Resonance
Np
Nab-paclitaxel
NSCLC
Non-Small Cell Lung Cancer
NYHA
New York Heart Association
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-counter
pCR
Pathological Complete Response
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
PIN
Personal Identification Number
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
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SD
Stable Disease
SOC
Standard of Care
 
 
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Abbreviation/Term
Definition
SOP
Standard Operating Procedures
T3
Total thriiodothyronine
T4
Free thyroxine 
TCGA
The Cancer Genome Atlas
TCR
T Cell Receptor
TILs
Tumor-Infiltrating Lymphocytes
TNBC
Triple-negative Breast Cancer
Tregs
Regulatory T Cells
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
WBC
White Blood Cell
 
 
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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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