Phase II Study of Pembrolizumab and Nab-paclitaxel in HER-2 Negative Metastatic Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: NYU Langone Health

 
 
Official Title: 
Phase II Study of Pembrolizumab and Nab-paclitaxel in HER-2 
Negative Metastatic Breast Cancer   
NCT Number: 
NCT02752685 
Study Number: 
15-00441 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
August 3, 2021 
 
 

Product: Pembrolizumab and Nab-paclitaxel 
Protocol/Amendment: NYU S15-00441, version date 2021 July 21 
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Title: Phase II Study of Pembrolizumab and Nab-paclitaxel in 
HER-2 Negative Metastatic Breast Cancer 
 
CONFIDENTIAL 
 
Regulatory Sponsor/ 
Principal Investigator: 
Sylvia Adams, MD 
New York University Cancer Institute 
Clinical Cancer Center 
160 East 34th Street 
New York, NY 10016 
Tel: (212) 731-5795 
sylvia.adams@nyumc.org 
 
Funding Source: 
Merck and Celgene 
 
Study Product: 
Pembrolizumab (supplied by Merck) 
Nab-paclitaxel (supplied by Celgene) 
 
Protocol Number: 
NYU S15-00441, Celgene AX-CL-BRST-PI-006499, Merck 
MISP53173 
 
IND Number: 
129859 (IND Exempt) 

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Protocol/Amendment: NYU S15-00441, version date 2021 July 21 
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Co-Investigator- Biostatistician: 
Judith D. Goldberg, Sc.D. 
650 First Avenue 5 534 
New York, NY 10016 
Tel: (212) 263-0314 
 
Regulatory/Nursing/Data Management Support: 
NYU Cancer Institute Clinical Trials Office 
Tel: (212) 263-2171 
 
Medical Monitor: 
Zujun Li, MD 

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TABLE OF CONTENTS 
1 
TRIAL SUMMARY ....................................................................................................... 7 
2 
TRIAL DESIGN ............................................................................................................. 7 
2.1 Trial Design ................................................................................................................ 7 
2.1.1 Primary Study Endpoints ...................................................................................... 7 
2.1.2 Secondary Study Endpoints .................................................................................. 8 
2.1.3 Exploratory Endpoints .......................................................................................... 8 
2.2 Trial Diagram… ..........................................................................................................8 
3 
OBJECTIVES & HYPOTHESES ................................................................................ 9 
3.1 Primary Objectives & Hypotheses ............................................................................... 9 
3.2 Secondary Objectives ................................................................................................. 10 
3.3 Exploratory Objectives .............................................................................................. 10 
4 
BACKGROUND & RATIONALE ............................................................................. 11 
4.1 MK-3475 (pembrolizumab)..................................................................................... 11 
4.1.1 Background… ........................................................................................... 11 
4.1.2 Pharmaceutical and Therapeutic Background—Immune surveillance and PD1-
PDL1 axis ............................................................................................................ 11 
4.1.3 Preclinical and Clinical Trial Data ...................................................................... 12 
4.2 Taxane-based chemotherapy in metastatic breast cancer .................................... 12 
4.2.1 
Background….................................................................................................... 12 
4.2.2 
Nab-paclitaxel and Taxanes in Metastatic Breast Cancer… .............................. 12 
4.3. Rationale for the Trial and Selected Subject Population…...................................13 
4.3.1 
Metastatic Breast Cancer… ............................................................................. 13 
4.3.2 
Triple Negative Breast Cancer (TNBC)… ........................................................ 13 
4.3.3 
Anti-PD-1 Immunotherapeutics in metastatic TNBC (as single agent)… ...... 13 
4.3.4 
Rationale for Combination Therapy of anti-PD-1 antibody pembrolizumab with 
Nab-paclitaxel in this Protocol… ..................................................................... 14 
4.3.5 
Rationale for Dose Selection/Regimen/Modification ........................................ 15 
4.3.6.  Rationale for Identifying Mutated Tumor Antigens… ........................................ 18 
4.3.7 Role of the Gut Microbiome as a Possible Modulator of Antitumor Immunity.. 20 
4.3.8 Rationale for Endpoints ....................................................................................... 20 
4.3.8.1 Efficacy Endpoints… ........................................................................... 20 
4.3.8.2 Biomarker Research… ......................................................................... 20 
4.3.8.3 Study Calendar… ................................................................................. 22 
5 METHODOLOGY ......................................................................................................... 23 
5.1 Entry Criteria ........................................................................................................... 23 
5.1.1 Diagnosis/Condition for Entry into the Trial....................................................... 23 
5.1.2 Subject Inclusion Criteria .................................................................................... 24 
5.1.3 Subject Exclusion Criteria ................................................................................... 26 
5.2 Trial Treatments ...................................................................................................... 27 
5.2.1 Dose Selection/Modification ............................................................................... 29 
5.2.1.1 
Dose Selection… ................................................................................. 28 

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5.2.1.2 Dose Modification… ............................................................................ 28 
5.2.2 Timing of Dose Administration .......................................................................... 41 
5.2.3 Trial Blinding/Masking ....................................................................................... 42 
5.3 Randomization or Treatment Allocation ............................................................... 42 
5.4 Stratification ............................................................................................................. 42 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) ........................ 42 
5.5.1 Acceptable Concomitant Medications ................................................................ 42 
5.5.2 Prohibited Concomitant Medications .................................................................. 43 
5.6 Rescue Medications & Supportive Care ................................................................ 44 
5.6.1 Supportive Care Guidelines ................................................................................ 44 
5.7 Diet/Activity/Other Considerations ........................................................................ 47 
5.7.1 Diet ...................................................................................................................... 47 
5.7.2 Contraception ...................................................................................................... 47 
5.7.3 Use in Pregnancy................................................................................................. 42 
5.7.4 Use in Nursing Women ....................................................................................... 50 
5.8 
Subject Withdrawal/Discontinuation Criteria .................................................... 50 
5.9 
Subject Replacement Strategy .............................................................................. 51 
5.10 Clinical Criteria for Early Trial Termination ..................................................... 51 
6 TRIAL 
PROCEDURES………………………………………………………… 
…45 
6.1 Trial Procedures… ................................................................................................... 45 
6.2 Administrative Procedures… ................................................................................. 45 
6.2.1 
Informed Consent…........................................................................................... 45 
6.2.2 
General Informed Consent… ............................................................................. 46 
6.2.3 
Inclusion/Exclusion Criteria .............................................................................. 47 
6.2.4 
Medical History ................................................................................................. 47 
6.3 Prior and Concomitant Medications Review… ........................................... 48 
6.3.1 
Prior Medications… .......................................................................................... 48 
6.3.2 
Concomitant Medications… ............................................................................. 48 
6.4 
Disease Details and Treatments… ........................................................................ 48 
6.4 1 
Disease Details… ............................................................................................... 48 
6.4.2 
Prior Treatment Details… .................................................................................. 48 
6.4.3 
Subsequent Anti-Cancer Therapy Status… ....................................................... 48 
6.4.4 
Assignment of Screening Number… ................................................................. 49 
6.4.5 
Assignment of Randomization Number… ........................................................ 49 
6.4.6 
Trial Compliance… .......................................................................................... 50 
6.5 Clinical Procedures/Assessments… ....................................................................... 50 
6.5.1 
Adverse Event (AE) Monitoring… ................................................................... 50 
6.5.2 
Physical Exam… ....................................................................................... 50 
6.5.4 
Vital Signs… ..................................................................................................... 50 
6.5.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale… ............. 51 
6.5.6 
Tumor Imaging and Assessment of Disease… ................................................. 51 
6.6 Tumor Tissue Collection and Correlative Studies Blood Sampling… .............. 51 

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6.6.1 
Tumor Specimens… ......................................................................................... 51 
6.6.2 
Diversity in antigen-specific T cell receptor (TCR) and TCR clonality………52 
6.6.3 
Identification of Tumor Antigens… ................................................................. 52 
6.6.4 
Peripheral Blood… ........................................................................................... 55 
6.6.5 Gut Microbiome Analysis… ................................................................................ 56 
6.6.6 Laboratory Procedures/Assessments… ................................................................ 56 
6.7 Pharmacokinetic/Pharmacodynamic Evaluations… ............................................. 57 
6.8 Other Procedures… ................................................................................................... 57 
6.8.1 
Withdrawal/Discontinuation… ....................................................................... 57 
6.9 Blinding/Unblinding .................................................................................................. 57 
6.10 Screening/Treatment… ............................................................................................ 57 
6.10.1 
Screening Period… ......................................................................................... 57 
6.10.2 
Treatment Period… ........................................................................................ 57 
6.11 Post Treatment Visits… .......................................................................................... 57 
6.11.1 
Safety Follow-Up Visit… .............................................................................. 57 
6.11.2 
Follow-up Visits… ........................................................................................ 58 
6.11.3 
Survival Follow-up ........................................................................................ 58 
6.12 Assessing and Recording Adverse Events ............................................................... 58 
6.12.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
NYU PI and to Merck and Celgene… .......................................................... 59 
6.12.2 
Reporting of Pregnancy and Lactation to medical monitor, Merck and 
Celgene… ..................................................................................................... 60 
6.13 Immediate Reporting of Adverse Events to the NYU PI, Merck and 
Celgene… .......... 60 
6.13.1 
Serious Adverse Events… ............................................................................. 60 
6.13.2 
Events of Clinical Interest ............................................................................. 62 
6.13.3 
Evaluating Adverse Events ............................................................................ 63 
6.13.4 
Responsibility for Reporting Adverse Events ................................. 66 
6.13.5 
Investigator Reporting Responsibilities… .................................................... 66 
7 
STATISTICAL ANALYSIS PLAN… .............................................................69 
7.1 Statistical Analysis Plan Summary ................................................................. 69 
7.2 Statistical Analysis Plan........................................................................................... 69 
7.2.1 
General Methods ............................................................................................ 69 
7.2.2 
Safety ............................................................................................................. 70 
7.2.3 
Correlative Analysis ...................................................................................... 71 
8 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 71 
8.1 Investigational Product ........................................................................................... 71 
8.2 Packaging and Labeling Information .................................................................... 72 
8.3 Clinical Supplies Disclosure .................................................................................... 72 
8.4 Storage and Handling Requirements ..................................................................... 72 
8.5 Returns and Reconciliation ..................................................................................... 72 
9 
ADMINISTRATIVE AND REGULATORY DETAILS ......................................... 72 
9.1 
Confidentiality ........................................................................................................ 72 

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9.2 
Compliance with Financial Disclosure Requirements ........................................ 73 
9.3 
Compliance with Law, Audit and Debarment ..................................................... 73 
9.4 
Compliance with Trial Registration and Results Posting Requirements .......... 74 
9.5 
Quality Management System ................................................................................ 74 
9.6 
Data Management .................................................................................................. 74 
10 
APPENDICES ............................................................................................................. 76 
10.1 ECOG Performance Status… ........................................................................ 76 
10.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE)… ...........76 
10.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors… .............................................................. 77 
10.4 Immune-Related RECIST Evaluation in Solid Tumors… ................................ 77 
10.5 Events of Clinical Interest Guidance Document… ............................................. 79 
10.6 NYU Multi-Institution Data and Safety Monitoring Plan… .............................. 79 

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1.0 TRIAL SUMMARY 
 
Abbreviated Title 
Pembrolizumab and nab-paclitaxel in metastatic breast cancer 
Trial Phase 
II 
Clinical Indication 
Metastatic HER2-negative breast cancer 
Trial Type 
Single-arm open-label multi-cohort 
Type of control 
N/A 
Route of administration 
Intravenous (IV) 
Trial Blinding 
No 
Treatment Groups 
All cohorts receive pembrolizumab and nab-paclitaxel 
Number of trial subjects 
70 
Estimated enrollment period 
4 years 
Estimated duration of trial 
9/2015-12/2019 
Duration of Participation 
9/2015-12/2019 
 
This document is a protocol for a human research study. This study is to be conducted in 
accordance with US government research regulations, and applicable international standards 
of Good Clinical Practice, and institutional research policies and procedures. 
 
 
2.0 TRIAL DESIGN 
 
2.1 
Trial Design 
 
This is a single-arm open-label multi-cohort Phase II study evaluating the safety/tolerability 
and clinical activity of the combination of nab-paclitaxel and the antibody against programmed 
cell death 1 (PD-1), pembrolizumab, in patients with human epidermal growth factor receptor 
(HER-2) negative metastatic breast cancer (n=50). There will be two cohorts of patients 
consisting of a triple negative breast cancer (TNBC) cohort with 30 subjects and a hormone 
receptor (HR)-positive cohort with 20 subjects. There will be an initial safety run-in with 12 
subjects (patients from both, TNBC and HR-positive cohort are eligible, we expect 
approximately 6 patients from each cohort). If no unexpected toxicity is observed (as defined 
in the study protocol), then enrollment will continue to complete both cohorts (30 total TNBC, 
20 total in HR positive cohort). The subjects from the run in safety part will be included in the 
Phase II analysis. Tumor expression of programmed cell death ligand 1 (PD-L1) is not required 
for enrollment in the study, but will be assessed as possible predictive marker. 
 
Amendment 2/2019: addition of a 20 patient TNBC cohort, who will be receive a 
pembrolizumab-run in cycle (cycle 1) before starting the combination of pembrolizumab/nab- 
paclitaxel with cycle 2 (rationale discussed in section 4.3.5). This cohort is labeled as 
immunotherapy-run in cohort (iTNBC). The TNBC cohort in the initial trial is labeled as 
chemotherapy-run in cohort (cTNBC). 

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2.1.1 Primary Study Endpoints 
 
The primary endpoint for the safety run-in group is safety and tolerability of the combination 
of nab-paclitaxel and pembrolizumab (anti PD-1 antibody). A prior study in TNBC of the 
combination of nab-paclitaxel and atezolizumab (an anti-PD-L1 antibody) showed tolerability 
of the treatment in 32 women with metastatic disease with no increase in toxicity beyond what 
has been observed for either single agent (Adams S, et al. Presented at: San Antonio Breast 
Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract P2-11-06). 
 
Safety success is defined as avoidance of excess toxicity with the combination compared to 
known single agent toxicity. 
 
The primary endpoint for Phase II is best overall response rate (BORR) based on Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 in the cTNBC cohort who will be treated 
with the combination regimen as either first, second, or third line therapy for metastatic disease. 
 
2.1.2 Secondary Study Endpoints 
 
The BORR will also be estimated based on RECIST 1.1 in the iTNBC cohort who will be 
treated with the combination regimen as either first, second, or third line therapy for metastatic 
disease. 
 
For the TNBC cohorts (iTNBC and cTNBC), BORR will also be evaluated using immune- 
related RECIST criteria; see Appendix (Section 10.4) for criteria details. Progression-free 
survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response 
(DOR) using RECIST 1.1 as well as immune-related RECIST criteria will be used in this 
cohort. In addition, the subset of patients with confirmed PD-L1 expression in both the TNBC 
and HR-positive cohorts will be analyzed for efficacy. It is anticipated that efficacy will be 
highest in the PD-L1 expressors, regardless of HR status. However, efficacy will also be 
assessed preliminarily in PD-L1 expressors by HR subgroup (although there will be limited 
power in the HR-positive group). 
 
2.1.3 Exploratory Endpoints 
 
In the HR-positive cohort, BORR using RECIST 1.1 as well as immune-related RECIST 
criteria will be evaluated in women with metastatic breast cancer previously treated with 0-2 
lines of chemotherapy in the metastatic setting. 
 
Predictive markers of response including PD-1 expression on peripheral leukocytes, TILs by 
histopathological assessment, TCR by immunosequencing, immune gene profiles in tumors 
and the gut microbiome composition and abundance by 16S ribosomal RNA sequencing will 
be explored. Nab-paclitaxel induced changes in tumoral PD-L1 expression and immune 
infiltrates in TNBC and HR-positive tumors will be assessed. 
 
Pembrolizumab induced changes in tumoral PD-L1 expression and immune infiltrates in 
TNBC will be assessed (iTNBC + cTNBC) 

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Mutational and neoantigen load in TNBC will be evaluated for frequency and as predictive 
marker of response (iTNBC + cTNBC) 
 
Efficacy (BORR, PFS and OS) will be explored in each of the iTNBC and cTNBC cohorts. 
 
2.2 
Trial Diagram 

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Protocol/Amendment: NYU S15-00441, version date 2021 July 21 
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3.0 OBJECTIVES & HYPOTHESES 
 
3.1 
Primary Objectives & Hypotheses 
 
(1) Objectives: 
 
a) Phase II-safety run-in: To evaluate the safety and tolerability of the combination of 
nab-paclitaxel and pembrolizumab in women with metastatic HER2-negative breast 
cancer. 
 
b) Phase II: In the cTNBC cohort, to evaluate the best overall response rate (BORR) using 
RECIST 1.1 of nab-paclitaxel with pembrolizumab in women with breast cancer 
treated with 0-2 lines of chemotherapy in the metastatic setting. 
 
Hypotheses: 
 
a) Treatment with the combination of nab-paclitaxel and pembrolizumab is safe and 
tolerable. 
 
b) Phase II study will show for the cTNBC cohort that the combination of nab- 
paclitaxel and pembrolizumab as 1st to 3rd line of therapy for women with metastatic 
breast cancer will result in a clinically significant BORR, greater than 30% based 
on RECIST 1.1. 
 
3.2 
Secondary Objectives 
 
(1) Objectives: 
 
a) In the TNBC cohorts, to evaluate BORR using immune-related RECIST criteria. 
 
b) In the TNBC cohorts, to evaluate progression-free survival (PFS), disease control rate 
(DCR), and duration of response (DOR) using RECIST 1.1 as well as immune- 
modified response criteria. Overall survival (OS) will be evaluated. 
 
c) To evaluate efficacy in the subset defined by PD-L1 expression in subjects with TNBC 
and HR-positive tumors. 
 
3.3 
Exploratory Objectives 
 
(1) 
Objectives: 
 
a) In the HR-positive cohort, to evaluate BORR using RECIST 1.1 as well as immune- 
related RECIST criteria in women with metastatic breast cancer previously treated with 
0-2 lines of chemotherapy in the metastatic setting. 

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b) To explore predictive markers of response including PD-1 expression on peripheral 
leukocytes, TILs by histopathological assessment, TCR by immunosequencing, and 
immune gene profiles in tumors. 
 
c) To assess nab-paclitaxel induced changes in tumoral PD-L1 expression and immune 
infiltrates in cTNBC and HR-positive tumors. 
 
d) To assess pembrolizumab induced changes in tumoral PD-L1 expression and immune 
infiltrates in iTNBC. 
 
e) To assess the frequency of mutational and neoantigen load in TNBC (discussed in 
Section 4.3.6) 
 
f) To explore mutational and neoantigen load as predictive markers of response in TNBC. 
 
g) To explore the relationship between the gut bacterial microbiome and antitumor 
response with anti-PD-1 therapy by evaluating bacterial composition by 16S ribosomal 
RNA sequencing. 
 
h) To explore differences in efficacy (BORR, PFS and OS) in TNBC patients between the 
iTNBC and cTNBC cohorts. 
 
 
4.0 BACKGROUND & RATIONALE 
 
4.1 
MK-3475 (pembrolizumab) 
 
4.1.1. Background: (Drug information provided by Merck) 
 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475 (pembrolizumab). 
 
4.1.2. Pharmaceutical and Therapeutic Background—Immune surveillance and PD1- 
PDL1 axis 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T- 
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 

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member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2). The structure of 
murine PD-1 has been resolved. PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade. The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins. PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells. Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non- 
hematopoietic tissues as well as in various tumors . Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low 
levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas 
PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid 
tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function 
in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers 
were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested 
to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL). This suggests 
that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 
4.1.3 Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
4.2 Taxane-based chemotherapy in metastatic breast cancer 
 
4.2.1. Background 

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Refer to the package insert/approved labeling for detailed background information on nab- 
paclitaxel. 
 
4.2.2. Nab-paclitaxel and Taxanes in Metastatic Breast Cancer 
 
Taxane-based chemotherapy is a first-line standard of care in metastatic breast cancer1. 
Paclitaxel has been well studied, and response rates is about 25 percent for single agent 
paclitaxel in patients with metastatic breast cancer as first-line treatment2-4. Nanoparticle 
albumin-bound-paclitaxel is an albumin-bound formation of paclitaxel that was developed to 
avoid toxicities associated with intravenous administration of solvent-based (sb)-paclitaxel 
(polyethylated castor oil and polysorbate 80). Nab-paclitaxel has been shown to have a 33% 
higher uptake in the tumor in preclinical models compared to paclitaxel. It also has a shorter 
infusion time than paclitaxel and can be administered without steroid premedication. 
 
4.3. 
Rationale for the Trial and Selected Subject Population 
 
4.3.1. 
Metastatic Breast Cancer 
 
Breast cancer is the most common cancer among women, affecting 1 in 8 women, and is the 
second leading cause of mortality from cancer5. The majority of breast cancer-related deaths 
are a result of complications from recurrent or metastatic disease. Metastatic breast cancer is 
uncommon as an initial presentation, occurring in less than 10% of newly diagnosed cases. 
However, up to 30% of women who are initially diagnosed with early stage breast cancer will 
develop recurrent or metastatic disease. In the metastatic setting, general treatment goals are 
to prolong life, control symptoms, and maintain quality of life. 
 
4.3.2 
Triple Negative Breast Cancer (TNBC) 
 
Triple negative breast cancer (TNBC) is characterized by lack of estrogen receptor (ER), 
progesterone receptor (PR), and HER-2 and occurs in approximately 20% of all patients with 
breast cancer6. Of the three subtypes of breast cancer (HR-positive, HER-2 positive, and 
TNBC), TNBC carries the worse prognosis. TNBC is characterized by a more aggressive 
biological behavior that includes higher-grade tumors and visceral and distant metastases 
including brain metastases7,8. Patients with metastatic TNBC typically exhibit rapid disease 
progression and a median overall survival (OS) of less than 1.5 years9. Patients with TNBC 
derive no benefit from endocrine therapy or trastuzumab (monoclonal antibody against HER- 
2 receptor) and are primarily treated with systemic chemotherapy. Although TNBC may 
initially respond to chemotherapy (response rate to chemotherapy combinations or single 
agents is less than 40%), including taxanes, there are no approved targeted therapies and 
responses to chemotherapy are short lasting10. There is therefore an important and unmet need 
for novel therapeutic approaches to TNBC. In addition, in 2010, the American Society of 
Clinical Oncology (ASCO) and College of American Pathologists11 lowered the 
immunohistochemistry (IHC) threshold for determining ER positivity from the previous value 
of 10% to 1% of stained cells12. This has led to a subclass of low-ER positive (1-9%) breast 
tumors (formerly classified as TNBC), of which the majority tends to behave like TNBC as 
compared to HR-positive cancers13. 

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4.3.3 Anti-PD-1 Immunotherapeutics in metastatic TNBC (as single agent) 
 
Evading anti-tumor immunity is a hallmark for the development and progression of cancer14. 
Tumors may use various mechanisms to avoid recognition by the host immune system 
including expression of PD-1. Immunotherapies, especially checkpoint inhibitors, have 
demonstrated durable responses in several immunogenic advanced solid tumors including 
melanoma, renal cell carcinoma, and non small cell lung cancer (NSCLC)15 and have shown 
preliminary efficacy in TNBC as single agents (anti-PD-1 and anti-PD-L1)16-18. A phase Ib 
study that was presented at San Antonio Breast Cancer Symposium (SABC) in 2014 showed 
that pembrolizumab (MK-3475) as a single agent (at 10mg/kg IV every 2 weeks) achieved a 
long-lasting response rate of 18% in a phase Ib trial of women (n=32) with heavily pretreated 
metastatic TNBC with PD-L1 expression16. One patient had a complete response (CR) and 
four had partial response (PR) to treatment which were durable. An additional seven had stable 
disease. Another study reported that atezolizumab (MPDL3280A), an investigational 
monoclonal antibody against PD-L1, had a similar overall response rate of 19% among 21 
patients with metastatic TNBC in a phase Ia trial17,18. This included two CRs in subjects with 
high PD-L1 expression (at least 5%) and three with PR; three of the four responses are ongoing. 
These results suggest that immunotherapy may have a durable therapeutic role in the 
management of patients with TNBC by targeting the PD-1/PDL-1 axis. 
 
TNBC is the most immunogenic breast cancer subtype with higher PD-L1 expression levels 
and more tumor-infiltrating lymphocytes (TILs). Ghebeh et al. identified PD-L1 expression in 
22 (50%) of 44 tumors evaluated; in 18 tumors (41%), it was identified in TILs and in 15 (34%) 
it was found in the tumor epithelium19. Intramural expression of PD-L1 was also associated 
with high histological grade and negative hormone receptor status. Studies by our group and 
others have provided level I evidence that pre-existing TILs in TNBC, indicative of an 
endogenous adaptive anti-tumor response, significantly and independently predicts and 
influences disease-free survival (DFS), distant recurrence-free interval (DRFI), and overall 
survival (OS)20,21. However, tumor upregulation of PD-L1 expression is often induced by the 
release of interferon (IFN)-gamma(γ) from TILs which can inactivate T-cells expressing PD- 
1 receptor and block the anti-tumor response22. This is a mechanism in which tumor cells evade 
the antitumor immune response of tumor-specific T cells. In breast cancer, PD-1 expression on 
TILs is highest in basal-like tumors as is constitutive PD-L1 expression in TNBC (linked to the 
degree of lymphocytic infiltrate)23-26. Assay methods for protein and gene expression for either 
target vary widely as do cut-offs for positivity, therefore making a comparison across studies 
difficult. Proprietary PD-L1 assays used at Merck have demonstrated 58% positivity for 
TNBC16 and 17% positivity for HR-positive tumors (unpublished data). Predictor of response 
in early clinical trials utilizing PD-1 and PD-L1 inhibitors involved tumoral PD-L1 expression, 
however responses (albeit lower) were also observed without target expression17,18. 

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4.3.4 Rationale for Combination Therapy of anti-PD-1 antibody pembrolizumab with 
Nab-paclitaxel in this Protocol 
 
While the observed single agent activity of pembrolizumab in TNBC has been encouraging, 
efficacy may be enhanced by the addition of chemotherapy for several reasons: 
 
1) Cytotoxic chemotherapy can maintain clinical stability in these highly aggressive 
tumors until responses can be induced by immunotherapy (median time to response in 
TNBC with pembrolizumab was 18 weeks)16. 
 
2) Cytotoxic chemotherapy can be used to lower the tumor burden, which is a known 
predictive factor for success with immunotherapy. 
 
3) Immune effects of chemotherapy can be harnessed. For example, paclitaxel-based 
neoadjuvant chemotherapy has been shown to increase TILs in breast cancer, and more 
so in patients who respond to chemotherapy27. It enhances the antigenicity of tumor 
cells by increasing the expression of major histocompatibility complex (MHC) class I 
molecules and has been shown to sensitize mouse cancer cell lines to the cytotoxic 
functions of cytotoxic T lymphocytes (CTLs) by increasing the expression of mannose- 
6-phosphate receptor (M6PR) on the cell surface28. M6PR augments the permeability 
of the plasma membrane to granzyme B, one of the main CTL effector molecules and 
leads to tumor cell killing by CTLs, independent from perforin. 
 
4) Taxanes may reduce local immunosuppressive mechanisms such as intratumoral 
myeloid-derived suppressor cells (MDSCs), transforming growth factor-ß (TGF-ß), 
interleukin (IL)-10, and regulatory T cells (Tregs)29. 
 
5) PD-L1 expression has been shown to be induced by chemotherapeutics including 
taxanes30. 
 
6) Nab-paclitaxel is specifically chosen as a combination partner with pembrolizumab as 
it is FDA approved for the treatment of metastatic breast cancer and does not require 
steroid premedication, which could dampen the immune response. 

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Very high response rates were observed in a recently presented study evaluating the 
combination of nab-paclitaxel with another checkpoint inhibitor (atezolizumab, anti PD-L1) 
in metastatic TNBC (Adams S, et al. Presented at: San Antonio Breast Cancer Symposium; 
December 8-12, 2015; San Antonio, TX. Abstract P2-11-06). In 24 patients evaluable for 
response, the ORR was 70.8% (confirmed ORR at time of presentation 41.7%), far exceeding 
responses observed with taxanes or checkpoint inhibitors as single agents in TNBC. 
Importantly, responses were also observed in patients with PD-L1 negative tumors, 
highlighting the promising potential for combination of immunotherapy with chemotherapies 
as well as the need to develop additional predictive biomarkers. 
 
4.3.5 Rationale for Dose Selection/Regimen/Modification 
 
Pembrolizumab (drug information provided by Merck) 
 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475. The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors. All three dose levels were well tolerated and no dose- 
limiting toxicities were observed. This first in human study of MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. 10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and 
D of this protocol to test for initial tumor activity. Recent data from other clinical studies 
within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL- 
2 release assay) suggested that peripheral target engagement is durable (>21 days). This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule. 
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights. MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication. The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 

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the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe. 
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type.  As outlined 
below, this dose is justified by: 
 
• Clinical data from 8 randomized studies in melanoma and NSCLC indications demonstrating 
flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg  Q2W, 
representing an approximate 5- to 7.5-fold exposure range (refer to IB, Section 5.2.2) 
• Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of exposures, 
supporting suitability of 200 mg Q3W 
• 
Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 
200 mg Q3W 
 
 
 
Nab-paclitaxel (drug information provided by Celgene) 
 
Nab-paclitaxel (ABRAXANE® for Injectable Suspension [Abraxis BioScience, LLC, a wholly 

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owned subsidiary of Celgene Corporation, Summit, New Jersey, United States; hereafter 
referred to as “Celgene”], ABI-007) is a proprietary solvent-free, protein-stabilized 
formulation of paclitaxel comprised of paclitaxel in a noncrystalline amorphous state and 
human albumin with a mean particle size of approximately 130 nanometers. nab-Paclitaxel has 
been developed to improve the therapeutic index of paclitaxel, also reducing the toxicities 
associated with Taxol and the CrEL and ethanol vehicle. This may be achieved in part by taking 
advantage of endogenous transport pathways to deliver higher doses of paclitaxel to the tumor. 
Because nab-paclitaxel does not contain a solvent vehicle, micellar entrapment observed with 
Taxol does not occur31-33. nab-Paclitaxel displays linear pharmacokinetic (PK) characteristics. 
The novel albumin-bound particle formulation of paclitaxel in nab-paclitaxel conferred the 
ability to achieve a higher maximum tolerated dose (MTD) based on every 3- weeks dosing: 
300 mg/m2 for nab-paclitaxel (Study DM97-123) versus 175 mg/m2 for Taxol34. The use of 
albumin-bound paclitaxel also enables nab-paclitaxel to be given in a shorter, more convenient 
infusion time of 30 - 40 minutes compared with 3 hours to 24 hours with Taxol. Due to its 
distinct pharmacological and PK properties and therapeutic index, nab-paclitaxel has been 
approved by regulatory authorities worldwide in over 40 countries/regions as a new product, 
rather than as a generic formulation of Taxol. nab-Paclitaxel may be given without steroid and 
anti-histamine premedication, which is required for Taxol to prevent solvent- related HSRs35. 
Cremophor EL has been shown to leach plasticizers, specifically di(2- 

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ethylhexyl)phthalate (DEHP), from polyvinyl chloride (PVC) bags and polyethylene-lined 
tubing36-41. Although no controlled epidemiologic toxicity studies have been conducted in 
humans exposed to DEHP, severe effects (eg, carcinogenicity, cardiopulmonary toxicity, 
hepatotoxicity, and nephrotoxicity) have been observed in experimental models. The Taxol 
prescribing information instructs users to prepare, store, and administer solutions in glass, 
polypropylene, or polyolefin containers; non-PVC-containing infusion sets (eg, those with 
polyethylene lining) should be used (Taxol US prescribing information). By comparison, 
standard tubing and intravenous (IV) bags may be used for the IV administration of nab- 
paclitaxel31,34. 
 
As of October 2014, nab-paclitaxel is approved under the trade name of ABRAXANE® in 51 
countries worldwide for the treatment of patients with metastatic breast cancer. ABRAXANE® 
is also approved in 8 countries worldwide for the first-line treatment of locally advanced or 
metastatic non-small cell lung cancer (NSCLC), and in 40 countries for the first-line treatment 
of metastatic adenocarcinoma of the pancreas, and it is approved in Japan for treatment of 
advanced gastric cancer. 
 
Based upon an important randomized phased III trial,42 nab-paclitaxel was approved for the 
treatment of metastatic breast cancer. In this study, patients received either nab-paclitaxel at 
260 mg/m2 (n=229) or paclitaxel at 175 mg/m2 (n=225) given every three weeks42. Enrolled 
patients had not received a prior taxane for metastatic disease or had not relapsed less than 
twelve months after receiving a taxane for adjuvant treatment. Patients who received nab- 
paclitaxel had a higher response rate compared to paclitaxel (33% versus 19%, respectively, 
p=0.001). The median time to disease progression was longer for the nab-paclitaxel group 
compared to the control group (23.0 versus 16.9 weeks, respectively, HR=0.75, p=0.006). In 
terms of adverse events, the incidence of grade 4 neutropenia was lower for nab-paclitaxel 
compared to paclitaxel (9% versus 22%, p<0.001). No hypersensitivity reactions occurred with 
nab-paclitaxel despite a shorter infusion time and absence of premedications (which were given 
with paclitaxel). Grade 3 sensory neuropathy was more common with the nab-paclitaxel group 
(10% versus 2%, p<0.001), but was easily manageable with dose reduction or treatment 
interruption. 
 
The dosing of nab-paclitaxel at 260 mg/m2 every three weeks in the FDA label established 
from the above study42 is not generally used in clinical practice. Instead, weekly dosing of nab-
paclitaxel is the most commonly utilized schedule due to better tolerability and the suggestion 
of increased efficacy of weekly dosing compared to every three week dosing. The superiority 
of the weekly regimen of nab-paclitaxel was shown in a randomized Phase II study of previously 
untreated patients with metastatic breast cancer (n=302) who received either nab- paclitaxel 300 
mg/m2 q3w, 100 mg/m2 weekly, or 150 mg/m2 weekly or docetaxel 100 mg/m2 q3 weeks43. In 
the four arms of this study, the overall response rates (ORRs) were 37% with q3w nab-
paclitaxel, 45% with weekly nab-paclitaxel 100 mg/m2 (3-weeks-on and 1-week- off), 49% 
with weekly nab-paclitaxel 150 mg/m2 (3-weeks-on and 1 week off), and 35% with q3w 
docetaxel 100 mg/m2. Progression free survival (PFS) was 11.0 months, 12.8 months, 
12.9 months and 7.5 months, respectively. The difference in PFS and ORR between the 100 
and 150 mg/m2 weekly dose levels of nab-paclitaxel was not statistically significant, however 

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patients receiving the higher dose experienced a greater incidence of Grade 3 or 4 neutropenia 
(44% vs. 25%) and Grade 3 sensory neuropathy (14% vs. 8%). 
 
Another phase III trial (CALGB 40502) enrolled patients with HER2-negative metastatic 
breast cancer and no prior chemotherapy44. Patients (n=799) were randomized to one of either 
three arms: paclitaxel 90 mg/m2, nab-paclitaxel 150 mg/m2, or ixabepilone 16 mg/m2, on a 3- 
week-on/1-week-off schedule. All agents were given in combination with bevacizumab. 
Median PFS for paclitaxel was 11 months and 7.4 months for ixabepilone (hazard ratio, 1.59; 
95% CI, 1.31 to 1.93; P <0.001). Nab-paclitaxel was not superior to paclitaxel (PFS, 9.3 
months; hazard ratio, 1.20; 95% CI, 1.00 to 1.45; P = 0.054). Hematologic and non- 
hematologic toxicities were increased with nab-paclitaxel, leading to frequent dose reductions. 
 
At this time, 100 mg/m2 of weekly nab-paclitaxel has been shown to be well tolerated with 
suggestion of improved efficacy and decreased toxicity compared with the higher weekly 
dosing at 150 mg/m2 or the every three week dosing at 260 mg/m2. The patients enrolled in this 
study will therefore receive nab-paclitaxel 100 mg/m2 on Days 1 and 8 of every 21 day cycle 
(Day 15 will be omitted because each cycle length will be 21 days instead of a 28 day cycle, 
and pembrolizumab is also given on Day 1 of every 21 day cycle). 
 
Pembrolizumab Immunotherapy run-in: rationale 
 
The rationale for combining anti PD-1 or PD-L1 antibodies with chemotherapy is outlined in 
section 4.3.4. The current protocol with the chemotherapy-run in was amended to include a 
cohort of patients who will be treated with a immunotherapy run-in after results from the 
GeparNuevo trial were presented. GeparNuevo showed an increase of pCR rates when anti- 
PD-L1 antibodies were administered before initiation of chemotherapy. The GeparNuevo is a 
randomized phase II study examining the addition of durvalumab, an antibody against PD-L1, 
to standard neoadjuvant chemotherapy with nab-paclitaxel followed by epirubicin and 
cyclophosphamide (NCT02685059) in patients with early TNCB. In the subgroup of patients 
starting with durvalumab prior to chemotherapy the pCR rate in the exploratory analysis was 
significantly higher compared to the subgroup receiving placebo prior to chemotherapy (61.0 
% vs. 41.4 %) 45. This was an unexpected finding as it was thought that the immunogenic 
effects of chemotherapy would stimulate an initial immune response, but as we recently 
published from a phase 1 trial nab-paclitaxel does not induce changes in the tumor 
microenvironment consistent with strong T-cell priming46. It is possible that by administering 
chemotherapy before or with the first cycle of immunotherapy, the immune response could be 
dampened. By including an initiation boost with pembrolizumab monotherapy prior to 
chemotherapy, activation of anti-tumor immune response may be increased due to the immune 
modulating effects of pembrolizumab. This study seeks to preliminarily assess whether a 
window for an initiation boost with pembrolizumab could improve response rates, biomarkers 
of response will be assessed in serial biospecimens for this iTNBC cohort as planned in the 
cTNBC cohort. 
 
 
4.3.6 Rationale for Identifying Mutated Tumor Antigens 

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Mutation-derived tumor antigens may play a key role in the anti-tumor immune responses 
achieved with immune checkpoint blockade. 
 
The precise mechanism of action leading to tumor regression in response to treatment with 
immune checkpoint blockade is not fully understood. There is evidence that these agents may 
unmask the endogenous adaptive response to specific tumor antigens47-50. However, little is 
known about the identity of the tumor antigens that function as the targets of T cells activated 
by immune checkpoint blockade. Such knowledge may be critical, however, to optimizing 
existing immunotherapies and to generating “personalized” vaccines that are highly tumor- 
specific. Emerging evidence suggests that mutation-derived tumor antigens (MTA) may 
predominate in this regard51,52. Rammensee et al.53 combined whole-exome and transcriptome 
sequencing analysis with mass spectrometry, followed by structural modeling to identify 
immunogenic neo-epitopes that were accessible to T-cell antigen receptors and which were 
therapeutically effective in animal models of cancer. Gubin et al. used genomics and 
bioinformatics approaches to identify MTAs as a major class of T-cell rejection antigens 
following immune checkpoint blockade therapy in tumor-bearing mice and subsequently 
showed that these mutant epitopes (i.e., “MTA-vaccines”) induce tumor rejection comparably 
to immune checkpoint blockade54. Synder et al.45 and Rizvi et al.55 applied a similar approach 
to identify MTAs in a cohort of patients with metastatic melanoma or lung cancer, respectively, 
treated with CTLA-4 blockade (ipilimumab) or PD-1 blockade (pembrolizumab). These 
investigators demonstrated that higher mutational load was associated with a higher likelihood 
of clinical benefit with CTLA-4 blockade and that a MTA signature could be used to predict 
patient benefit. Importantly, work from The Cancer Genome Atlas Project has shown that 
TNBC harbors significant mutational loads and recent studies have shown that PD-L1 
blockade can lead to clinical activity in patients with metastatic disease56,57. The proposed trial 
will assess, in a similar manner, whether mutational load (nonsynonymous mutation burden), 
and more specifically, patient specific neoantigen load, associates with clinical benefit. This 
approach will be used to identify the range and median number of nonsynonymous mutations 
per sample. Higher somatic nonsynonymous mutation burden (> median burden) will be 
associated with clinical efficacy of pembrolizumab using the Mann-Whitney test. 
 
Computational biology approaches can be used to identify patient specific mutated antigens 
that may serve as the basis for personalized MTA-based vaccines. 
 
The major histocompatibility complex (MHC) is responsible for the presentation of 
peptide antigens to the cellular arm of the adaptive immune system. The cell-mediated adaptive 
immune response to peptide antigens is determined by the physical interaction between the T 
cell receptor (TCR) which is used to scan the surface of the combined peptide-MHC molecule 
(pMHC)47. Recognizing the importance of this process, a great deal of effort has gone into 
characterizing the peptide-MHC binding event48. Rammensee et al. identified distinct patterns 
in the frequency with which amino acids are represented at specific positions in MHC-I 
ligands49,50,51. This discovery was evidence that the process of binding to the MHC-I molecule 
is a deterministic event predictable based on amino acid sequence information. Subsequently 
hundreds of thousands of independent peptide-MHC binding affinity measurements have been 
performed for both human and murine MHC-I molecules, and the results made publicly 

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available by repositories such as SYFPETHI and the Immune Epitope Database52,56,57. Based 
on this data investigators have created statistical models which are designed to distinguish 
between amino acid sequences which will (ligands) and will not (non-ligands) bind to a given 
MHC-I molecule58-60. The work of multiple authors has demonstrated that MTA may be 
identified through the sequential use of whole exome sequencing (WES) followed by peptide- 
MHC binding affinity prediction61-63. Subsequently the sensitivity of this approach has been 
formally assessed by Fritsch et al. and Rajasagi et al64,65. We have now applied NetMHCcons 
v1.1 to correctly define 46 of 54 known MTA as MHC-I ligands, for a combined sensitivity 
across all tested MHC-1 molecules of 0.852. This analysis demonstrates that NetMHCcons 
v1.1 can be correctly used to identify MHC-1 ligands arising from novel amino acid sequences 
and is the approach that will be used to determine patient specific neoantigens. 
 
4.3.7 Role of the Gut Microbiome as a Possible Modulator of Antitumor Immunity 
 
The gut microbiome has been shown to play an important role in modulating the 
immune response. In particular, commensal bacterial microbiota may influence the anti-tumor 
effects of checkpoint blockade with anti-PD-1/anti-PDL-1 and anti-CTLA-4 antibodies66. 
Sivan et al. studied the gut bacterial microbiome in a murine model of melanoma and found 
that there were differences in anti-tumor immunity among mice with distinct commensal 
microbiota67. An anti-tumor effect was associated with the presence of Bifidobacterium 
(identified by bacterial 16S ribosomal RNA gene sequencing). When a cocktail of 
Bifidobacterium species was administered orally to mice with tumors, these mice displayed 
improved anti-tumor control in comparison to those not treated with Bifidobacterium. 
Interestingly, the treated mice had improved tumor control similar to treatment with anti-PD- 
L1 therapy, and those mice that received the combination had nearly completely resolution of 
tumor growth. This effect was mediated by the modulation of dendritic cell function leading 
to improved effector function of CD8+ T cells and accumulation in the tumor 
microenvironment. Similarly, Vétizou et al. showed that in both mice and patients with 
melanoma, Bacteroides played a role in the efficacy of antibodies against CTLA-468. These 
results show that gut bacterial microbial composition may potentially influence anti-tumor 
immunity as well as response to immunotherapy with checkpoint blockade. 
 
4.3.8 Rationale for Endpoints 
 
4.3.8.1 Efficacy Endpoints 
 
The gold standard for evaluating tumor response is the response rate and best overall response 
rate (BORR) will be determined byRECIST 1.1 criteria (see Appendix, Section 10.3). Immune-
related RECIST criteria is also important for the evaluation of immune therapy activity in solid 
tumors and will also be used as a secondary endpoint (see Appendix, Section 10.4). 
Progression-free and overall survival will also be assessed in each cohort. 
 
4.3.8.2 Biomarker Research 
 
The most promising correlatives for monitoring effects of PD-1 blockade are changes in the 
tumor microenvironment, therefore sequential sampling of tumors is proposed (3 time points: 

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at baseline, after nab-paclitaxel alone in HR+ breast cancer and cTNBC or pembrolizumab 
alone in iTNBC (Cycle 1), and after nab-paclitaxel and pembrolizumab (Cycle 2). Associations 
of correlative biomarkers with BORR and other efficacy parameters will be explored within 
each cohort. Biomarkers in circulating leukocytes will be simultaneously evaluated to correlate 
with in situ changes and to assess for predictive association. The impact of nab-paclitaxel on 
tumoral PD-L1 expression will also be explored. 

 
24 
 
 
 
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4.3.8.3. Study Calendars 
 
4.3.8.3.1 Treatment Phase 
 
Baseline 
Cycle 1a 
(21 days) 
Cycle 2a 
(21 Days) 
Cycle ≥ 3a 
(21 days) 
Every 3 cycles a 
End of Treatment a,r 
Follow upq 
Days -30 to -1 
Da 
y 1 
Day 
8t 
Day 
15 
Day 1 
Day 8 
u 
Day 
15 
Day 
1 
Day 
8u 
Signed informed consent form 
X 
Medical, surgical, cancer, prior 
therapy histories 
X 
Full physical exam 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
Hematologyb, c 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistryb, d 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation panel (aPTT, 
PT/INR) 
X 
Hepatitis serologye 
X 
Serum or urine pregnancy testf 
X 
Xf 
Xf 
Xf 
Urinalysis 
X 
X 
X 
X 
X 
TSH, total T3, free T4 
X 
X 
X 
X 
EKGg 
X 
Adverse event and concomitant 
medication assessment 
X 
X 
X 
X 
X 
X 
X 
Xr, s 
Xs 
Vital signs, height, weightp 
X 
X 
X 
X 
X 
X 
X 
X 
BEFORE 2/2019 for TNBC 
and BEFORE+AFTER 2/2019 
for HR+BC: Nab-paclitaxelh 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
BEFORE 2/2019 for TNBC 
and BEFORE+AFTER 2/2019 
for HR+BC: Pembrolizumabj 
-- 
-- 
Xi 
Xi 
AFTER 2/2019 for TNBC 
only: Pembrolizumabj 
Xi 
-- 
Xi 
Xi 
AFTER 2/2019 FOR TNBC 
only: Nab-paclitaxelh 
-- 
-- 
Xi 
Xi 
Xi 
Xi 

 
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Tumor assessmentk 
X 
Every 9 weeks from date of allocation (=/- 7 days) for the first 12 months (minimum of 5 scans), then 
every 12 weeks thereafter until disease progression 
X 
X 
Newly obtained or archival 
tissue for correlative studiesl 
X 
Xm 
Xm 
Xm 
Blood for correlative studiesn 
X 
X 
X C3,4&C6 
only 
Stool for microbiome analysiso 
X 
Xo 
X 
X, C4&C6 
only 
Survival statusq 
X 
a Unless noted otherwise, all procedures can be performed within a +/- 4 day window if there is no safety concern in the opinion of the investigator. 
b. About 15 cc of blood will be collected at each visit while the patient is receiving study drug. Results for clinically significant laboratory values (ANC, hemoglobin, platelet count, creatinine, bilirubin, 
AST and ALT) must be reviewed by the investigator or qualified designee and found to be acceptable prior to each dose of trial treatment. 
c. Hematology consists of hematocrit, hemoglobin, platelet count, white blood cell count (total and differential), red blood cell count, absolute neutrophil count, absolute lymphocyte count. 
d. Chemistry consists of albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate or CO2, calcium, chloride, creatinine, glucose, lactate dehydrogenase 
(LDH), potassium, sodium, total bilirubin, total protein, blood urea nitrogen (BUN). LDH is only required on day 1 of each treatment cycle. 
e. Hepatitis testing will be required at screening: Hepatitis B (HBsAg, HBsAB and HBcAB) and Hepatitis C (HCV AB, if positive reflex to HBV-RNA [qualitative]). 
f. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required. Beyond screening, perform urine or serum pregnancy as clinically indicated. 
g. 5-min resting, single 12-lead EKG 
h. Nab-paclitaxel will be given for a minimum of 4 cycles, after which the investigator will determine whether to continue the drug based on safety profile and clinical judgment. If the nab-paclitaxel is 
stopped for any reason, pembrolizumab may be continued. 
i. Trial treatment may be administered up to 3 days before or after the scheduled Day 1/8 of each cycle due to administrative reasons. Dosing interruptions are permitted in the case of medical / surgical 
events or logistical reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Medical monitor or PI. The reason for interruption should be documented in the patient's study record. 
j. BEFORE 2/2019 for TNBC and BEFORE+AFTER 2/2019 for all HR+ BC: Pembrolizumab is not given during cycle 1. The first dose of pembrolizumab will be given on cycle 2, day 1, then on day 
1 of every cycle thereafter. 
AFTER 2/2019 for TNBC only: Nab-paclitaxel is not given during cycle 1. The first dose of nab-paclitaxel will be given on cycle 2, day 1, then on day 8, and d1/8 of every cycle thereafter. Pembrolizumab 
will be given for 24 months of uninterrupted treatment or 35 administrations of study medication, whichever is later. 
k. CT of the chest and abdomen/ pelvis with IV contrast will be used, and per investigator discretion, PET CT can be substituted. If IV contrast is contraindicated, a non-contrast CT chest/abdomen/pelvis 
is acceptable. Bone scans may be used if clinically indicated. MRI brain or CT brain with IV contrast is required at baseline and as clinically indicated thereafter. The same imaging methods should be 
used throughout the trial. Baseline imaging can be obtained within 42 days of day 1. A 7-day window will be allowed around post-baseline imaging scans (i.e. should be obtained every 9 weeks from the 
date of allocation (+/- 7 days)). Imaging studies will be obtained every 12 weeks (+/- 7 days) after 12 months on study treatment (a minimum of 5 scans). Tumor assessment dates are fixed and should not 
be adjusted for dose interruptions, delays, or modifications. 
l. Refer to section 6.6.1. Newly obtained tissue biopsies are mandatory at baseline. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. 
Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the PI. Whenever possible, the 
baseline biopsy should be taken from a lesion amenable to serial biopsies and should not be the sole measurable lesion per RECIST 1.1 criteria. A minimum of 2 cores are required at each time point. Soft 
tissue and bone lesions are acceptable. Subsequent biopsies should be taken from the same lesion, if feasible.. At time of progression, however, sample collection is optional and patients will be asked if 
they would be willing to undergo a tumor biopsy for correlative immune studies (if clinically feasible). 
m. Fresh tissue biopsies to be collected between days 15-21 of cycles 1 and 2. Biopsies may be done prior to treatment on C2D1 and C3D1, if needed. 
n. About 60 cc of blood will be collected at baseline, C2D1, C3D1, C4D1 and C6D1. 
o. Patients will be given a stool collection kit with specific instructions at baseline. In the event a stool specimen cannot be obtained between days -30 and treatment start, a pre-dose specimen is acceptable 
on cycle 1, day 1. Refer to section 6.6.5. +/- 1 week window for stool collection 
p. Vital signs are defined as blood pressure, pulse, oxygen saturation, respiration rate, and temperature. Height is required at baseline only. Weight is required prior to treatment on day 1 of every cycle. 

 
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q. Following study completion, patients will enter routine follow-up with their primary oncologist, who may be contacted to provide follow-up information on the patient’s clinical and disease status until 
death or withdrawal of consent, whichever occurs first. 
r. The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first. 
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. 
s. After the end of treatment, each subject will be followed for 30 days for adverse event monitoring (serious adverse events will be collected for 90 days after the end of treatment as described in Section 
6.11.1). SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should also be followed and recorded. 
t. AFTER 1/2019 amendment: the cycle 1 day 8 visit will be eliminated (as no treatment), therefore no blood draw, vitals and concomitant medications will be assessed. AE assessment will be performed 
by telephone by research personnel. 
u If day 8 treatment is planned to be held per the investigator, the clinic visit, lab assessments and exam/vitals are optional if considered safe and, to diminish burden for the patient (for instance for patients 
who come to the clinic from out of state). AEs can be collected via phone call by research personnel. 
 
 
 
5 METHODOLOGY 
 
5.1 Entry Criteria 
 
5.1.1 Diagnosis/Condition for Entry into the Trial 
 
Subjects with histologically confirmed metastatic breast cancer that is either TNBC or HR-positive (see inclusion and exclusion 
criteria below). 
 
5.1.2 Subject Inclusion Criteria 
 
In order to be eligible for participation in this trial, the subject must: 
 
1. Have histologically confirmed adenocarcinoma of the breast that is either TNBC or HR positive/HER-2 negative. TNBC is 
defined as: ER/PR <1% and HER-2 negative disease (IHC 0-1+ or 2+ with HER2/17 ratio on FISH ≤1.8) according to 
ASCO/CAP guidelines11,69. HR positive is defined as: ER/PR >= 1% and HER-2 negative as per ASCO/CAP guidelines. Subjects 
with tumors expressing ER/PR1-4% are eligible if the investigator is not planning endocrine therapy. 
 
2. Have received 0-2 lines of cytotoxic chemotherapy for metastatic breast cancer. Prior endocrine therapy and/or targeted therapy 
is allowed. 
 
3. Be willing and able to provide written informed consent/assent for the trial. 

 
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4. Be ≥ 18 years of age on day of signing informed consent. 
5. Have measurable disease based on RECIST 1.1. 
 
6. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a 
specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples 
cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from 
the PI or designee. 
 
7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
8. Be willing to undergo tissue biopsies as mandatory as per protocol for patients with biopsy accessible disease. 
 
9. Must have </= Grade 1 pre-existing peripheral neuropathy (as per CTCAE). 
 
10. Demonstrate adequate organ function as defined in Table 1all screening labs should be performed within 14 days of treatment 
initiation. 
 
Table 1 Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 /mcL (transfusion independent, defined as not receiving 
platelet transfusions within 7 days prior to laboratory sample) 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 

 
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Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Alkaline phosphatase 
≤ 2.5 X ULN, unless bone metastasis is present (<5 X ULN) in 
the absence of liver metastasis. 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
 
11. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the 
first dose of study medication. This applies even if the subject practices true abstinence* from heterosexual contact. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
 
12. A female subject of childbearing potential is a sexually mature women who (1) has not undergone hysterectomy [the surgical 
removal of the uterus] or bilateral oophorectomy [the surgical removal of both ovaries] or (2) has not been naturally 
postmenopausal for at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]. 
The female subject must: either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly 
basis), or agree to use, and be able to comply with, effective contraception without interruption (2 methods of birth control), 28 
days prior to starting IP therapy (including dose interruptions), and while on study medication or for a longer period if required 
by local regulations following the last dose of IP. 
 
13. Male subjects must practice true abstinence* or agree to use a condom during sexual contact with a pregnant female or female 
of childbearing potential starting with the first dose of study therapy, during dose interruptions, and for up to 6 months following 
last dose of study therapy, even if he has undergone a successful vasectomy. 

 
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* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]. 
 
5.1.3 Subject Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject: 
 
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study 
therapy or used an investigational device within 4 weeks of the first dose of treatment. 
 
2. 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. 
 
3. Has a known history of active TB   (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 
 
6. Taxane therapy within the past 3 months (90 days) prior to study Day 1. 
 
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who 
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. 
 
- 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. 
 
- 
Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications 
from the intervention prior to starting therapy. 

 
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8. Has a known additional malignancy that progressed or required treatment within the last five years. Exceptions include basal 
cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
 
9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated 
brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or 
enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability. 
 
10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
 
11. Has known history of or active (non-infectious) pneumonitis/interstitial lung disease requiring treatment with steroids Has an active 
infection requiring systemic therapy. 
 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, 
interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, 
in the opinion of the treating investigator. 
 
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 
 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with 
the pre-screening or screening visit through 120 days after the last dose of trial treatment. 
 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies, testing not mandatory). 
 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). 

 
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18. Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of study therapy. 
 
Note: Administration of killed vaccines is allowed.  
 
5.2 Trial Treatments 
 
The treatment to be used in this trial is outlined below in Table 2. 
Table 2 Trial Treatment 
Drug 
Dose/Potency 
Dose frequency 
Route of 
Administration 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Experimental 
Nab-paclitaxel 
100 mg/m2 
Days 1 and 8 of 
21-day cycle 
IV infusion 
Standard 
of 
care therapy 
 
Pembrolizumab will be administered first, followed by nab-paclitaxel. 
 
BEFORE 2/2019 amendment for TNBC, and BEFORE+AFTER 2/2019 for all HR+BC: In the first cycle pembrolizumab is omitted in 
all patients in order to conduct tissue analyses after treatment with nab-paclitaxel alone. 
 
AFTER 2/2019 amendment (ONLY FOR TNBC): In the first cycle nab-paclitaxel is omitted in all patients – see rationale in section 
4.3.5. 
 
Nab-paclitaxel will be given for a minimum of 4 cycles and afterwards, the investigator will determine whether to continue the drug 
based on safety profile and clinical judgment. If the nab-paclitaxel is stopped (regardless of reason), pembrolizumab may be continued. 

 
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Pembrolizumab will be given for a maximum of 24 months of uninterrupted treatment 
or 35 administrations of study medication, whichever is later. 
 
Risks associated with Pemrolizumab 
 
Very common side effects seen in >20% of patients treated with pembrolizumab/KEYTRUDA 
include the following: 
 
• Itching of the skin 
• Feeling tired, lack of energy 
• Feeling not hungry 
• Short of breath 
• Cough 
 
Very common side effects seen in ≥10% to 20% of patients treated with pembrolizumab/ 
KEYTRUDA include the following: 
 
• Joint pain 
• Fever 
• Swelling of legs &/or feet 
• Weakness 
• Back pain 
• Rash 
• Low level of salt in the blood that may cause you to feel tired, confused, headache, 
muscle cramps or upset stomach 
• Stomach pain 
• Sick to your stomach 
• Loose or watery stools 
• Infrequent or hard stools 
• Vomiting 
• Decrease in blood cells that carry oxygen which may cause you to feel tired or short 
of breath 
• Loss of skin color 
 
Common serious side effects seen in 1% to 4% of patients treated with 
pembrolizumab/KEYTRUDA include the following: 

 
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• Short of breath 
• Feeling tired, lack of energy 
• Low level of salt in the blood that may cause you to feel tired, confused, headache, 
muscle cramps or upset stomach 
• Stomach pain 
• Decrease in blood cells that carry oxygen that may cause you to feel tired or short of 
breath 
• Inflammation of the lungs so you may feel short of breath and cough. Rarely this 
might lead to death 
• Joint pain 
• Weakness 
• Back pain 
• Inflammation of the bowels/gut that can cause stomach pain with loose or watery 
stools, or stools that are black, tarry, sticky or have blood or mucus 
• Feeling not hungry 
• Loose or watery stools 
• Sick to your stomach 
• Fever 
• Vomiting 
 
Immune-mediated serious side effects seen in 1.0% or less of patients treated with 
pembrolizumab/KEYTRUDA include the following: 
 
• Inflammation of the skin so you may have widespread peeling of the skin, itching, 
skin redness 
• Inflammation of the bowels/gut so you may feel stomach pain with loose or watery 
stools, or stools that are black, tarry, sticky or have blood or mucus 
• Inflammation of the lungs so you may feel short of breath and cough. Rarely this 
might lead to death 
• Inflammation of the liver that may cause a poor appetite, feeling tired, mild fever, 
muscle or joint aches, upset stomach and vomiting, bleeding and bruising more easily 
than normal, stomach pain, yellow eyes and skin, and dark urine 
• Inflammation of the pituitary gland (a gland in the head), which may cause 
headaches, upset stomach, changes in behavior, double vision, few to no menstrual 
cycles, weakness, vomiting and dizziness or fainting. This inflammation of the 
pituitary gland may cause the adrenal glands (on top of the kidneys) to not make 
enough hormone causing tiredness, weight loss, muscle weakness, feeling faint, joint, 
muscle and abdominal aches, nausea, vomiting, diarrhea, fever, salt craving, rapid 
heart rate, and sometimes darkening of the skin like a suntan. 
• Too much thyroid hormone so you may feel anxious, angry, can’t sleep, weak, 
tremble, increased sweating, weight loss, hair loss, tired, have diarrhea 

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• Too little thyroid hormone so you may feel tired, gain weight, feel cold, voice gets deeper, hair loss, have infrequent or hard 
bowel movements 
• Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, swelling and low back pain 
• Inflammation of the muscles so you may feel weak or pain in the muscles 
• Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you may have severe upper abdominal pain 
that may move to the back, sick to your stomach, and vomiting that gets worse when you eat 
• Inflammation of the eye so you may have redness of the eye, blurred vision, sensitive to light, have eye pain, see floaters or have 
headaches 
• Dizziness or fainting (low blood pressure), flushing, rash, fever, shortness of breath or upset stomach at the time of receiving your 
infusion (IV) or just after, or pain at the site of infusion 
• Inflammation of the pancreas (diabetes) so you may have too much sugar in your blood, may need to urinate more often, lose 
weight, feel thirsty, and may need regular insulin shots 
• Inflammation of the nerves that may cause pain, weakness or tingling in the hands and feet, and may spread to the legs, arms and 
upper body leading to severe muscle weakness 
 
5.2.2 Dose Selection/Modification 
 
5.2.2.1 Dose Selection 
 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background and Rationale. 
Details on preparation and administration of pembrolizumab and nab-paclitaxel are provided in the Pharmacy Manual. 
5.2.2.2 Dose Modification 
 
Pembrolizumab 
 
AEs associated with pembrolizumab exposure, including coadministration with additional compounds, may represent an immunologic aetiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last dose of pembrolizumab/combination treatment and may 
affect more than one body system simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based on 

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existing clinical study data, most irAEs were reversible and could be managed with interruptions of pembrolizumab/combination treatment, 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. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab/combination treatment are provided in Table 6. 
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure, including coadministration with additional compounds, 
may represent an immunologic etiology. These adverse events may occur shortly after the first dose or several months after the last dose 
of pembrolizumab/combination treatment and may affect more than one body system simultaneously. Based on existing clinical study data, 
most irrAEs were reversible and could be managed with interruptions of  Pembrolizumab must be withheld for drug-related toxicities 
and severe or life-threatening AEs as per Table 3 below. See Section 5.6.1 and Events of Clinical Interest Guidance Document for 
supportive care guidelines, including use of corticosteroids. 
 
 
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to a single component is likely to be 
difficult.  Therefore, while the investigator may attribute a toxicity event [to the combination,  to [xxxxx alone] or to pembrolizumab alone], for 
adverse events listed in [Table 6], both interventions must be held according to the criteria in [Table 6 Dose Modification and Toxicity 
Management Guidelines for Immune-Related Adverse Events Associated with Pembrolizumab]. 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered immune-related, both interventions should be held according 
to recommended dose modifications. 
Restarting Study Interventions: 
Participants may not have any dose modifications (no change in dose or schedule) of pembrolizumab in this study, as described in [Table 6]. 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant must be discontinued from all study interventions. 

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• If the toxicities do resolve and conditions are aligned with what is defined in [Table 6], the combination of [XXXX and pembrolizumab] may 
be restarted at the discretion of the investigator.[In these cases where the toxicity is attributed to [the combination or to XXXX alone], re-
initiation of pembrolizumab as a monotherapy may be considered at the principal investigator’s discretion .] 
 
 
 
Table 3: Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
 

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General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
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 
• Add prophylactic antibiotics for 
opportunistic infections 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
 
Recurrent Grade 2, 
Grade 3 or 4 
 
Permanently 
discontinue 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 

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AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 a 
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 b or 4 c 
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 β-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 
discontinued 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with nonselective beta- 
blockers (eg, propranolol) or 
thionamides as appropriate 
• 
Monitor for signs and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinued 
Hypothyroidism 
Grade 2-4 
Continue 
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of 
thyroid disorders. 

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Nephritis : grading 
according to 
increase creatinine 
or acute kidney 
injury 
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 
Neurological 
Toxicities 
Grade 2 
Withhold 
• •  Based on severity of AE 
administer corticosteroids 
• 
•  Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
• •  Based on severity of AE 
administer corticosteroids 
• 
•  Ensure adequate evaluation to confirm 
etiology or exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All other immune-
related AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 
Withhold or 
discontinue based on 
the type of event. 
Events that require 
discontinuation 
include and not 
limited to: Gullain-
Barre Syndrome, 
encephalitis 

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Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 

 
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Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Medical Monitor or PI. The reason 
for interruption should be documented in the patient's study record. 
 
 
Nab-paclitaxel 
As of Oct 6, 2014, approximately 11,867 subjects have been treated with nab-paclitaxel in 
clinical studies, with 3,905 in the Celgene development program worldwide and an estimated 
7,962 in non-Celgene-sponsored studies globally. It is estimated that cumulative exposure to 
nab-paclitaxel during marketing experience is approximately 296,427 patients. Therefore, 
overall estimated cumulative exposure to nab-paclitaxel during clinical trials and commercial 
experience is approximately 308,294 patients. Clinically significant adverse drug reactions 
identified during clinical trials or post-marketing surveillance, considered by Celgene to be at 
least possibly associated with nab-paclitaxel, are provided below. 
 
Very common (≥ 10%): 
• anemia, red blood cell count decreased 
• febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombocytopenia 
• constipation 
• diarrhea 
• nausea 
• vomiting 
• abdominal pain, abdominal pain upper 
• stomatitis, mucosal inflammation 
• SMQ peripheral neuropathy 

 
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• dizziness 
• headache 
• asthenia, fatigue 
• arthralgia, back pain, bone pain, chest pain, musculoskeletal pain, myalgia, pain in 
extremity 
• edema, edema peripheral 
• pyrexia 
• chills 
• decreased appetite 
• dysgeusia 
• weight decreased 
• insomnia 
• depression 
• cough 
• dyspnea 
• alopecia 
• rash, generalized rash, maculopapular rash 
• pruritus 
• nail disorder, nail discoloration, onycholysis 
• alanine aminotransferase increased, aspartate aminotransferase increased 
• dehydration 
• epistaxis 
• hypokalemia 
 
Common (≥ 1% to < 10% ): 
• bone marrow depression (failure), pancytopenia 
• candidiasis, cholangiitis,folliculitis, lower respiratory infection, nail infection, oral 
candidiasis, pneumonia, upper respiratory tract infection, urinary tract infection 
• neutropenic sepsis, sepsis 
• bronchitis 
• pneumonitis 
• colitis, intestinal obstruction, small intestinal obstruction 
• dysphagia 
• dyspepsia 
• hyperbilirubinaemia, blood alkaline phosphatase increased, blood bilirubin increased, blood 
creatinine increased 
• acute renal failure 
• hematuria 
• ataxia 
• muscle weakness 
• anxiety 
• nasal congestion 
• oropharyngeal pain 

 
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• dry mouth, dry throat, nasal dryness 
• hemoptysis 
• pulmonary embolism, deep vein thrombosis 
• pleural effusion 
• flushing, erythema 
• dry skin 
• palmar-plantar erythrodysaethesia syndrome 
• hypertension 
• hypotension 
• tachycardia, cardiac failure congestive, palpitations 
• increased lacrimation 
• visual disturbance, visual Impairment vision blurred 
• infusion site extravasation, infusion site inflammation, infusion site rash, infusion site 
reaction, injection site reactions, injection site infection, extravasation 
• lymphedema 
 
Uncommon (0.1% < 1.0%): 
• left ventricular dysfunction 
• arrhythmia, sinus bradycardia, atrioventricular block, supraventricular tachycardia 
• cardiac arrest 
• drug hypersensitivity, hypersensitivity, dermatitis allergic 
• thrombotic thrombocytopenic purpura, hemolytic uremic syndrome 
• cystoid macular edema, maculopathy 
• conjunctivitis 
• keratitis 
• fluid retention 
• malaise 
• lethargy 
• skin exfoliation 
• urticaria 
• erythema multiforme 
• facial palsy, VIIth nerve paralysis 
 
Elderly 
In subjects ≥ 65 years old with metastatic breast cancer who received nab-paclitaxel 
monotherapy, a higher incidence of epistaxis, diarrhea, dehydration, fatigue and peripheral 
edema has been reported. 
 
Table 4: Dose Modification for Drug-Related Adverse Events with Nab-paclitaxel 
 
Hematologic Toxicity 
 
The absolute neutrophil count (ANC) must be ≥1500/μL, and platelet count must be 

 
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≥100,000/μL on Day 1 of each cycle. Nab-paclitaxel should not be administered on Day 8 of 
the cycle until counts recover to ANC ≥500 cells/μL and platelets ≥50,000 cells/μL. If nab- 
paclitaxel cannot be administered on Day 8 of the cycle, the next dose of nab-paclitaxel should 
be administered on Day 1 of the following cycle when ANC and platelets counts have 
recovered to the acceptable levels. Nab-paclitaxel dose reductions for hematologic toxicity are 
as per below in the table. 
 
Hematologic toxicity 
Occurrence 
Nab-paclitaxel weekly 
dose (mg/m2) 
• Neutropenic fever (ANC nadir 
<500/μL with fever >38 C), or 
First 
75 
• Delay of next cycle by greater 
than 7 days for ANC nadir 
<1500/μL (grade 1 to 4 
neutropenia), or 
Second 
50 
• ANC nadir <500/μL (grade 4 
neutropenia) for greater than 7 
days 
Third 
Discontinue 
treatment 
Platelet count nadir <50,000 μL 
First 
75 
Second 
Discontinue 
treatment 
 
Neurologic Toxicity 
 
Nab-paclitaxel will be withheld for Grade 3 or 4 peripheral neuropathy and may be 
resumed at reduced doses when peripheral neuropathy recovers to Grade 1 or resolves. 
 
Neurologic toxicity 
Occurrence 
Nab-paclitaxel 
weekly dose modification 
Grade 3 or 4 peripheral 
neuropathy 
First 
Withhold treatment until improves to 
Grade =< 1, then resume at 75 mg/m2 
Second 
Withhold treatment until improves to 
Grade =< 1, then resume at 50 mg/m2 

 
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Third 
Discontinue treatment 
 
 
Hepatic Toxicity 
 
Nab-paclitaxel should be withheld for Grade 3 or 4 hepatic toxicity. 
 
Hepatic toxicity 
Nab-paclitaxel weekly dose modification 
AST level <10x ULN 
or 
Bilirubin level >ULN to 1.25x ULN 
No dose modification, give 100 mg/m2 
AST level <10x ULN 
and 
Bilirubin level 1.26x to 2x ULN 
Interrupt treatment until AST level <10x 
ULN and bilirubin level =< 1.25x 
ULN, then reduce to 75 mg/m2. If 
toxicity does not resolve to above 
criteria by 3 weeks, discontinue 
treatment. 
AST level <10x ULN 
or 
Bilirubin level 2.01x to 5x ULN 
Interrupt treatment until AST level <10x 
ULN and bilirubin level =< 1.25x 
ULN, then reduce to 50 mg/m2. If 
toxicity does not resolve to above 
criteria by 3 weeks, discontinue 
treatment. 
AST level >10x ULN 
or 
Bilirubin level >5x ULN 
Discontinue treatment 
 
5.2.3 Timing of Dose Administration 
 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed in the Study Calendar (Section 4.3.8.3). Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. In the first cycle pembrolizumab is omitted in all patients in order to 
conduct tissue analyses after treatment with nab-paclitaxel alone. After 2/2019 amendment, all 

 
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TNBC patients will receive an immunotherapy run-in first, in the first cycle nab-paclitaxel is 
omitted and oly pembolizumab is fiven. 
 
All trial treatments will be administered on an outpatient basis. 
 
First, pembrolizumab 200 mg will be administered as a 30 minute IV infusion D1 every 3 
weeks. Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
Second, nab-paclitaxel 100 mg/m2 will be injected into a vein [intravenous (I.V.) infusion] 
over 30 minutes D1,8 every 3 weeks. Sites should make every effort to target infusion timing 
to be as close to 30 minutes as possible. However, given the variability of infusion pumps from 
site to site, a window of -5 minutes and +10 minutes is permitted. It should not be infused at a 
faster rate (completing infusion in less than 25 minutes, see overdose in section 6.12.1). The 
use of an in-line filter is not recommended. Following administration, the intravenous line 
should be flushed with sodium chloride 9 mg/ml (0.9%) solution for injection to ensure 
complete administration of the complete dose, according to local practice. 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
and nab-paclitaxel infusion fluid and administration of infusion solution. 
 
5.2.4 Trial Blinding/Masking 
 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
 
5.3 Randomization or Treatment Allocation 
 
N/A 
 
5.4 Stratification 
 
Please see cohorts as described above in Section 2.0. 
 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
Dr. Adams and the medical monitor. If necessary, Dr. Adams will discuss the situation with 
Merck, and/or Celgene Clinical Teams. The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the subject's primary physician. 

 
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5.5.1 Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and Events of Clinical Interest (ECIs). 
 
5.5.2 Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 
• Antineoplastic systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy 
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion. 
• Live vaccines or live-attenuated vaccines within 30 days prior to the first dose of trial 
treatment and while participating in the trial. Administration of killed vaccines is 
allowed. 
 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with the Medical Monitor 
or PI. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Subjects 
may receive other medications that the investigator deems to be medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 

 
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There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.6 Rescue Medications & Supportive Care 
 
5.6.1 Supportive Care Guidelines 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the ECI 
guidance document. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid tapering 
may be necessary as symptoms may worsen when the steroid dose is decreased. For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related 
to pembrolizumab. 
 
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
 
• Pneumonitis: 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
 
• Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). 

 
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o All subjects who experience 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. For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
 
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 
• Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 

 
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o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism 
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
 
Table 5 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 5: Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 

 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
pembrolizumab (MK-3475) with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
 
5.7 Diet/Activity/Other Considerations 
 
5.7.1 Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
5.7.2 Contraception 
 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. Non-pregnant, non- 

 
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breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study. The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to 120 days after the 
last dose of study therapy. 
 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 6.12.2-Reporting of Pregnancy 
and Lactation to the medical monitor, Merck, and Celgene. If there is any question that a 
subject will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
 
5.7.3 Use in Pregnancy 
 
Pembrolizumab 
 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab or within 
at least 28 days of the subject’s last dose of the drug, the subject will immediately be removed 
from the study. The site will contact the subject at least monthly and document the subject’s 
status until the pregnancy has been completed or terminated. The outcome of the pregnancy 
will be reported to Dr. Adams, the NYU research coordinator, NYU regulatory specialist, 
NYUPCCsafetyreports@nyumc.org and Merck without delay and within 24 hours to Dr. 
Adams, the NYU research coordinator, NYU regulatory specialist, the medical monitor, Dr. 
Zujun Li,  NYUPCCsafetyreports@nyumc.org and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life- threatening complication to the mother or newborn). 
 
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the medical monitor and 
Merck. If a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to Dr. Adams, the NYU research 

 
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coordinator, NYU regulatory specialist, 
the 
medical 
monitor, 
Dr. 
Zujun 
Li,  
NYUPCCsafetyreports@nyumc.org and to Merck and followed as described above and in 
Section 6.12.2. 
 
Nab-paclitaxel 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
or disease state) of a female subject occurring while the subject is on IP, or within at least 28 
days of the subject’s last dose of IP), are considered immediately reportable events. IP is to be 
discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to Dr. Adams, the NYU research coordinator, NYU regulatory specialist, 
NYUPCCsafetyreports@nyumc.org and Celgene Drug Safety immediately by facsimile, or 
other appropriate method, using the Pregnancy Initial Report Form, or approved equivalent 
form. The female subject may be referred to an obstetrician-gynecologist (not necessarily one 
with reproductive toxicity experience) or another appropriate healthcare professional for 
further evaluation. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Dr. Adams, the NYU research coordinator, NYU regulatory specialist, the medical 
monitor, Dr. Zujun Li, NYUPCCsafetyreports@nyumc.org and Celgene Drug Safety 
immediately about the outcome of the pregnancy (either normal or abnormal outcome) using 
the Pregnancy Follow-up Report Form, or approved equivalent form. 
 
IF THE OUTCOME OF THE PREGNANCY WAS ABNORMAL (E.G., SPONTANEOUS 
OR THERAPEUTIC ABORTION), THE INVESTIGATOR SHOULD REPORT THE 
ABNORMAL OUTCOME AS AN AE. IF THE ABNORMAL OUTCOME MEETS ANY 
OF THE SERIOUS CRITERIA, IT MUST BE REPORTED AS AN SAE TO CELGENE 
DRUG SAFETY IMMEDIATELY BY FACSIMILE, OR OTHERAPPROPRIATE 
METHOD, WITHIN 24 HOURS OF THE INVESTIGATOR’S KNOWLEDGE OF THE 
EVENT USING THE SAE REPORT FORM, OR APPROVED EQUIVALENT FORM. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to the medical monitor and 
Celgene Drug Safety immediately by facsimile, or other appropriate method, within 24 hours 
of the Investigator’s knowledge of the event using the SAE Report Form, or approved 
equivalent form. 
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. Male patients treated with nab-paclitaxel 
are advised not to father a child during and up to 6 months after treatment. 

 
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5.7.4 Use in Nursing Women 
 
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. 
 
5.8 Subject Withdrawal/Discontinuation Criteria 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons. Specific details 
regarding discontinuation or withdrawal are provided in Section 6.8.1 – Other Procedures. 
 
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. 
 
• Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, and 
continuation is in the best interest for the patient, per investigator. 
 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
 
Note: 24 months of study medication is calculated from the date of first dose. 
 
• Administrative reasons 

 
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After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events will be collected for 90 days after the end of treatment as 
described in Section 6.11.1). Subjects who discontinue for reasons other than progressive 
disease will have post-treatment follow-up for disease status until disease progression, 
initiating a non-study cancer treatment, withdrawing consent or becoming lost to follow-up. 
After documented disease progression each subject will be followed by telephone for overall 
survival until death, withdrawal of consent, or the end of the study, whichever occurs first. 
 
5.9 Subject Replacement Strategy 
 
N/A 
 
5.10 
Clinical Criteria for Early Trial Termination 
 
Early trial termination will be the result of the criteria specified below: 
 
1. Quality or quantity of data recording is inaccurate or incomplete 
 
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 Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
6.0 TRIAL PROCEDURES 
 
6.1 Trial Procedures 
 
The Study Calendar in section 4.3.8.3 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 PI, Celgene and/or 
Merck 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. 

 
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6.2 Administrative Procedures 
 
6.2.1 Methods of Subject Identification and Recruitment 
 
The patients who are eligible for this research study come directly from the study 
investigators’ clinical patient population. Thus, the investigators are very familiar with their 
patients’ disease status and potential eligibility given the protocol’s inclusion and exclusion 
criteria. The investigator will approach eligible potential subjects and explain the study in a 
private room, including the reasons why subjects will be eligible, risks, benefits, and the 
regimes to be evaluated. Consent will be obtained in a private room by the PI, Co-I, or 
research coordinator/research nurse at the time of the subject’s visit prior to any study 
assessments/procedures. The subjects will be given a chance to ask questions to the person 
consenting him/her and will be able to take the consent home to discuss it with family/friends 
prior to signing. If the subject agrees s/he will sign the consent form either at the first contact 
(if the investigator/delegate is convinced that the subject understands) or at the time of a 
return visit after having had time to study the consent in more depth. Study procedures will 
not begin until after the consent form has been properly obtained. The subject is entitled to 
decide not to participate in the trial, without affecting their right to other medical care, and 
may discontinue participation in the trial at any time without penalty or loss of benefits to 
which they are entitled. 
 
6.2.2 Process of Informed Consent 
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations. 
 
Consent will be obtained only by an IRB approved participating investigator who has completed 
requisite training for human subject research and has been instructed by the Principal Investigator 
about the research study and consent process. Investigators will review the informed consent form 
with patients and address any questions or concerns prior to obtaining written informed consent 
for participation and HIPAA authorization. 
 
Patients who are evaluated and/or treated by physicians in the oncology program will be given a 
consent form (attached) describing participation in the study. Patients will be given adequate time 
to read the consent form. After patients have been evaluated by their physician, they will be 
given time to ask questions about the study in private exam rooms. Questions will be answered 
by a participating physician, nurse practitioner, or research nurse all of whom have completed 
requisite training for human subject research. Investigators will review the informed consent 

 
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form with patients and address any questions or concerns prior to obtaining written informed 
consent for participation. Investigators will stress that participation in the study is completely 
voluntary and will not affect the care patients receive or result in any loss of benefits to which 
patients are otherwise entitled. 
 
For non-English speaking patients, institutional translation services will be utilized. For these 
patients the consent letter and all other information will be administered orally and a witness, not 
related to the research project, will be present while the oral presentation is given. A short form 
will be utilized for the subject to sign in his/her name and the translator and/or witness must sign 
the short form. The translator will also sign the main consent form. 
 
For patients who cannot read a witness, not related to the research study will be present. The 
consent will be read to the patient. The patient will also be allowed to ask any questions s/he may 
have. The investigator will ask the patient questions to ensure s/he understands the study. If the 
investigator determines the subject understands the study, the patient will mark an X where 
his/her name would go and the witness will sign the consent form. 
 
 
Any subsequent revised written informed consent form and any written information provided 
to the subject will receive the IRB’s approval in advance of use. The subject will 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. 
 
 
6.2.3 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. 
 
6.2.4 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. Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
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6.2.5 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. 
 
6.2.6 Medical History 
 
A medical history will be obtained by the investigator or qualified designee. 
Medical history will include all active conditions, and any condition diagnosed 
within the prior 10 years that are considered to be clinically significant by the 
Investigator. Details regarding the disease for which the subject has enrolled in 
this study will be recorded separately and not listed as medical history. 
 
6.3 Prior and Concomitant Medications Review 
 
6.3.1 Prior Medications 
 
The investigator or qualified designee will review prior medication use, including 
any protocol-specified washout requirement, and record prior medication taken 
by the subject within 28 days before starting the trial. Treatment for the disease 
for which the subject has enrolled in this study will be recorded separately and 
not listed as a prior medication. 
 
6.3.2 Concomitant Medications 
 
The investigator or qualified designee will record medication, if any, taken by the 
subject during the trial. All medications related to reportable SAEs and ECIs 
should be recorded as defined in Section 6.13. 
 
6.4 Disease Details and Treatments 
 
6.4.1 Disease Details 
 
The investigator or qualified designee will obtain prior and current details 
regarding disease status. 
 
6.4.2 Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments 
including systemic treatments, radiation and surgeries. 
 
6.4.3 Subsequent Anti-Cancer Therapy Status 
 
The investigator or qualified designee will review all new anti-neoplastic therapy 
initiated after the last dose of trial treatment. If a subject initiates a new anti- 

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cancer therapy within 30 days after the last dose of trial treatment, the 30 day 
Safety Follow-up visit must occur before the first dose of the new therapy. Once 
new anti-cancer therapy has been initiated the subject will move into survival 
follow-up. 
 
6.4.4 Registration Procedures 
 
Each patient must sign and date an informed consent form before undergoing any 
study specific procedure unless a procedure is being performed as part of the 
patient’s standard of care. Once a patient has signed consent, the site must notify 
the designated NYU Research Coordinator and forward a copy of the signed 
consent to NYU Cancer Clinical Trials Office within 24 hours. 
 
Enrollment in the study requires that all inclusion and exclusion criteria have been 
met. Enrollment occurs upon confirmation of registration from the NYU CI 
Clinical Trials Office. The following materials must be submitted to the Research 
Coordinator for registration: 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated informed consent checklist 
3. Complete signed and dated eligibility checklist 
4. All supporting documentation verifying each criterion has been 
met 
 
Registration will occur within 24 hours of research coordinators receipt of all of 
the above documents. Once eligibility is verified, a unique patient study number 
will be issued. This number is unique to the participant and must be written on 
all data and correspondence for the participant. The NYU Clinical Trials Office 
research coordinator will return a signed eligibility confirmation worksheet with 
the subjects unique study number to the site study team upon registration. The 
patient will not be identified by name. This is the point, at which, the patient is 
considered on study. Subjects must not start any protocol procedures prior to 
registration. 
 
 
 
6.4.5 Benefits to Subjects 
 
It is possible that some study subjects who receive the study therapy may 
experience an improvement in their cancer. However, it is possible that subjects 
may not get any benefit from being in this research study. Other patients with 
breast cancer may benefit in the future from what we learn in this study. 

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6.4.6 Costs to Subjects and Payment for Participation 
 
Subjects will not be paid for their participation in this research study. However, 
up to $50 dollars can be reimbursed for expenses related for each of the study 
treatment visits (parking, transportation, meals) 
 
6.5 Clinical Procedures/Assessments 
 
6.5.1 Adverse Event (AE) Monitoring 
 
The investigator or qualified designee will assess each subject to evaluate for 
potential new or worsening AEs as specified in the Trial Flow Chart and more 
frequently if clinically indicated. Adverse experiences will be graded and 
recorded throughout the study and during the follow-up period according to NCI 
CTCAE Version 4.0 (see Section 10.2). Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to 
trial treatment. 
 
For subjects receiving treatment with pembrolizumab all AEs of unknown 
etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially 
immunologic etiology (termed immune-related adverse events, or irAEs); see the 
separate ECI guidance document in Appendix 4 regarding the identification, 
evaluation and management of potential irAEs. 
 
Please refer to section 6.12 for detailed information regarding the assessment and 
recording of AEs. 
 
6.5.2 Physical Exam 
 
The investigator or qualified designee will perform a complete physical exam 
during the screening period. Clinically significant abnormal findings should be 
recorded as medical history. A full physical exam should be performed during 
screening. 
 
6.5.3 
 
Not applicable. 
 
6.5.4 Vital Signs 
 
The investigator or qualified designee will take vital signs at screening and prior 
to the administration of each dose of trial treatment . Vital signs should include 
temperature, pulse, respiratory rate, oxygen saturation, weight and blood 
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6.5.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
The investigator or qualified designee will assess ECOG status (see Section 10.1) 
at screening and prior to the administration of each dose of trial treatment. 
 
6.5.6 Tumor Imaging and Assessment of Disease 
 
CT of the chest and abdomen/ pelvis with IV contrast will be used, and per 
investigator discretion, PET/CT can be substituted. If IV contrast is 
contraindicated, a non-contrast CT of chest/abdomen/pelvis is acceptable. Bone 
scans may be used if clinically indicated. MRI brain or CT brain with IV contrast 
is required at baseline and as clinically indicated thereafter. The same imaging 
methods should be used throughout the trial. The gold standard for evaluating 
tumor response and BORR during the study will be RECIST 1.1 criteria (see 
Appendix, Section 10.3). Because of the distinct biologic mechanisms of anti- 
cancer activity of immunotherapeutic agents, cancer patients treated with 
immunotherapy need to be evaluated with special attention to the characteristics 
of immune-related tumor response. The immune related response criteria have 
been developed to adequately characterize additional patterns of response and 
progression specific to patients treated with immunotherapy, that cannot be 
captured by the conventional criteria such as such as RECIST. Immune-related 
RECIST criteria will therefore also be used in this study (see Appendix, Section 
10.4). A 7-day window will be allowed around post-baseline imaging scans (i.e. 
should be obtained every 9 weeks from the date of allocation (+/- 7 days)). 
Frequency of imaging studies will be every 12 weeks (+/- 7 days) after 12 months 
on study treatment. Tumor assessment dates are fixed and should not be adjusted 
for dose interruptions, delays, or modifications. 
 
6.6 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 
6.6.1 Tumor specimens 
 
Formalin-fixed, paraffin-embedded (FFPE) tumor samples or newly obtained 
tumor samples will be obtained from all patients with biopsy accessible disease 
at baseline, then after monotherapy (cycle 1), and then after combination therapy 
with nab-paclitaxel and pembrolizumab (cycle 2), and at the time of disease 
progression (if patient consents and it is clinically feasible). Collection of these 
tumor samples is mandatory to conduct the correlative analysis as part of the 
objectives of the protocol is to establish predictive biomarkers. These samples will 
be analyzed and stored at the locations specified below. Only coded samples will 
be shared with the laboratories. Samples remaining after completion of the study 
will be destroyed once this study is completed at all participating sites. None of 
the samples collected in this study will be used to create a repository for future 
research studies. 

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• Immune Core lab and Department of Pathology , Tisch Cancer Institute, 
NYU Langone Medical Center 
 
The University of Texas at Austin, 107 W Dean Keeton Street, Austin, 
TX 78712   
• Adaptive Biotechnologies, 1551 Eastlake Ave E, Ste 200, Seattle, WA 
98102 
 
• QualTek Molecular Laboratories, 300 Pheasant Run, Newtown, PA 
18940 
 
• Histogenetics, LLC. 300 Executive Blvd, Ossining, NY 10562 
Whenever possible, the lesion biopsied should be taken amenable to serial 
biopsies and should not be the sole measurable lesion per RECIST 1.1 criteria. A 
minimum of 2 cores are required at each time point. Soft tissue and bone lesions 
are acceptable. Subsequent biopsies should be taken from the same lesion, if 
feasible. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 
days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained 
samples cannot be provided (e.g. inaccessible or subject safety concern) may 
submit an archived specimen only upon agreement from the medical monitor. 
Sections will be evaluated for stromal lymphocytes by hematoxylin and eosin 
(H&E) stain as per our group’s previous work and our international guidance 
document on evaluation of TILs in breast cancer20,70. PD-1 expression in 
lymphocytes by IHC, PDL-1 expression (IHC in collaboration with Merck), and 
immune gene panels by Prosigna (NanoString Technologies Inc., Seattle, WA, 
http://www.nanostring.com) will also be performed. Changes in tumoral PDL-1 
expression before and after nab-paclitaxel monotherapy will be investigated. 
 
6.6.2 Diversity in antigen-specific T cell receptor (TCR) and TCR clonality 
 
In 
collaboration 
with 
Adaptive 
Biotechnologies 
(Seattle, 
WA, 
http://adaptivebiotech.com), which have developed a novel method that amplifies 
rearranged TCR CDR3 sequences, the capacity of high-throughput sequencing 
technology will be used to sequence tens of thousands of TCR CDR 3 chains 
simultaneously. Because the technology utilizes genomic DNA, the frequency of 
sequenced CDR3 chains is representative of the relative frequency of each CDR 
sequence in the starting population of T cells. For each study sample, we will 
sequence 40,000 genomes at each time point. 
 
6.6.3 Identification of Tumor Antigens 
 
Collection and Processing of Tumor Specimens. Archived or newly obtained tumor 
specimen acquired from surgical resection, surgical/punch biopsy or core biopsy will be 

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processed per institutional guidelines, at NYULMC via the NYULMC Biorepository and 
Pathology Core Laboratory. 
 
Tumor specimen acquired from surgical resection, surgical/punch biopsy or core 
biopsy will be preserved as formalin-fixed, paraffin-embedded (FFPE) slides. 
Archival tissue specimens—such as a flash-frozen or formalin-fixed, paraffin- 
embedded block—will be handled in a similar fashion. Participating sites will 
transport specimens under this clinical trial agreement to the laboratories 
performing the correlative analyses as specified in this protocol: NYU Langone 
Medical Center Core Laboratories and the Icahn School of Medicine (ISMMS) 
Biorepository and Pathology Core Laboratory. 
 
Processing of Tumor Sample for Whole Exome and RNA Sequencing. The 
NYU or ISMMS Biorepository and Pathology Core Laboratory will then isolate 
genomic DNA, as well as total RNA from the specimens using standard tissue 
disruption, nucleic acid extraction and purification kits (Qiagen). The quantity 
and quality of isolated DNA and RNA are determined using a Qubit fluorometer 
(Life Technologies), as well as a Bioanalyzer 2100 (Agilent). 
 
Whole Exome Sequencing and RNA Sequencing. Purified DNA and RNA will be 
transported from the pathology suite by a study coordinator to the NYU or ISMMS 
Genomics Core Facility (GCF) a Clinical Laboratory Improvement Amendments (CLIA) 
certified clinical genetics laboratory maintained by the NYU OSR or ISMMS 
Department of Genetics and Genomic Sciences. Sequencing of tumor specimens at 
ISMMS is done via a standardized urgent cancer sequencing pipeline which specifically 
prioritizes the preparation, sequencing and data analysis of subjects enrolled in clinical 
trials. 
 
Whole Genome DNA Methylation Analysis: We will utilize the analysis of epigenetic 
changes for molecular classification and prediction of therapeutic response. Epigenetic 
changes of DNA are increasingly recognized as a potential driver in cancers where driver 
mutations were not identified. The Infinium MethylationEPIC BeadChip builds upon the 
Infinium HumanMethylation450 BeadChip with original CpGs plus an additional 
350,000 CpGs in enhancer regions. The array provides quantitative methylation 
measurement at the single-CpG–site level with coverage of CpG islands, RefSeq genes, 
ENCODE open chromatin, enhancers and transcription factor binding sites, DNase 
hypersensitivity sites, miRNA promoter regions, and FANTOM5 enhancers. Technical 
components and performance of both arrays (450k and 850k) remain the same and data 
are compatible between both platforms. It has recently been shown that this assay can be 
equally well applied to DNA extracted from fresh frozen or formalin-fixed paraffin- 
embedded (FFPE) tissue with minimal amounts of input material. the RF is an ensemble 
method, which combines the outputs of many classification trees to produce a more 
powerful classifier. A classification tree separates samples into tumor subgroups by 
repeatedly applying binary splitting rules in a hierarchical manner. These splitting rules 
are 'learnt' by first providing the known classes of a reference sample set. Starting at the 

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'root' of a tree, a splitting rule is applied to separate the reference set into two subsets. To 
establish this rule the algorithm picks the feature that leads to 'purest' split, i.e. the 
samples assigned to a resulting subset are mostly tumor entities of the same classes. The 
quality of the split is measured by the Gini impurity measure. The process is then repeated 
iteratively for each of the resulting subsets until no further improvement can be made. 
Figure 1 shows an example of a classification tree that uses CpG probes to separate 
between several tumor entities. Methylation of the Tumor DNa is compared to the 
methylation of the Normal DNA to elucidate differentially methylated sites between 
neoplastic and non-neoplastic DNA. 
 
 
 
 
Figure 1. An example of a binary 
classification tree. From top, the 
'root' of the tree, to the final 'leaves' 
the figure displays the hierarchical 
order of binary splitting rules. Each 
'leaf' corresponds to a tumor entity. 
At each split, the identifier of the 
CpG probe and the actual splitting 
rule are shown. 
 
 
 
 
 
 
To 
'grow' 
a 
random 
forest, 
thousands of randomly generated trees are built. Each tree uses a random subset of the 
samples (drawn with replacement) and a random subset of CpG probes (drawn without 
replacement). In order to classify new samples, each tree assigns the sample into a 
particular class, and we say the tree 'votes' for the class. The random forest takes the 
majority vote of all trees to make a final prediction. In addition, the proportion of trees 
voting for a certain class can be interpreted as an empirical probability that the sample 
belongs to that class. The reference sample cohort can be regularly updated as new 
profiles are generated, as the tool has been optimized to take only a few hours for training 
and cross-validation with each update. Class prediction for each new sample takes a 
matter of seconds. 
 
DNA methylation data will be correlated with mutational landscape identified by the 
NYU NGS580 analysis. 

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NGS 580 sequencing: The clinically approved panel provides extremely deep analysis 
(700x on average) of the 580 genes known to be associated with cancer. NYU NGS580 
is a paired Tumor—Normal hybrid capture based massive parallel sequencing assay. 
NYU NGS580 is a custom targeted panel assay focused on a set of 580 genes implicated 
in both solid tumors and hematological malignancies. The panel aims to identify somatic 
aberrations- in a variety of specimen and cancer types- including single nucleotide 
variants (SNV), insertions and deletions (indel) and copy number variants (CNV) 
including focal amplifications and homozygous deletions. The bioinformatics pipelines 
can provide further information in terms of tumor mutation burden and mutational 
signatures. 
 
The results of the NYU NGS 580 will be correlated with Liquid biopsy findings. 
 
Whole Exome Sequencing. Whole exome sequencing (WES) will performed on 
sequencing libraries, which are prepared according to the manufacturer’s protocol. The 
sequencing library is constructed as follows: The E210 focused acoustic energy system 
is used to shear genomic DNA which has been prepared according to the procedure 
outlined in § 5.6.2 into 250 base pair long fragments (Covaris). The fragments are 
extended in the presence of T4 DNA polymerase and polynucleotide kinase to create 
blunt-ends (New England Biolabs). Illumina PE genomic DNA adapters (Illumina) are 
then ligated to the DNA fragments in the presence of T4 DNA ligase (New England 
Biolabs). The adapter-ligated DNA fragments are amplified by ligation-mediated 
polymerase chain reaction (LM-PCR), and then purified using the SPRI AMPure XP 
magnetic bead purification system (Beckman Coulter). The concentration of DNA in the 
resulting sample is then assessed using a Bioanalyzer 2100 (Agilent) and Qubit 
fluorometer (Life Technologies). The gDNA adapter-ligated library is then dried in the 
presence of human Cot-1 DNA and blocking paired-end polymerase chain reaction 
oligomers (Integrated DNA Technologies). The dried sample is then reconstituted in 
hybridization buffer with Component A (Roche). The samples is denatured and then 
combined with the NimbleGen SeqCap EZ Exome oligonucleotide library (Roche), and 
the mixture is loaded onto a Tetrad Thermal Cycler (BIO-RAD) and allowed to hybridize 
for seventy-two (72) hours, at forty-seven (47) degrees Celsius. The sample is then 
combined with streptavidin Dynabeads (Invitrogen), and then washed. Washed bead- 
conjugated samples are then reconstituted, amplified by LM-PCR, and purified with the 
SPRI AMPure XP magnetic bead purification system. The concentration of DNA in the 
resulting sample is then assessed using a Bioanalyzer 2100 and Qubit fluorometer. The 
enriched sample is also analyzed by a quantitative PCR (qPCR) SYBR green reaction 
using control oligonucleotide primers (NimbleGen) on a LightCycler 480 II thermal 
cycler (Roche). 
 
The enriched library is then added to one of eight flow cells at the DNA concentration 
indicated by the manufacturer (Illumina). The sample is then amplified using cBot 
(Illumina), and PhiX ver 3 DNA (Illumina) added for control purposes. The flow cell is 
then loaded into the HiSeq 2500 platform (Illumina), and sequenced according to 
manufacturers one hundred (100) base pair, paired-end protocol. Quality control 

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parameters such as the graphical focus quality of the captured images, the fluorescence 
intensity of individual bases, as well as per-base and per-cycle error rates are periodically 
monitored. If a deviation in quality control metrics is observed, corrective actions are 
taken with the help of a trained Illumina Service Engineer and Field Application 
Scientist. If the corrective actions are deemed to be inadequate the individual sequencing 
run is aborted. Base calling from captured images is performed by the HiSeq 2500 using 
software provided by the manufacturer. The results of an individual sequencing run are 
transferred via a secure connection to a dedicated server maintained by the ISMMS GCF. 
The primary sequencing data is used to generate an internal quality control report, before 
the data are made available to the Production Bioinformatics Group for downstream 
analysis. 
 
RNA Sequencing. The RNA sequencing library is generated using the using the TruSeq 
mRNA Seq kit (Illumina). The primary sequencing data is used to generate an internal 
quality control report, before the data are made available to the Production 
Bioinformatics Group for downstream analysis. 
 
Sequencing Data Transport and Handling. Data containing raw sequencing reads 
generated from each sequencing run are transferred via a secure connection from the 
ISMMS GCF primary storage server to two dedicated high-performance computer 
clusters maintained by the ISMMS Department of Genetics and Genomic Sciences. 
 
Sequencing Data Analysis 
 
Whole Exome Sequencing Data. Base quality score recalibration, insertion and deletion 
realignment, duplicate removal, genotyping variant calling is performed using the GATK 
toolkit. Somatic variant calling is performed using both Varscan2 and Mutect. Variants 
meeting quality control metrics are then manually reviewed by visual inspection of the 
read alignment and base calls using the Integrated Genome Viewer. 
 
RNA Sequencing. RNASeq read mapping and expression analysis is conducted using 
TopHat and Cufflinks. 
 
Validation of Sequence Variants Identified by High-throughput Sequencing. 
Variants are then cross-validated by the ISMMS GCF using an orthogonal high- 
throughput platform (Ion Proton™ or Ion PGM™, Life Technologies | Pacific 
Biosciences RS II, Pacific Biosciences) or by conventional Sanger sequencing. Upon 
completion of validation a variant calling file containing list of all somatic variants, as 
well as all associated pertinent information are then made available for use in antigen 
identification. 
 
Reporting of Information Derived from Cancer Sequencing. Cancer sequencing is a 
major component of this particular research study, however, data derived from WES 
and/or RNASeq performed in the context of this study is considered to be for research 
purposes only. While clinical sequencing may be of additional benefit to the subject and 

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his/her physician this type of data reporting is outside of the scope of the present study 
and as such no genetic information will be reported back to the subject. 
 
Human Leukocyte Antigen Genotyping. This HLA typing is done solely for the 
purpose of immune analyses as specified in this protocol, results will not be shared with 
the patient or physician. Genomic DNA isolated from peripheral blood mononuclear cells 
collected during study visit v1 will be used to determine the subject specific nine locus 
HLA haplotype type for use in epitope prediction. Subject HLA haplotype will be assess 
by sequence-based HLA typing, which relies on locus and group-specific amplification 
and sequencing of exons 2 and 3 of HLA-A, B, C; as well as exon 2 of HLA-DRB1, 
DRB3/4/5, DQB1, DQA1, DPA1, and DPB1 as per American Society for 
Histocompatibility and Immunogenetics/National Marrow Donor Program requirements 
for bone marrow transplant registration. This assessment will be performed by 
Histogenetics, LLC. (Ossining, NY), an American Society for Histocompatibility and 
Immunogenetics (ASHI) (Member #: 03-1-NY-2602) and CLIA-certified (Certificate: 
33D0985173) laboratory. 
 
Systematic identification of Mutation Derived Tumor Antigens (MTA) 
 
MTA may be identified through the sequential use of WES followed by peptide-MHC 
binding affinity prediction48,49. We will use NETMHCCons v1.1 to identify patient 
specific neoantigens. RNA seq will be used to ensure expression of the variant antigen 
by the patient’s tumor. 
 
6.6.4 Peripheral blood 
 
Key immune biomarkers will be evaluated on circulating leukocytes (PD-1, PD- 
L1, granzyme B, perforin, NKp44, HLA-DR, CD69) to evaluate changes during 
PD-1 blockade, as well as to evaluate them as predictive biomarkers. In addition, 
we will comprehensively evaluate the immune cell subset frequencies and 
expression of key receptors on peripheral blood mononuclear cells (PBMCs) and 
identify changes that occur after PD-1 blockade. Included in the analyses are 
CD4/CD8 and Th1/Th2 profiles, immunosuppressive Tregs (the development of 
which is promoted by PD-1 and PD-L1 ligation), dendritic cells 71 which are 
important antigen presenting cells (APCs), and inhibitory receptors PD-1, CTLA- 
4, TIM-3, and LAG-3, which can all contribute to T-cell exhaustion. Differential 
expression of these inhibitory receptors on subset of CD8 T cells is associated 
with differential cytokine production and degranulation, and there are also 
therapeutic immune checkpoint targets under development that may be altered on 
T cells after PD-1 blockade. Multi-parametric flow cytometry (12-color) will be 
used to quantify these biomarkers. Sequential samples of PBMC will be analyzed 
from patients before and during treatment with pembrolizumab. 
 
Liquid Biopsy: Liquid biopsy enables analysis of tumor cells and tumor DNA 
directly from blood. We will perform a comprehensive liquid biopsy program in 

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which whole tumor cells as well as cell-free tumor DNA are captured from blood 
and profiled. Genetic heterogeneity is analyzed on a single cell level and 
compared with the levels of cell-free tumor DNA to determine response to 
therapy and predict disease recurrence. DNA from circulating leukocytes is used 
as a control for DNA NGS and methylation. 
 
 
6.6.5 Gut Microbiome Analysis 
 
Subjects will receive specific instructions about collection of stool. They will be 
given a stool collection kit to be returned at the required time points, along with 
instructions on how to use it. The stool will be aliquoted and stored at -80oC until 
the time of analysis. Bacterial microbiome taxonomy, diversity, and abundance 
will be analyzed by pyrosequencing of 16S ribosomal RNA (rRNA) amplicons. 
 
 
6.6.6 Laboratory Procedures/Assessments 
 
Tumor tissues, stool and blood Samples will be analyzed at the two 
collaborating academic centers: NYU Langone Core Laboratories and The 
University of Texas at Austin 
107 W Dean Keeton Street, Austin, TX 78712. Additionally, commercial 
laboratories will perform analyses as described in this protocol, no identifying 
information will be shared with these laboratories. 
 
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) will be 
performed at the clinical laboratories of the participating sites. 
 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified 
in the study calendar. 

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Laboratory tests for cycle1 should be performed within 10 days prior to the first dose of 
treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior 
to dosing. Results for clinically significant laboratory values (ANC, hemoglobin, platelet count, 
creatinine, bilirubin, AST and ALT) must be reviewed by the investigator or qualified designee 
and found to be acceptable prior to each dose of trial treatment. 
 
6.7 Pharmacokinetic/Pharmacodynamic Evaluations n/a 
 
6.8 Other Procedures 
 
6.8.1 Withdrawal/Discontinuation 
 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 6.12 - Assessing and Recording 
Adverse Events. 
 
6.9 Blinding/Unblinding 
N/A 
6.10 Screening 
 
6.10.1 Screening Period 
 
During the screening period, patient evaluation for trial entry will be performed based upon 
enrollment criteria (inclusion/exclusion criteria), history and physical exam, ECOG 
performance status (PS), EKG, and standard of care 69 labs. 
 
6.10.2 Treatment Period 
 
Patient evaluation will be performed at each visit that the patient receives the study drug and 
include history and physical exam, ECOG PS, measurement of SOC labs, and assessment of 
adverse events. Imaging will be performed every 9 weeks from the date of allocation (+/- 7 
days) until after twelve months on study treatment during which imaging will be performed 
every 12 weeks (+/- 7 days). Tumor assessment dates are fixed and should not be adjusted for 
dose interruptions, delays, or modifications. 
 
6.11 Post-Treatment Visits 
 
6.11.1 Safety Follow-Up Visit 
 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded. SAEs 

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that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded. 
 
6.11.2 Follow-up Visits 
 
N/A 
 
6.11.3 Survival Follow-up 
 
Following study completion, patients will enter routine follow-up with their primary 
oncologist, who may be contacted to provide follow-up information on the patient’s clinical 
and disease status until death or withdrawal of consent, whichever occurs first. 
 
6.12 Assessing and Recording Adverse Events 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable 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 Merck and/or Celgene 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. 
 
Merck 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 Merck for human use. 
 
Adverse events may occur during the course of the use of the Merck and/or Celgene product 
in clinical trials or within the follow-up period specified by the protocol, or prescribed in 
clinical practice, from overdose (whether accidental or intentional), from abuse and from 
withdrawal. 
 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 

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All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 6.13. 
 
6.12.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
NYU PI and to Merck and Celgene 
 
Pembrolizumab 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose). No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non- 
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
Dr. Adams, the NYU research coordinator, NYU regulatory specialist, the medical monitor, 
Dr. Zujun Li and to NYUPCCsafeteyreports@nyumc.org and within 2 working days hours to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
Nab-paclitaxel 
 
Overdose, as defined for this protocol, refers to pembrolizumab and nab-paclitaxel dosing only. 
 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of pembrolizumab and nab-paclitaxel assigned to a given patient, regardless of any 
associated adverse events or sequelae. 
 
PO 
any amount over the protocol-specified dose 
IV 
10% over the protocol-specified dose 
SC 
10% over the protocol-specified dose 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency. 

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On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified 
rate. For nab-paclitaxel, an infusion completed in less than 25 minutes may increase Cmax by 
approximately 20%, therefore a nab-paclitaxel infusion completed in less than 25 minutes will 
meet the infusion rate criterion for an overdose. Complete data about drug administration, 
including any overdose, regardless of whether the overdose was accidental or intentional, 
should be reported in the case report form. 
 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ 07922 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
 
 
6.12.2 Reporting of Pregnancy and Lactation to Dr. Adams, Merck and Celgene 
 
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), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the 
pregnancy continues to term, the outcome (health of infant) must also be reported. 
 
Such events must be reported within 24 hours to the PI, NYU research coordinator, regulatory 
specialist, the medical monitor Dr. Zujun Li, and to NYUPCCsafeteyreports@nyumc.organd 
within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 
993-1220) 
 
6.13 Immediate Reporting of Adverse Events to the PI , Merck and Celgene 
 
6.13.1 Serious Adverse Events 
 
Expedited Reporting to Merck 
 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 
• Results in death; 

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• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is an other important medical event 
Refer to Table 6 for additional details regarding each of the above criteria. 
 
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 that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to Dr. Adams, the NYU research coordinator, the regulatory 
specialists, the medical monitor Dr. Zujun Li and to NYUPCCsafeteyreports@nyumc.org and 
within 2 working days to Merck Global Safety. 
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs. 
 
Additionally, any serious adverse event, considered by an IRB approved investigator who is a 
qualified physician to be related to Merck product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to Dr. Adams, the NYU research coordinator, the regulatory 
specialists, the medical monitor, Dr. Zujun Li and to NYUPCCsafeteyreports@nyumc.org and 
to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number: +1-215-993-1220 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
Expedited Reporting to Celgene 
 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness 
of events of being related to ABRAXANE® based on the Investigator Brochure. In the United 
States, all suspected unexpected serious adverse reactions (SUSARs) will be reported in an 
expedited manner in accordance with 21 CFR 312.32. 

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Serious adverse events (SAE) are defined above. The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours 
of being aware of the event. The written report must be completed and supplied to Celgene by 
facsimile within 24 hours. The initial report must be as complete as possible, including an 
assessment of the causal relationship between the event and the investigational product(s). 
Information not available at the time of the initial report (e.g., an end date for the adverse event 
or laboratory values received after the report) must be documented on a follow-up report. A 
final report to document resolution of the SAE is required. The Celgene tracking number (AX- 
CL-BRST-PI-006499) and the institutional protocol number should be included on SAE 
reports (or on the fax cover letter) sent to Celgene. A copy of the fax transmission confirmation 
of the SAE report to Celgene should be attached to the SAE and retained with the patient 
records. Participating study sites must report SAEs to Celgene as described and within 24 hours 
of awareness. Participating sites should also report SAEs to the primary study site. 
 
6.13.2 Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to Dr. Adams, the NYU research coordinator, the regulatory 
specialists, the medical monitor Dr. Zujun Li and to NYUPCCsafeteyreports@nyumc.org and 
within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 
993-1220)Events of clinical interest for this trial include: 
 
1. an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to Dr. Adams, the NYU research coordinator, the 
regulatory 
specialists, 
the 
medical 
monitor 
Dr. 
Zujun 
Li 
and 
to 
NYUPCCsafeteyreports@nyumc.org, 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). 
 
1. Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-Related 

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Adverse Event Guidance Document”). This document can be found in Appendix 4 and 
provides guidance regarding identification, evaluation and management of ECIs and irAEs. 
 
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 90 days following cessation of treatment, or 30 days 
after the initiation of a new anticancer therapy, whichever is earlier, need to be reported 
within 24 hours to Dr. Adams, the NYU research coordinator, the regulatory specialists, 
the medical monitor, Dr. Zujun Li and to NYUPCCsafeteyreports@nyumc.org and within 
2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-
1220), regardless of attribution to study treatment, consistent with standard SAE reporting 
guidelines. 
 
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune- 
related event. Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes. If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes. If no other cause is found, then it is assumed to be immune-related. 
 
6.13.3 Evaluating Adverse Events 
 
An IRB approved investigator who is a qualified physician will evaluate all adverse events 
according to the NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any 
adverse event which changes CTCAE grade over the course of a given episode will have each 
change of grade recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

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Table 6 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 Merck 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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
Is a new cancer; (that is not a condition of the study) or 
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken 
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck 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 Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to the Merck 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 Merck 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 
to Merck 
product 
(continued) 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
Dechallenge 
Was the Merck 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 Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
Rechallenge 
Was the subject re-exposed to the Merck 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) Merck 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 MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR 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 Merck 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 Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product. The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable. The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE. (Also entered for a subject with overdose without an associated AE.) 

 
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6.13.4 Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
 
6.13.5 Investigator Reporting Responsibilities 
 
The following describes events that must be reported to Dr. Adams in an expedited fashion. 
 
Initial Report: Within 24 hours: 
The following events must be reported to the study sponsor by telephone within 24 hours of 
awareness of the event: 
• Unanticipated problems related to study participation, 
• Serious adverse events, regardless of whether they are unexpected. 
 
 
Additionally, 
an 
FDA 
Form 
3500A 
(MEDWATCH 
Form; 
see 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/UCM082 
728.pdf) must be completed by the investigator and faxed to the study sponsor within 24 hours. 
The investigator shall maintain a copy of the MEDWATCH Form on file at the study site. 
Forward all medwatch to the Principal Investigator: 
 
Dr. Sylvia Adams: 212-731-5795 
 
Follow-up Report: Within 48 hours: 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, 
the investigator shall provide further information, as applicable, on the unanticipated device 
event or the unanticipated problem in the form of a written narrative. This should include a 
copy of the completed Unanticipated Problem form, and any other diagnostic information that 
will assist the understanding of the event. Significant new information on ongoing 
unanticipated adverse device effects shall be provided promptly to the study sponsor. 
 
Other Reportable Events: 
• Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s 
IRB approval before they are initiated. Any protocol deviations initiated without 
Sponsor and the investigator’s IRB approval that may affect the scientific 
soundness of the study, or affect the rights, safety, or welfare of study subjects, 
must be reported to the Sponsor and to the investigator’s IRB as soon as a 
possible, but no later than 5 working days of the protocol deviation. 
 
• Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the 

 
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investigator’s reviewing IRB as soon as a possible, but no later than 5 working 
days of the IRB notification of withdrawal of approval. 
 
Investigator Reporting: Notifying the IRB 
Federal regulations require timely reporting by investigators to their local IRB of 
unanticipated problems posing risks to subjects or others. The following describes the 
NYULMC IRB reporting requirements, though Investigators at participating sites are 
responsible for meeting the specific requirements of their IRB of record. 
 
Report Promptly, But no Later than 5 Working Days: 
Researchers are required to submit reports of the following problems promptly but 
no later than 5 working days from the time the investigator becomes aware of the 
event: 
• Unanticipated problems including adverse events that are unexpected and 
related 
– Unexpected: An event is “unexpected” when its specificity and severity are 
not accurately reflected in the protocol-related documents, such as the IRB- 
approved research protocol, any applicable investigator brochure, and the 
current IRB-approved informed consent document and other relevant 
sources of information, such as product labeling and package inserts. 
– Related to the research procedures: An event is related to the research 
procedures if in the opinion of the principal investigator or sponsor, the 
event was more likely than not to be caused by the research procedures. 
– Harmful: either caused harm to subjects or others, or placed them at 
increased risk 
 
6.13.6 Other Reportable Events: 
The following events also require prompt reporting to the IRB, though no later 
than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks 
or the complaint cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and 
accidental/unintentional deviations from the IRB approved protocol) for any of 
the following situations: 
–one or more participants were placed at increased risk of harm 
–the event has the potential to occur again 
–the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved 
under Subpart C and the investigator believes it is in the best interest of the 
subject to remain on the study. 

 
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• New Information indicating a change to the risks or potential benefits of the 
research, in terms of severity or frequency. (e.g. analysis indicates lower-than- 
expected response rate or a more severe or frequent side effect; Other research 
finds arm of study has no therapeutic value; FDA labeling change or withdrawal 
from market) 
 
6.13.7 Reporting Process 
The reportable events noted above will be reported to the IRB using the form: 
“Reportable Event Form” or as a written report of the event (including a description 
of the event with information regarding its fulfillment of the above criteria, follow- 
up/resolution and need for revision to consent form and/or other study 
documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept 
in the Clinical Investigator’s regulatory binder. 
 
 
 
IND Annual Reports 
 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date. 21 CRF 312.33 
provides the data elements that are to be submitted in the report. The Annual Report should be 
filed in the study's Regulatory Binder, and a copy provided to Merck and Celgene Corporation 
as a supporter of this study: 
Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
Celgene Corporation 
Attn: Medical Affairs Operations 
Connell Corporate Park 
400 Connell Drive Suite 700 
Berkeley Heights, NJ 07922 
Tel: (908) 673-9000 
 
All adverse experience reports must include the patient number, age, sex, weight, severity of 
reaction (e.g. mild, moderate, severe), relationship to drug (e.g. probably related, unknown 
relationship, definitely not related), date and time of administration of test medications and all 
concomitant medications, and medical treatment provided. The investigator is responsible for 
evaluating all adverse events to determine whether criteria for “serious” and as defined above 
are present. The investigator is responsible for reporting adverse events to Celgene as described 
in the protocol. Participating study sites should NOT report SAEs to the FDA. Rather, 
participating sites should report SAEs to Celgene and the primary study site, and the primary 
site will be responsible for reporting to FDA. 

 
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Notifying participating investigators: It is the responsibility of the study sponsor to notify all 
participating investigators of any adverse event that meets the FDA 15-day reporting 
requirement criteria as note above in section 8.3.4. The same materials and timeline used to 
report to the FDA are used for notifying participating investigators. 
 
 
7 
STATISTICAL ANALYSIS PLAN 
 
7.1 Statistical Analysis Plan Summary 
 
For the TBNC cohort (primary cohort), a total sample size of 30 subjects (both male and female 
of all races) with metastatic TNBC treated with 0-2 prior lines of therapy for metastatic disease 
will be enrolled to evaluate the anti-tumor activity of the combination of nab-paclitaxel and 
pembrolizumab. The primary efficacy analysis in this TNBC cohort will be BORR based on 
RECIST 1.1. BOR is defined as the best response recorded from the start of the study treatment 
until disease progression. BORR is the number of subjects with a BOR of CR or PR, divided 
by the number of treated subjects. Assuming nab-paclitaxel would have a maximum BORR 
(defined as a best response with CR or PR) of approximately 30% for TNBC31 in 1st to 3rd line 
monotherapy with a sample size of 30 subjects, the estimated exact 95% Clopper Pearson 
confidence interval would be 14.7% to 49.4% if the underlying rate is 30%. (Calculations from 
PASS 2014, NCSS J. Hintze, Kaysville, Utah). For the HR-positive (exploratory) cohort, an 
additional 20 subjects with metastatic HR-positive breast cancer will be enrolled to provide an 
initial understanding of the efficacy profiles of the combination of nab-paclitaxel and 
pembrolizumab in these patients. Descriptive statistics will be provided for efficacy endpoints. 
An estimated 65 patients will be screened for eligibility to reach a goal of about 50 participants. 
 
The two analysis populations will be defined as: 
 
• safety run-in population: all patients who receive any amount of study drug 
(pembrolizumab) 
 
• efficacy evaluable population: all patients who receive any amount of study drug 
(pembrolizumab) and have at least one post-baseline disease assessment (similar to a 
modified intent to treat population). Analysis of efficacy endpoints will be performed 
on the efficacy evaluable population. 
 
7.2 Statistical Analysis Plan 
 
7.2.1 General Methods 
 
Within each cohort, all baseline demographic, disease and treatment characteristics, will be 
summarized using frequency distributions for qualitative variables and summary statistics (mean, 
medians, standard deviations, etc.) and graphical displays (e.g., boxplots) for quantitative 
variables. 

 
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All endpoints will be summarized overall and by cohort (cTNBC, HR-positive, iTNBC 
groups). For the primary endpoint of BORR, 2 sided exact 95% Clopper Pearson confidence 
intervals will be provided for each cohort. Time to event analysis (PFS and OS for the TNBC 
group) will be performed using Kaplan-Meier methods. PFS is defined as the time elapsed 
between study enrollment date and date of tumor progression or death from any cause, with 
censoring of patients who are lost to follow-up. OS is defined as the time from date of study 
enrollment until death from any cause. Both, PFS and OS are measured in the intent-to-treat 
population (all patients who receive at least one dose of treatment). As the primary cohort of 
cTNBC is a single-arm cohort, any hypothesis testing to be performed among subgroups is 
for descriptive and future study purposes only. 
 
7.2.2 Safety 
 
Adverse events 72 as well as immune-related events will be closely monitored throughout the 
study. Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) for purposes of summarization. All AEs occurring during the study will be 
included in by-subject data listings and tabulated by MedDRA system organ class and 
preferred term. Safety endpoints for adverse events include the following: incidence of AEs, 
all treatment-emergent AEs (TEAEs) and all serious adverse events (SAEs). Severity of 
event, relationship to study drug, and discontinuation of patients from study therapy due to 
AEs and due to deaths will be recorded. 
 
Counts and percentage of AE will be provided. Confidence intervals for rates of AEs will be 
estimated using exact binomial confidence intervals. A formal dose-limiting toxicity (DLT) 
evaluation (assessed on day 42) will be done after 12 patients during the safety run in have 
been treated with the combination of nab-paclitaxel and pembrolizumab (Phase Ib). If more 
than 4 of the first 12 patients have DLT (clinically significant, pre-specified AEs), then 
consideration would be given to modifying the nab-paclitaxel dose. 
 
In the recently reported TNBC combination trial of nab-paclitaxel chemotherapy with 
immunotherapy (atezolizumab) (n=32 patients), grade 3/4 AEs had occurred in 56% of 
patients, including neutropenia (41%), thrombocytopenia (9%), and anemia (6%) (Adams, et 
al, SABCS 2015). At least one AE of any grade occurred in all patients in the trial. There were 
no treatment-related deaths observed in the study. Five patients discontinued nab-paclitaxel as 
a result of an AE (fatigue (n = 1; grade 2), asthenia (n = 1; grade 2), and peripheral neuropathy 
(n = 3; grade 1, 2, and 3)). 
 
DLT specifically for this combination study (which is to avoid excess toxicity with the 
combination compared to known single agent toxicity) is defined as one of the following 
toxicities occurring during the DLT assessment window and considered by the investigator to 
be related to any of the study drugs. 
 
Hematologic Toxicities: 
 
• Grade 4 thrombocytopenia lasting greater than seven days 

 
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• Grade 4 neutropenia lasting greater than 14 days 
 
Nonhematologic Toxicities: 
 
• AST =/> 10x ULN 
• ALT =/> 10x ULN 
 
• Pneumonitis of Grade 3 or higher 
• Colitis of Grade 3 or higher 
 
 
7.2.3 Correlative Analyses 
 
Analyses of immune cell subsets are exploratory in nature and will contribute to general 
understanding of the immunologic effects of PD-1 blockade. Importantly, we will assess 
baseline PD-L1 expression in tumors and immune cells and will examine the association with 
BORR within each cohort using graphical displays. Cell counts from flow cytometry and 
staining levels expressed as mean fluorescence intensity (MFI) or % positivity will be 
summarized using descriptive statistics. Staining levels expressed as scores will be tabulated 
categorically. Changes over time will be portrayed graphically by group, and marker 
expression will be quantified and plotted during course of therapy for individual patients. 
Changes in immune parameters on serial samples will be evaluated graphically and the 
association with changes in PD-1 checkpoint inhibition and changes in expression of functional 
indicators (CD107A, IFN-gamma, Ki-67, annexin, pAkt) during treatment will be explored. 
 
 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
 
7.3 Investigational Product 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
Commercially packaged supplies of Pembrolizumab will be provided by Merck as summarized 
in Table 7. 
 
Table 7 Product Descriptions 
 
Dosage Form 
Product Name & Potency 

 
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Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
7.4 Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. Merck will provide Pembrolizumab (KEYTRUDA) in marketed package. 
 
7.5 Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the subject, the trial site personnel, and pharmaceutical 
companies supplying the drugs are not blinded to treatment. Drug identity (name, strength) is 
included in the label text; random code/disclosure envelopes or lists are not provided. 
 
7.6 Storage and Handling Requirements 
 
Upon receipt of the of the study treatment supplies, an inventory will be performed and a drug 
receipt log filled out and signed by the person accepting the shipment. The designated study 
staff will count and verify that the shipment contains all the items noted in the shipment 
inventory. Any damaged or unusable study drug in a given shipment will be documented and 
the sponsor manufacturer will be notified. 
 
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. 
 
7.7 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck and Celgene or designee, the amount dispensed to and returned by the subjects 
and the amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to a r r a n g e f o r disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 

 
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8 
ADMINISTRATIVE AND REGULATORY DETAILS 
 
8.1 Confidentiality 
 
The study team will maintain clinical and laboratory data in a designed manner to ensure 
patient confidentiality. All study personnel have passed human subject protection courses. If 
applicable, tissue samples sent to collaborators outside of NYU will only be labeled with an 
assigned protocol-patient identification number without patient identifiers. Only IRB approved 
study personnel at NYU/Clinical trials office will have a link to the code. Systems used for 
electronic data capture are HIPPA compliant. All documents are kept in strictly confidential 
files and are only made accessible for review of sponsors, monitors and authorized 
representatives of regulatory agencies as described in the informed consent document. 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed subject authorization informing the subject of the 
following: 
 
• What protected health information 23 will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization. For subjects that have revoked authorization to collect or use PHI, the 
investigator cannot collect information regarding status until it is available from publically 
available website. 
 
8.2 Compliance with Financial Disclosure Requirements 
 
The study will comply with NYULMC applicable University conflict of interest policies for 
financial disclosure requirements. Any investigator who has a conflict of interest with this 
study (patent ownership, royalties, or financial gain greater than the minimum allowable by 
their institution, etc.) will have the conflict reviewed by a properly constituted Conflict of 
Interest Committee with a Committee-sanctioned conflict management plan. 
 
8.3 Compliance with Law, Audit and Debarment 
 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, 
the sponsor, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 

 
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Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality 
assurance offices. 
 
8.4 Compliance with Trial Registration and Results Posting Requirements 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. 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. 
 
8.5 Quality Management System 
 
The proposed trial entails moderate risks to subjects. 
At the NYU Cancer Institute, all investigator-initiated protocols are subject to a standardized 
data and safety monitoring, which includes scientific peer review, Institutional Review Board 
(IRB) review, and Data and Safety Monitoring Committee (DSMC) review as well as internal 
auditing. 
The review of AEs and trial conduct for this trial occurs at several levels: 
(1) Principal Investigator: Adverse events are evaluated monthly by the principal investigator 
in conjunction with the research nurses, data manager and research team. 
(2) DSMC: See section 10.6 
(3) IRB: An annual report to the IRB is submitted by the trial PI for continuation of the 
protocol. It includes a summary of all AEs, total enrollment with demographics, protocol 
violations, and current status of subjects as well as available research data. 
(4) In addition, the internal audit committee will inspect the source documents, including 
consent forms for randomly selected enrolled participants at regular intervals throughout the 
trial to verify adherence to the protocol; the completeness, accuracy and consistency of the 
data; and adherence to ICH Good Clinical Practice guidelines. 
 
8.6 Data Management 
 
The NYU Clinical Trials Office will oversee the data management of this trial. 
 
Velos, an electronic database system will be used to house the data for this trial. Data is 
required to be input in the study database within 1 week of the patients visit. Each site will be 
responsible for entering the data into Velos. 
 
Data Storage and Confidentiality: 
We will take all necessary precautions to maintain confidentiality of data and prevent 

 
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unauthorized access to the data. All data will be maintained on a secure server and will be 
password protected with access limited to IRB-approved investigators/researchers. The 
matching clinical data may be collected from several sources including the medical record, lab 
facilities and from physician office charts. 
 
The database will contain subject demographics, medical history, number of prior treatments, 
current therapy, all protocol required labs and radiology reports, adverse events, clinical 
response to the current intervention, and overall survival as well as information regarding the 
patient’s preferences regarding re-contacting for future research. 
 
All data that is subsequently utilized for research will be stripped of any personal identifiers 
and all subjects will be assigned a unique study ID number. No individual identifying 
information will be used in any reports or publications resulting from this database. Any 
unauthorized access to medical record information contained within the database will be 
reported to the IRB. 

 
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9 
APPENDICES 
 
10.1 ECOG PERFORMANCE STATUS 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
10.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 

 
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10.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
In addition, volumetric analysis will be explored by central review for response assessment. 
 
10.4 
Immune-Related RECIST Evaluation in Solid Tumors 
Immune-Related RECIST (irRECIST) 
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor response 
seen with immuno-therapeutics. irRECIST will be used by site investigators and local 
radiology review to assess tumor response and progression, and make treatment decisions. This 
data will be collected in the clinical database. 
 
irRECIST takes into account the clinical condition/stability of subjects, as described in the 
Table below, in addition to response or progression via tumor imaging. 
 
Clinically stable is defined by the following criteria: 
• Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
 
Table irRECIST: Tumor Imaging and Treatment after 1st Radiologic Evidence of PD or 
SD, CR or PR 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st 
radiologic 
Repeat imaging at > 4 
weeks 
at 
site 
to 
May continue study 
treatment 
at 
the 
Repeat imaging at > 4 
weeks to confirm PD 
Discontinue treatment 

 
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evidence of PD 
confirm PD 
Investigator’s 
per 
physician 
discretion 
while 
discretion only 
awaiting 
confirmatory scan by 
site 
Repeat scan confirms 
No 
additional 
Discontinue treatment 
No 
additional 
N/A 
PD 
imaging required 
(exception is possible 
imaging required 
upon 
consultation 
with PI or medical 
monitor). 
Repeat scan shows 
Continue 
regularly 
Continue 
study 
Continue 
regularly 
May 
restart 
study 
SD, PR or CR 
scheduled 
imaging 
treatment 
at 
the 
scheduled 
imaging 
treatment if condition 
assessments 
Investigator’s 
assessments 
has improved and/or 
discretion 
clinically stable per 
Investigator’s 
discretion. Next scan 
should 
occur 
according to the every 
9 week (63 ± 7 days) 
imaging schedule. 
 
In determining whether or not the tumor burden has increased, decreased or stayed stable, 
site investigators should consider all target lesions as well as non-target lesions. 
 
Any subject deemed clinically unstable should be discontinued from trial treatment at 
first evidence of progressive disease by tumor imaging and is not required to have repeat 
tumor imaging for confirmation. 
 
For a clinically stable subject with first radiologic evidence of progressive disease (i.e., 
unconfirmed progression of disease), it is at the discretion of the site investigator to 
continue treating the subject with the assigned treatment per protocol until progression of 
disease is confirmed at least 28 days from the date of the tumor imaging first suggesting 
PD. If progression is not confirmed on the subsequent tumor imaging, the subject should 
continue to receive study therapy and have tumor imaging performed every 9 weeks from 
the date of allocation (± 7 days) in the first year or every 12 weeks after the first year, or 
sooner if clinically indicated, to monitor disease status. If radiologic progression is 
confirmed by subsequent tumor imaging, then the subject will be discontinued from trial 
treatment. 
 
NOTE: If a subject with confirmed progression by tumor imaging (i.e. 2 scans at least 28 
days apart demonstrating progressive disease) is clinically stable or clinically improved, 
and there is no further increase in the tumor burden at the confirmatory scan, an exception 
may be considered to continue treatment upon consultation with the PI or medical monitor. 

 
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10.5 Events of Clinical Interest Guidance Document -attached 
 
10.6 NYU Multi-Center Data Safety and Monitoring Plan: 
 
The data and safety monitoring of this trial is based on the 2011 NCI (National Cancer Institute) 
approved Data and Safety Monitoring Plan (DSMP). 
 
Per the NYU Perlmutter Cancer Center (NYUPCC) Institutional DSMP, this phase II trial will 
be monitored by the NYUPCC Date and Safety Monitoring Committee (DSMC). The DSMC 
is a multidisciplinary committee (consisting of clinical investigators/oncologists, 
biostatisticians, nurses and research administration staff knowledgeable of research 
methodology and design and in proper conduct of clinical trials) that is responsible for 
monitoring safety, conduct and compliance in accordance with protocol data monitoring plans 
for clinical trials conducted in the NYUPCC. The DSMC reports to the Director of the 
NYUPCC (Benjamin Neel, MD, PhD). 
 
This phase II trial will be monitored by the NYUPCC DSMC annually (from the date first 
patient is enrolled), at the completion of DLT evaluation for the run-in phase, and at the 
completion of the study prior to study closure. The annual review includes accrual data, subject 
demographics and adverse events. Additional interim reviews can be scheduled based on SAE 
reports, investigator identified issues, external information, etc. Besides the annual review, 
new SAEs are also reviewed by the DSMC monthly. Cancer Center’s Phase I/II Committee 
also monitors the study monthly for AEs. The annual DSMC reports will be submitted to the 
IRB at the time of annual review. 
 
Record Retention 
 
Sponsor-Investigator will retain study essential documents for at least 2 years after the 
completion of the study with the IRB. After this time period, study documents will be 
archived at an outside location for a time period of 10 years. 
 
 
 
 
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