Clinical trial NCT03018080
Conditions: Breast - Female Male Breast Cancer
Sponsor: Wake Forest University Health Sciences
Start date: 2017-06-12; Completion date: 2022-08-05
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to assess the safety and feasibility of the following two regimens: Cohort A) phased regimen of pembrolizumab in which paclitaxel is followed by paclitaxel plus pembrolizumab and Cohort B) concurrent regimen of paclitaxel plus pembrolizumab. The primary safety objective is to evaluate the overall grade 3 or 4 treatment-related adverse event rate for each cohort and compare them to relevant historical controls.

Detailed description:
This is an open-label randomized pilot research study to determine if the study drug, pembrolizumab, is safe to use in combination with a chemotherapy drug called paclitaxel. This study will have the following two regimens: Cohort A) phased regimen of pembrolizumab in which paclitaxel is followed by paclitaxel plus pembrolizumab and Cohort B) concurrent regimen of paclitaxel plus pembrolizumab. A total of 40 evaluable subjects will be enrolled over an enrollment period of 18-24 months. The study is planned to enroll approximately 20 evaluable subjects in each treatment cohort.

Arms: arm 1: Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days. arm 2: Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.
Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel
Intervention descriptions: intervention 1: IV (in the vein) on day 1 of a 21 day cycle intervention 2: IV (in the vein) on days 1 and 8 of a 21 day cycle

Protocol documents:
Prot_SAP_000.pdf: 
Protocol #:  LCI-BRE-H2N-PEPP-001 
TITLE: A PILOT STUDY OF PACLITAXEL PLUS PEMBROLIZUMAB IN PATIENTS WITH 
METASTATIC HER2-NEGATIVE BREAST CANCER (THE PePPy TRIAL) 
LAY TITLE: A STUDY OF PACLITAXEL PLUS PEMBROLIZUMAB IN PATIENTS WITH 
METASTATIC HER2-NEGATIVE BREAST CANCER 
Coordinating Site: 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
Sponsor-Investigator: 
Antoinette R. Tan, MD, MHSc  
Levine Cancer Institute  
1021 Morehead Medical Drive 
Charlotte, NC 28204  
Telephone: (980) 442-6305 
E-mail: antoinette.tan@carolinashealthcare.org 
 
Statistician: 
James Symanowski, PhD  
Levine Cancer Institute  
1100 Blythe Boulevard 
Charlotte, NC 28204 
Telephone: (980) 442-2371  
E-mail: james.symanowski@carolinashealthcare.org  
 
Investigational drug/device: Pembrolizumab 
Commercial agent: Paclitaxel 
Supported by: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc. 
 
Investigational New Drug (IND)#: 132021 
______________________________________________________________________________ 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 


ii 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Sponsor-Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 
 
 
Commercial Agent: Paclitaxel                                 Phase II / Version 5 / 4/13/2021 
PROTOCOL SUMMARY 
A. Study Title 
A Pilot Study of Paclitaxel plus Pembrolizumab in Patients with Metastatic 
HER2-negative Breast Cancer (The PePPy Trial) 
B. Indication 
Metastatic HER2-negative breast cancer; no more than three prior lines of 
cytotoxic chemotherapy for metastatic disease 
C. Clinical Phase Phase II  
 
D. Summary of 
Rationale 
 
 
Pembrolizumab is a potent and highly selective humanized monoclonal 
antibody designed to directly block the interaction between PD-1 (programmed 
death-1) and its ligands, PD-L1 and PD-L2. A strategy of combining 
chemotherapy with immunotherapy is a promising approach for treatment of 
HER2-negative breast cancer. There is little known about the optimal sequence 
of administration of chemotherapy and immunotherapy in breast cancer. This 
study will evaluate the safety of a phased regimen, paclitaxel only for 2 cycles 
then pembrolizumab and paclitaxel, and a concurrent regimen, 
pembrolizumab given concurrently with paclitaxel upfront.  
E. Study 
Objectives 
The primary objective of this study is to assess the safety and feasibility of the 
two regimens. 
 
Secondary objectives are to assess overall survival (OS), progression-free 
survival (PFS), objective response rate (ORR), duration of response (DoR), and 
disease control rate (DCR).   
 
Exploratory objectives include assessment of PD-L1 status and genomic profile 
of tumors. 
F. Sample 
40 evaluable subjects 
G. Inclusion/ 
Exclusion 
Inclusion: 
• HER2-negative metastatic breast cancer 


iii 
 
• Age ≥ 18 years  
• ECOG ≤ 2 
• Measurable or evaluable disease  
• Adequate organ and bone marrow function 
 
Exclusion: 
• More than three prior lines of chemotherapy for metastatic disease 
• Pregnant and/or breastfeeding 
• Prior therapy with anti PD-1m, anti PD-L1, anti PD-L2, or other co-
inhibitory T-cell receptor agent 
 
H. Dosage/ 
Dosage 
Form, Route, 
And Dose 
Regimen 
Pembrolizumab 200 mg IV over 30 minutes, on day 1 every 21  days  
Paclitaxel 80 mg/m2 IV over 60 minutes, on days 1 and 8 every 21 days  
 
 
 


iv 
 
SCHEMA 
LCI-BRE-H2N-PEPP-001: A Pilot Study of Paclitaxel Plus Pembrolizumab in Patients with 
Metastatic HER2-Negative Breast Cancer (The PePPY Trial) 
Sponsor-Investigator: Dr. Antoinette Tan 
 


v 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Spelled out abbreviation. Listed in alphabetical order. 
AST 
Aspartate aminotransferase 
ALT 
Alanine aminotransferase 
BRAF 
B-Raf proto-oncogene 
CTCAE 
Common terminology criteria for adverse events 
CTLA-4 
Cytotoxic T-lymphocyte associated protein 4 
CrCL 
Creatinine clearance 
CNS 
Central nervous system 
CTMS 
Clinical trials management system 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECIs 
Events of clinical interest 
eCRFs 
Electronic case report forms 
ER 
Estrogen receptor 
GFR 
Glomerular filtration rate 
HER2 
Human epidermal growth factor receptor type 2 
HIV 
Human immunodeficiency virus 
Ig 
Immunoglobulin 
ITSM 
Immunoreceptor tyrosine-based switch motif 
IV 
Intravenous 
LCI 
Levine Cancer Institute 
mAb 
Monoclonal antibody 
MBC 
Metastatic breast cancer 
MTD 
Maximum tolerated dose 
NE 
Not evaluable 


vi 
 
 
 
 
 
 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PD-1 
Programmed death 1 
PD-L1 
Programmed death ligand 1 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
PO 
By mouth; taken orally 
PR 
Progesterone receptor 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
RECIST 
Response evaluation criteria in solid tumors 
SCLC 
Small cell lung cancer 
SHP-1, SHP-2 
Src-Homology 2 domain containing phosphatase-1 and -2 
TAMs 
Tissue associated macrophages 
TILs 
Tissue infiltrating lymphocyte 
TNBC 
Triple-negative breast cancer 
Tregs 
Regulatory T cells 
ULN 
Upper limit of normal 
v-type 
Variable-type 
WOCBP 
Women of childbearing potential 


vii 
 
TABLE OF CONTENTS 
 
PROTOCOL SUMMARY ........................................................................................................... ii 
SCHEMA ...................................................................................................................................... iv 
LIST OF ABBREVIATIONS ..................................................................................................... v 
TABLE OF CONTENTS .......................................................................................................... vii 
1. 
OBJECTIVES .................................................................................................................... 1 
1.1. 
Primary Objective ............................................................................................................ 1 
1.2. 
Secondary Objectives ....................................................................................................... 1 
1.3. 
Safety Objectives.............................................................................................................. 1 
1.4. 
Exploratory Objectives ..................................................................................................... 1 
2. 
BACKGROUND AND RATIONALE ............................................................................. 1 
2.1. 
Metastatic HER2-negative Breast Cancer ........................................................................ 1 
2.2. 
Taxanes in Breast Cancer ................................................................................................. 2 
2.3. 
Programmed Death-1 (PD-1) Checkpoint Inhibitor as a Strategy for Treatment of Breast 
Cancer.......................................................................................................................................... 3 
2.4. 
Pembrolizumab................................................................................................................. 4 
2.5. 
Chemotherapy in Combination with Immunotherapy ...................................................... 8 
2.6. 
Study Rationale .............................................................................................................. 12 
3. 
PATIENT SELECTION ................................................................................................. 12 
3.1.    Accrual ……………………………………………………………………………….. 13 
3.2. 
Inclusion Criteria ............................................................................................................ 13 
3.3. 
Exclusion Criteria ........................................................................................................... 14 
4. 
INVESTIGATIONAL PLAN ......................................................................................... 16 
4.1. 
Milestone Date Definitions ............................................................................................ 16 
4.2.   Overall Study Design …………………………………………………………………. 16 
4.3. 
Randomization/Registration/Enrollment ........................................................................ 17 
4.4. 
Pre-Treatment ................................................................................................................. 17 
4.5. 
Treatment ....................................................................................................................... 24 
4.6. 
End of Treatment ............................................................................................................ 25 


viii 
 
4.7. 
Follow-up ....................................................................................................................... 26 
4.8. 
Subject Withdrawal and Off Study ................................................................................ 26 
4.9. 
Screen Failures/Subject Replacements........................................................................... 27 
5. 
STUDY CALENDAR ...................................................................................................... 28 
6. 
TREATMENT PLAN ...................................................................................................... 30 
6.1. 
Drug Dosage and Administration ................................................................................... 30 
6.2. 
Paclitaxel ........................................................................................................................ 30 
6.3. 
Pembrolizumab............................................................................................................... 33 
6.4. 
Treatment Administration .............................................................................................. 33 
6.5. 
Concomitant Medications .............................................................................................. 33 
6.6. 
Duration of Therapy ....................................................................................................... 33 
6.7. 
Drug Accountability ....................................................................................................... 34 
6.8. 
Destruction ..................................................................................................................... 33 
7. 
DOSE MODIFICATIONS .............................................................................................. 34 
7.1. 
Pembrolizumab............................................................................................................... 34 
7.2. 
Paclitaxel ........................................................................................................................ 36 
8. 
TREATMENT-RELATED ADVERSE EVENTS ........................................................ 38 
8.1. 
Adverse Events Related to Pembrolizumab ................................................................... 38 
9. 
DATA AND SAFETY MONITORING PLAN ............................................................. 44 
9.1. 
Safety Monitoring .......................................................................................................... 44 
9.2. 
Data Quality Assurance .................................................................................................. 44 
9.3. 
Communication Between Sites ...................................................................................... 45 
10. 
SAFETY DATA COLLECTION, RECORDING AND REPORTING...................... 45 
10.1. Unanticipated Problem Definition ................................................................................. 45 
10.2. Adverse Event ................................................................................................................ 45 
10.3. Suspected Adverse Reaction Definition ......................................................................... 47 
10.4. “Unexpected” Definition ................................................................................................ 47 
10.5. “Serious” and “Life-Threatening” Definitions ............................................................... 47 
10.6. Serious Adverse Event Definition .................................................................................. 48 
10.7. Safety Reporting to the Sponsor-Investigator ................................................................ 48 


ix 
 
10.8. Safety Reporting to the FDA .......................................................................................... 49 
10.9. Safety Reporting to the IRB ........................................................................................... 49 
10.10.  Safety Reporting to Merck……………………………………………………………..49 
11. 
MEASUREMENT OF EFFECT .................................................................................... 50 
11.1. Anti-tumor Effect – Solid Tumor ................................................................................... 50 
12. 
STATISTICAL CONSIDERATIONS ........................................................................... 55 
12.1. Sample Size .................................................................................................................... 55 
12.2. Endpoint Definitions ...................................................................................................... 55 
12.3. Analysis Populations ...................................................................................................... 57 
12.4. Analysis Methods ........................................................................................................... 57 
12.5. Interim Analyses ............................................................................................................ 59 
13. 
STUDY COMPLETION ................................................................................................. 59 
13.1. Completion ..................................................................................................................... 59 
13.2. Termination .................................................................................................................... 60 
14. 
RETENTION OF RECORDS ........................................................................................ 60 
15. 
ETHICAL AND LEGAL ISSUES .................................................................................. 60 
15.1. Ethical and Legal Conduct of the Study......................................................................... 60 
15.2. Confidentiality ................................................................................................................ 61 
16. 
PUBLICATION POLICY ............................................................................................... 61 
REFERENCES ............................................................................................................................ 62 
APPENDICES ............................................................................................................................. 30 
 


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1. OBJECTIVES 
 
1.1. 
Primary Objective 
The primary objective of this study is to assess the safety and feasibility of the following two 
regimens: Cohort A) phased regimen of pembrolizumab in which paclitaxel is followed by 
paclitaxel plus pembrolizumab and Cohort B) concurrent regimen of paclitaxel plus 
pembrolizumab.  The primary safety objective is to evaluate the overall grade 3 or 4 
treatment-related adverse event rate for each cohort and compare them to relevant historical 
controls. 
 
1.2. 
Secondary Objectives 
Secondary objectives are to assess overall survival (OS), progression-free survival (PFS), 
objective response rate (ORR) duration of response (DoR), and disease control rate (DCR).  
PFS, ORR, DoR, and DCR will be evaluated using RECIST 1.1 criteria.    
 
1.3. 
Safety Objectives 
The safety objectives are to evaluate each cohort in terms of study drug administration, 
adverse events assessed by NCI Common Terminology Criteria for Adverse Events version 
4.0, serious adverse events including deaths on study, and laboratory parameters. 
 
1.4. 
Exploratory Objectives 
Exploratory objectives include 
• Assessment of PFS, ORR, DoR, and DCR using the immune-related RECIST 
(irRECIST) criteria 
• Assessment of tumor-associated PD-L1 (programmed death-ligand 1) 
expression  
• Assessment of tissue infiltrating lymphocytes (TILs) in tumor 
• Genomic analyses of the tumor 
• Evaluation of circulating tumor DNA 
• Collection of biomarkers in blood, including but not limited to cytokines 
• Development of a patient derived xenograft model if sufficient tumor is 
available 
 
2. BACKGROUND AND RATIONALE 
 
2.1. 
Metastatic HER2-negative Breast Cancer 


Protocol Number:  LCI-BRE-H2N-PEPP-001 
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An estimated 231,840 new cases of breast cancer are expected to be diagnosed in the United 
States during 2015 and it is estimated that there will be 40,730 deaths from breast cancer.1  
Single agent or combination chemotherapy produces response rates of 40-70% in the 
treatment of advanced breast cancer.  Although numerous regimens are effective in palliating 
symptoms and inducing tumor regression, the complete response rate is less than 20%.  
Moreover, the median duration of response is nine months with a median survival of 12-36 
months.  Most responses are of limited duration and nearly all patients with stage IV disease 
eventually die of disease progression.  Therefore, the treatment of patients with metastatic 
human epidermal growth factor receptor type 2 (HER2)-negative breast cancer warrants 
investigation of novel therapeutic strategies. 
The treatment algorithm for patients with metastatic breast cancer (MBC) is based on several 
factors which include clinical, pathologic, and histologic characteristics such as the presence 
or absence of human epidermal growth factor 2 amplification, hormone receptor status, prior 
response to endocrine therapy, disease extent and location of metastatic disease, pace of 
disease progression, and time to relapse since completion of adjuvant chemotherapy. While 
endocrine therapy is the preferred initial treatment for patients with hormone receptor-
positive disease, cytotoxic chemotherapy becomes appropriate for those with hormone 
refractory disease or rapidly progressive disease to achieve a rapid rate of response. For 
patients with triple-negative breast cancer, or breast cancer that is estrogen receptor (ER)- 
negative, progesterone receptor (PR)-negative, and HER2-negative, chemotherapy at present 
is the mainstay of treatment.  
 
2.2. 
Taxanes in Breast Cancer 
Taxanes are among the most active of chemotherapy agents for the treatment of MBC in 
terms of response rates or survival, based on a metaanalysis of three randomized trials 
comparing a taxane- with an anthracycline.2  The role of paclitaxel in the treatment of breast 
cancer has been well established in both the adjuvant and metastatic settings.  The response 
rates for paclitaxel administered as a single agent to patients with MBC are approximately 
25% in firstline- treatment.3,4 
 
The most common practice is to administer paclitaxel on a weekly schedule based on the 
results of a 2010 meta-analysis, which showed that compared with every three-week 
treatment, weekly administration of paclitaxel resulted in an improvement in overall survival 
(OS, hazard ratio [HR] 0.78, 95% CI 0.67-0.89).6  Allergic reactions are a potential side 
effect of treatment with paclitaxel as a result of the composition of paclitaxel, which is mixed 
with Cremophor. At most institutions, steroid premedication (IV dexamethasone 8-12 mg 30 
minutes prior to the paclitaxel dose) is administered, although it can usually be discontinued 
if the first two or three doses are tolerated.  


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2.3. 
Programmed Death-1 (PD-1) Checkpoint Inhibitor as a Strategy for Treatment 
of Breast Cancer 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing Tcell- responses against cancer can result 
in a significant survival benefit in patients with advanced malignancies.7-9 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.10 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 is an immunoglobulin (Ig) superfamily 
member related to CD28 and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), 
which has been shown to negatively regulate antigen receptor signaling upon engagement of 
its ligands (PD-L1 and/or PD-L2). 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. 
Following T cell stimulation, PD-1 recruits the tyrosine phosphatases Src-Homology 2 
domain-containing phosphatase-1 and -2 (SHP-1 and SHP-2) to the ITSM within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules, such as CD3ζ, 
Protein Kinase C theta (PKCθ) and Zeta-chain-Associated Protein kinase 70 (ZAP70), which 
are involved in the -Homology 2 domain-containing phosphatase-1 and -2 (SHP-1 and SHP-
2) to the ITSM within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules, such as CD3ζ, Protein Kinase C theta (PKCθ) and Zeta-chain-Associated Protein 
kinase 70 (ZAP70), which are involved in the CD3 T cell signaling cascade. PD-1 was 
shown to be expressed on activated lymphocytes, including peripheral CD4+ and CD8+ T 
cells, B cells, regulatory T cells (Tregs) and Natural Killer (NK) cells.12 CD3 T cell signaling 
cascade. PD-1 was shown to be expressed on activated lymphocytes, including peripheral 
CD4+ and CD8+ T cells, B cells, regulatory T cells (Tregs) and Natural Killer (NK) cells.  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types. 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.13   
Binding of either PD-1 ligand to PD-1 inhibits T cell activation triggered through the T cell 
receptor. PD-L2 is thought to control immune T cell activation in lymphoid organs, whereas 
PD-L1 serves to dampen unwarranted T cell function in peripheral tissues.  Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T cell inhibitor, which, via its interaction with the PD-1 receptor on 


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tumor-specific T cells, plays a critical role in immune evasion by tumors.14 As a 
consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in 
cancer.15 
The immune system plays an important and complex role in the biology of breast cancer.  
There is preclinical and clinical evidence suggesting that immunotherapy has the potential to 
improve clinical outcomes for patients with breast cancer. Immune modulatory agents have 
several unique features that make them attractive to combine with standard cytotoxic agents, 
and includes the observation that cancer immunotherapies cause fewer side effects, enabling 
them to be given for longer periods of time and in combination with other agents without 
added toxicity.  There also is potentially less likelihood to develop resistance to 
immunotherapy because of the immune system’s ability to simultaneously target multiple 
cancer antigens and adapt to mutating cancer cells.  
 
2.4. 
Pembrolizumab 
Pembrolizumab (Keytruda®) 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.  This blockade enhances functional activity of the target 
lymphocytes to facilitate tumor regression and ultimately immune rejection. 
 
2.4.1. Nonclinical Studies  
The nonclinical strategy of the pembrolizumab program was to demonstrate in vitro and 
in vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an 
acceptable safety profile, and to identify a Phase I starting dose.  Comprehensive 
pharmacology, PK, and toxicology evaluations were thus undertaken with 
pembrolizumab. 
The safety, pharmacokinetics, and toxicokinetics of pembrolizumab were investigated in 
mice and cynomolgus monkeys to support IV administration and to aid in projecting the 
appropriate starting dose in humans.  Given the high amino acid homology of the 
extracellular regions of PD-1 between cynomolgus monkey and human, the cynomolgus 
monkey was selected as the primary and relevant nonclinical model for understanding the 
toxicology of pembrolizumab. 
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for 
pembrolizumab supported entry into clinical studies, including providing adequate safety 
factors for the proposed Phase I starting doses.  The results of the preclinical program 
were consistent with the anticipated activity of pembrolizumab to enhance the functional 
activity of tumor-infiltrating lymphocytes to induce tumor regression and ultimately 
immune rejection by blocking the interaction between PD-1 and its ligands, PD-L1 and 


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PD-L2 and supported entry into clinical trials in patients. Refer to the pembrolizumab 
Investigator’s Brochure for details on the nonclinical studies.16 
 
2.4.2. Clinical Studies – Approval of Pembrolizumab 
Pembrolizumab was approved in the United States on September 4, 2014 by the FDA for 
the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. This indication is approved under accelerated approval based on tumor 
response rate and durability of response.  
Approval was based on the results of a multicenter, open-label, randomized (1:1), dose-
comparative, activity-estimating cohort conducted within Trial PN001, which was the 
first-in human dose cohort escalation study of pembrolizumab that enrolled subjects into 
4 parts (Parts A-D, A = any advanced solid tumor, B = melanoma, C =  NSCLC, and D = 
melanoma, 2 doses of pembrolizumab). 
 
In this cohort, 173 patients with unresectable or metastatic melanoma with disease 
progression within 24 weeks of the last dose of ipilimumab and, if BRAF V600 mutation 
positive, prior treatment with a BRAF inhibitor, were randomized to receive 
pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84) intravenously once every 3 weeks 
until disease progression or unacceptable toxicity. 
  
Key exclusion criteria were an autoimmune disease, a medical condition that required 
immunosuppression, and/or a history of severe immune-mediated adverse reactions from 
treatment with ipilimumab.  Severe immune-mediated adverse reactions were defined as 
any CTCAE Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity 
requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) 
for greater than 12 weeks. 
 
The major efficacy endpoints were confirmed objective response rate (ORR) according to 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as assessed by a blinded 
independent review committee and duration of response (DOR).  In the lower dose that 
was ultimately approved, 2 mg/kg, the ORR was 26% (95% CI, 17-37%). A total of 21 
patients showed a response, including one patient with a complete response. Three of the 
patients (14%) had disease progression at 2.8 months, 2.9 months, and 8.2 months after 
the initial response. The other 18 patients (86%) showed durable responses of 1.4 to 8.5 
months. Of note, eight patients (38%) had ongoing responses of ≥ 6 months. Similar 
ORR results were observed in the 10 mg/kg arm.17 Treatment was well tolerated, with 
similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. 
The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg 
groups were fatigue (33% vs 37%), pruritus (26% vs 19%), and rash (18% vs 18%). 
Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was 
the only drug-related grade 3 to 4 adverse event reported in more than one patient.  
 


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Additionally, two multicenter, randomized, controlled therapeutic confirmatory trials in 
patients with unresectable or metastatic melanoma, ipilimumab refractory (KEYNOTE-
002/Trial P002) and ipilimumab-naive (KEYNOTE-006/Trial P006), evaluated co-
primary endpoints of progression-free survival and overall survival, and have results.   
 
In the KEYNOTE-002 trial, 540 patients with ipilimumab-refractory advanced melanoma 
were randomly assigned to pembrolizumab at 2 mg/kg (n = 180), 10 mg/kg (n = 181), or 
chemotherapy (n = 179).18  Chemotherapy was selected by investigators and consisted 
primarily of paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or 
temozolomide. Pembrolizumab was administered every 3 weeks. Both pembrolizumab 
arms were significantly superior to chemotherapy (P <.0001). At the recommended 2-
mg/kg dose, pembrolizumab demonstrated a PFS of 34% at 6 months and 24% at 9 
months. In the chemotherapy arm, the PFS was 16% and 8%, at the 6- and 9-month 
analyses, respectively. 
 
At the 2-mg/kg dose, the ORR with pembrolizumab was 21% with a median duration of 
response that was not yet reached. The ORR in the chemotherapy arm was 4%, the 
median response duration was 37 weeks. At the analysis, 63% of responses were 
ongoing. Treatment was relatively well tolerated, with grade 3-5 adverse events reported 
in 11 and 14 percent of the pembrolizumab treatment arms, and 26 percent of those 
managed with chemotherapy. The most common pembrolizumab-related adverse events 
were fatigue, pruritus, and rash. Grade 3 immune related toxicity was reported in two 
patients treated with pembrolizumab 2 mg/kg (hepatitis, hypophysitis), and in eight 
patients given pembrolizumab 10 mg/kg (hepatitis, colitis, pneumonitis, and iritis or 
uveitis). 
 
In the phase III KEYNOTE-006 trial, pembrolizumab demonstrated significantly longer 
PFS and improved overall survival compared with ipilimumab as immunotherapy in 
patients with advanced melanoma.19 This trial included 834 patients with unresectable 
stage III or IV advanced melanoma who had received no more than one prior systemic 
therapy. Patients were randomized to receive four cycles of ipilimumab at 3 mg/kg every 
3 weeks (n = 278), 10 mg/kg of pembrolizumab every 3 weeks (n = 277), or 10 mg/kg of 
pembrolizumab every 2 weeks (n = 279). Patient response in KEYNOTE-006 was 
assessed at week 12 and every 6 weeks thereafter by RECIST 1.1. Median follow-up was 
8 months. Both doses of pembrolizumab were found to be superior to ipilimumab. At a 6-
month assessment, the PFS with pembrolizumab was 47% and 46% in the 2- and 3-week 
arms respectively. For ipilimumab, the PFS rate was 27%. At 9 months, PFS rates were 
40% and 42% compared with 16%, in the 2-week, 3-week, and ipilimumab arms, 
respectively. In the 3-week pembrolizumab arm, the 1-year OS rate was 68% compared 
with 58% for ipilimumab (HR, 0.69). In the 2-week arm, the 1-year OS rate was 74% 
(HR, 0.63). The objective response rates (ORR) were 33.7% and 32.9%, in the 2- and 3-
week arms. In the ipilimumab arm, the ORR was 11.9%. The toxicity profiles of the 
agents were consistent with other reported studies of the two checkpoint agents. Though 
pembrolizumab was administered for a longer duration, rates of grade 3-5 adverse events 
were numerically lower than in the ipilimumab arm (11.7% vs 19.9%).There were no 
differences in efficacy parameters in any patient subsets, with the exception of a lack of 


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improvement in overall survival associated with pembrolizumab in those patients whose 
tumors did not express PD-L1 using the Merck immunohistochemistry assay. The PFS, 
overall survival, response rates, and side effects profiles were fully consistent with those 
seen in earlier trials with both pembrolizumab and ipilimumab.  
 
These trials demonstrate the efficacy of pembrolizumab in the treatment of advanced 
melanoma. Ongoing clinical studies are being conducted in a number of other advanced 
solid tumor indications, including breast cancer.  
 
2.4.3. Clinical Studies in Breast Cancer with Pembrolizumab 
In the first report of clinical activity of an immune checkpoint inhibitor in metastatic 
breast cancer, a multi-center, non-randomized phase Ib trial (Keynote 012) showed that 
single-agent pembrolizumab given at 10 mg/kg Q2W is a well-tolerated and effective 
treatment with significant therapeutic activity in a subset of heavily pre-treated patients 
with metastatic triple-negative breast cancer (TNBC) 20.  
 
The phase Ib study enrolled 32 patients with TNBC who had recurrent or metastatic 
disease (47% of which had more than three lines of previous chemotherapy) with PD-L1 
expression in their tumor (58% of all patients screened had PD-L1- positive tumors.). 
Pembrolizumab was administered 10 mg/kg intravenously every 2 weeks, and treatment 
could continue indefinitely as long as patients were stable and their disease was not 
clearly progressing as assessed by RECIST v1.1 every 8 weeks. Treatment with PD-1 
blockade was tolerable, with 56% of patients reporting an adverse event, but only 16% 
with grade 3–5 toxicity. There was one treatment-related death caused by disseminated 
intravascular coagulation. The ORR was 19% (27 patients were evaluable for response) 
with one (4%) complete response, four (15%) partial responses, and seven patients (26%) 
with stable disease. Of note, the median time to response was 18 weeks (range, 7 to 32). 
 
There is an international, multi-center phase II clinical trial of pembrolizumab as 
monotherapy that is currently enrolling patients with metastatic triple-negative breast 
cancer (Keynote 086; NCT02447003).  The results of this trial and others that are 
evaluating checkpoint inhibitors in the treatment of metastatic breast cancer will help 
further the clinical development of immunotherapeutic agents in this breast cancer 
subtype.  
 
2.4.4. Rationale for Flat Dosing of Pembrolizumab  
An open-label Phase I trial (Protocol 001) has been conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab.  The dose escalation portion of that 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 


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pembrolizumab 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.  Recent data from other clinical studies within the pembrolizumab 
program has shown that a lower dose of pembrolizumab and a less frequent schedule may 
be sufficient for target engagement and clinical activity. The currently approved dose of 
pembrolizumab is 2 mg/kg IV over 30 minutes every 3 weeks.  
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life16.  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 evaluating a 
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 pembrolizumab 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.  Pembrolizumab 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 pembrolizumab 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 the NSCLC and 
melanoma indications. Therefore, we do not anticipate changes in exposure between 
different indication settings. 
 
The choice of the 200 mg Q3W dose of pembrolizumab (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 patient’s exposure in the 
exposure range established in melanoma that are well tolerated and safe.  
 


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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. 
 
2.5. Chemotherapy in Combination with Immunotherapy 
Although standard-dose chemotherapy was conventionally thought to suppress the immune 
system directly by decreasing lymphocyte numbers and limiting the expansion of activated 
lymphocytes, it has been demonstrated that chemotherapy also has the capacity to be 
leveraged effectively to potentially augment cancer immunity in several ways. For example, 
chemotherapy can decrease tumor burden, generate immunogenic cell death and can interrupt 
mechanisms of immune tolerance.21 
 
Paclitaxel is a common first-line regimen for the treatment of metastatic HER2-negative 
metastatic breast cancer.22  Paclitaxel therapy has been shown to increase tumor-associated 
macrophages (TAMs) infiltration in breast tumors.23  Paclitaxel has also been shown to 
upregulate PD-L1 expression in breast cancer cells, contributing to immune resistance.24  
Combining pembrolizumab, a human monoclonal immunoglobulin G4 antibody which binds 
to PD-1, with paclitaxel in HER2-negative breast cancer could be synergistic and potentiate 
the effect of chemotherapy via an anti-tumor immune response. In designing combination 
immunotherapy regimens, consideration needs to be given with regards to how chemotherapy 
impacts the immune system in order to guide the dose and schedule for combining 
chemotherapy and immunotherapy. The optimal drug dose and timing in relation to immune-
based therapy in early-phase clinical studies is necessary to help inform the design of future 
phase II and III clinical trials. 
 
The cytotoxic effects of paclitaxel are driven primarily by disturbing the microtubule 
dynamics and inducing apoptosis. In addition to the cytotoxic effect on tumor cells, 
paclitaxel has been reported to modulate the host immune system in a number of ways.21 
Regulatory T cells, which down-regulate immune effector activity, have been shown to be 
increased in the peripheral blood of patients with pancreatic, lung and breast cancer, 
potentially suppressing an anti-tumor response.25 
 
Paclitaxel therapy has demonstrated the ability to induce apoptosis and impair these T 
regulatory cells (potential drivers of peripheral tolerance) preferentially, but not effector T 
cells (potential drivers or effectors of tumor-cell killing), which could potentially shift the 
balance to anti-tumor immune activation. In addition, immune activation in lung cancer 
patients after paclitaxel treatment was reported and the generation of pro-inflammatory 
cytokines IFN- and IL-2, as well as the expression of T-cell activation markers was 
increased in lung cancer patients after paclitaxel treatment.24 


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Consistent with this observation, paclitaxel has been shown to also induce macrophage 
activation and release of inflammatory cytokines in mouse models.26 The perpetuation of an 
effective anti-tumor response requires a predominantly effector T-cell activation and further 
expansion, as well as pro-inflammatory cytokine release, which supports cytotoxic T-cell 
activation and a potential anti-tumor effect. This immune activation process may be 
subsequently attenuated and reversed by PD-1 expression on activated T cells and the PD-L1 
on tumors, conversely supporting T regulation and suppressing and eliminating cytotoxic T 
effectors. In fact, paclitaxel has also been show to upregulate PD-L1 expression, ultimately 
reversing its potential tumor immune activation.24 PD-1 expression is induced when T cells 
are activated.27 An important role of PD-1 is to limit T cell effector activation and enhance T 
regulatory mechanisms.28 
 
Pembrolizumab blocks the binding of PD-1 expressed on immune cells to its ligand (PD-L1) 
expressed in tumors, blocking of which potentially reverses down-regulation of cellular 
immunity to the tumor. Pembrolizumab has demonstrated promising anti-tumor activity in a 
variety of tumors, including known immunogenic tumors (i.e. melanoma), as well as tumors 
previously considered less immunogenic (i.e., NSCLC).  Chemotherapy in combination with 
anti-PD-1 has demonstrated enhanced activity against several mouse tumor models 
(Pembrolizumab IB) and clinical results support this combination approach.29  
 
When combining immunotherapy with chemotherapy, it is important to determine the 
optimal dose, schedule and sequence. There is some data on the optimal timing and dose of 
immunotherapy with chemotherapy. Results from two multicenter phase II lung cancer trials 
showed that a “phased regimen” in which immunotherapy begins after chemotherapy 
resulted in improved progression-free survival, compared with chemotherapy alone.  
 
Combining ipilimumab with paclitaxel and carboplatin, significantly improved immune-
related progression-free survival (irPFS) compared with chemotherapy alone in a phase II 
study in patients with NSCLC and extensive disease SCLC.29,30 However, the improvement 
in irPFS was only evident when the drugs were given on a phased schedule (e.g., two doses 
of placebo plus paclitaxel/carboplatin followed by four doses of ipilimumab plus 
paclitaxel/carboplatin), not when they were given concurrently. Phased ipilimumab, 
concurrent ipilimumab, and control, respectively, were associated with median irPFS of 5.7, 
5.5, and 4.6 months in patients with NSCLC, and 6.4, 5.7, and 5.3 months in patients with 
SCLC. The overall incidence of treatment-related grade 3/4 adverse events was similar 
across the arms, and ipilimumab did not appear to exacerbate the adverse events associated 
with chemotherapy. 
 


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There is no data with regards to the sequencing of pembrolizumab in relation to 
chemotherapy in the treatment of breast cancer. This pilot study will primarily assess the 
safety of dose and dosing schedule of pembrolizumab with the specific chemotherapy agent, 
paclitaxel. The tolerability will be assessed and the anti-tumor activity of two dosing 
schedules will be explored. Biomarkers studies to assess immune effects will also be 
included.  Two schedules will be explored. In Cohort A (phased), two cycles of paclitaxel 
followed by paclitaxel and pembrolizumab with the rationale that giving paclitaxel before 
pembrolizumab, will allow antigen release to occur, provide an initial tumor response, debulk 
the tumor, change the tumor’s immune microenvironment, and enhance pembrolizumab’s 
effect. For the exploratory comparison of Cohort B (concurrent), paclitaxel in combination 
with pembrolizumab starting at cycle 1 will be assessed, allowing pembrolizumab to be 
present at the earliest phase of chemotherapy-induced antigen release, and a schedule that is 
consistent with several treatment schedules already reported in ongoing trials with other 
cytotoxic therapy.  
 
2.5.1. Immunotherapy and Steroids 
Corticosteroids have nonspecific anti-inflammatory activity and can attenuate 
immunity.31 In general, minimal steroid exposure is preferred when being treated with 
immunotherapy. Corticosteroid premedications are administered before paclitaxel to 
decrease the hypersensitivity reactions that can occur, possibly a reaction to the vehicle 
Cremophor EL, a derivative of castor oil. Grade 2 or higher hypersensitivity reactions 
have been reported to occur at an incidence of less than 3% with weekly paclitaxel at 80 
mg/m2 given as a 1-hour infusion.32 An 8 to 12 mg dose of IV dexamethasone pre-
medication given 30 to 60 minutes prior to paclitaxel is a typical dose given to reduce the 
incidence and severity of reactions.33  
 
Infusion hypersensitivity reactions beyond the second dose are not common.  A 
retrospective study evaluated 449 patients receiving paclitaxel-based chemotherapy for 
the treatment of breast cancer during January 2011 to June 2013. After receiving the first 
two doses of paclitaxel-based chemotherapy without experiencing an infusion 
hypersensitivity reaction, 234 breast cancer patients had their premedications 
discontinued for all remaining paclitaxel doses. These patients tolerated future paclitaxel 
doses without severe or life-threatening complications related to infusion 
hypersensitivity. The majority of patients did not have any symptoms of an infusion 
reaction, with only two of these patients requiring rescue medication to treat an infusion 
hypersensitivity reaction with subsequent paclitaxel doses (0.85; 95 % confidence 
interval (CI), 0.10-3.05 %). Discontinuation of paclitaxel premedications in breast cancer 
patients who have not experienced an infusion hypersensitivity reaction with the first two 
doses of paclitaxel is not associated with increased rate of rescue medication use for 
infusion hypersensitivity.34 


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To reduce prolonged corticosteroid exposure in this trial where immunotherapy is being 
combined with paclitaxel, it would be reasonable to taper the steroids after the first cycle 
of chemotherapy. In this trial, dexamethasone 8 mg IV will be given 30 to 60 minutes 
before each paclitaxel administration during cycle 1. If tolerated, dexamethasone should 
then be tapered to 4 mg at Cycle 2 and discontinued at Cycle 3 for subsequent 
infusions.35 In the event of a future infusion reaction, steroid pre-medication can be added 
back into the regimen as clinically indicated. 
 
2.6. Study Rationale 
The optimal chemotherapy schedule, dose and timing of combination or sequence with 
pembrolizumab have not been clearly elucidated. Weekly paclitaxel is a mainstay for the 
adjuvant and neoadjuvant treatment of breast cancer.  Combining pembrolizumab with 
paclitaxel in the treatment of HER2-negative metastatic breast cancer could demonstrate 
synergy and potentiate the effect of chemotherapy by unleashing an anti-tumor immune 
response. 
 
This study will assess the feasibility and safety of phased vs concurrent dosing sequences of 
pembrolizumab with the combination of standard paclitaxel chemotherapy. It is important to 
determine the dosing, safety, and feasibility of giving weekly paclitaxel and pembrolizumab 
so that future trials may test the activity of this two-drug regimen in patients with early-stage 
and/or locally advanced breast cancer. 
 
2.6.1. Safety Endpoints 
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab and paclitaxel (phased vs concurrent) in subjects with HER2-negative 
metastatic breast cancer.  The primary safety analysis will be based on subjects who 
experienced toxicities as defined by CTCAE, Version 4.0 criteria. The attribution to 
study drug(s), time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded.  AEs will be analyzed including but not 
limited to all AEs, SAEs, fatal AEs, and laboratory changes. 
 
2.6.2. Rationale for Use of irRECIST Criteria 
Immunotherapeutic agents may produce antitumor effects by potentiating endogenous 
cancer-specific immune responses, which may be functionally anergic prior to treatment. 
The response patterns seen with such an approach may extend beyond the typical time 
course of responses seen with cytotoxic agents, and can manifest as a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions (transient 
tumor flare). Thus, standard RECIST criteria may not provide a complete response 


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assessment of immunotherapeutic agents, such as pembrolizumab.  To address this issue, 
RECIST 1.1 with the adaptation outlined in Table 10, termed irRECIST, will also be used 
after the subject’s first administration of pembrolizumab. 
 
3. PATIENT SELECTION 
 
3.1. Accrual 
A total of 40 evaluable subjects will be enrolled over an enrollment period of up to 36 
months. The study is planned to enroll approximately 20 evaluable subjects in each study 
treatment cohort. Evaluable subjects are those who are randomized and begin study therapy.  
Patients will be recruited through Levine Cancer Institute locations and through referrals. 
Women or men of any race or ethnic origin who meet the study criteria may participate in 
this clinical trial. Children are not included in this clinical trial because the effects of 
pembrolizumab are not known in the pediatric population, but may be eligible for other 
pediatric trials. 
 
3.2. Inclusion Criteria 
Subjects must meet all of the following criteria: 
1. Histologically or cytological confirmed diagnosis of HER2-negative metastatic breast 
cancer or locally advanced disease not amenable to resection.  
o Available ER and PR status from tumor sample with either hormone receptor 
positive or negative tumor(s). 
o For subjects with hormone receptor-positive, HER2-negative metastatic breast 
cancer, they are eligible if they have already received or been intolerant to at 
least two lines of endocrine therapies (including the adjuvant and/or metastatic 
setting), or are appropriate candidates for chemotherapy (i.e. large burden of 
visceral disease).  
2. Measurable disease by RECIST 1.1, or evaluable bone disease, i.e., bone lesions that 
are lytic or mixed (i.e. lytic + sclerotic) in the absence of measurable lesion. Refer to 
section 11 for the evaluation of measurable disease.  
3. Male or female age ≥18 years.   
4. ECOG performance status 0, 1 or 2.  
5. Must have normal organ and marrow function as defined below: 
 
o Hematologic 
▪ Absolute neutrophil count ≥1,500/mcL 
▪ Platelets ≥75,000/mcL 
▪ Hemoglobin ≥ 9 g/dL 


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o Renal 
▪ Creatinine ≤ 1.5X ULN or 
▪ Measured or calculated creatinine clearance (CrCl) ≥ 30 mL/min for 
subject with creatinine levels > 1.5X ULN [CrCl should be calculated 
per institutional standard; GFR can also be used in place of creatinine 
or CrCl] 
o Hepatic 
▪ Total bilirubin ≤1.5X ULN or for subjects with total bilirubin levels 
>1.5X ULN, direct bilirubin ≤ULN 
▪ AST(SGOT)/ALT(SGPT) ≤2.5X ULN 
o Coagulation 
▪ PT and PTT ≤ 1.5X ULN; subjects receiving anticoagulant therapy are 
eligible if PT or PTT is within therapeutic range of intended use of 
anticoagulants per investigator discretion. 
▪ INR ≤ 1.5; Patients receiving anticoagulant therapy are eligible if their 
INR is stable and within the recommended range for the desired level 
of anticoagulation per investigator discretion. 
6. Female subjects of childbearing potential must have a negative serum or urine 
pregnancy test within 14 days prior to receiving C1D1.  
7. Female subjects of childbearing potential must be willing to use an adequate method 
of birth control as outlined in Section 8.1.10, be surgically sterile, or abstain from 
heterosexual activity for the course of the study and 120 days after the last dose of 
study therapy.  Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for > 1 year. Male subjects of 
reproductive potential should agree to use an adequate method of contraception 
starting with the first dose of study therapy and 120 days after the last dose of study 
therapy. Abstinence is acceptable if this is the established and preferred contraception 
for the subject. 
8. Has completed the screening requirement of a core or punch biopsy of a tumor lesion 
per Section 5 (bone tissue not acceptable). Biopsy of the breast tumor or other 
regional areas is acceptable (i.e. lymph nodes, skin lesions).  
o Subjects who are unable to meet the screening requirement of a tumor biopsy 
due to inaccessible tumor, subject safety concern, or bone-only disease may 
submit an archived tumor specimen from primary tumor or metastatic biopsy 
collected within 12 months from consent.  
o Subjects who decline tumor biopsy may submit archived tumor specimen as 
specified above (within 12 months from consent) only after Sponsor-
Investigator approval. 
9. Ability to understand and the willingness to sign the written informed consent 
document. 


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3.3. Exclusion Criteria 
Subjects must not meet any of the following criteria: 
1. Prior chemotherapy within 3 weeks, prior targeted small molecule therapy or 
radiation therapy within 2 weeks, or prior anti-cancer monoclonal antibody 
(mAb) for direct anti-neoplastic treatment within 4 weeks prior to Cycle 1 Day 1. 
2. Not recovered (i.e., ≤ Grade 1) from adverse events due to agents previously 
administered. 
o Note: Subjects with ≤ Grade 2 neuropathy or alopecia of any grade 
are an exception and may qualify for the study. 
3. More than three prior lines of chemotherapy for HER2-negative metastatic 
disease or for locally advanced disease that is not amenable to resection.  
o Note: Non-Chemotherapy regimens do not count as prior lines (ex: 
hormonals, biologics) 
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or 
with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, 
OX-40, CD137) or has participated in Merck MK-3475 trial(s) and received MK-
3475 as part of protocol therapy. 
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to Cycle 1 Day 
1 
6. Has had major surgery within 3 weeks prior to Cycle 1 Day 1. 
7. Has received any other investigational agents within 4 weeks of Cycle 1 Day 1 of 
study therapy. 
8. Known active uncontrolled or symptomatic central nervous system (CNS) 
metastases and/or carcinomatous meningitis as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth.  
o Note: Subjects with treated CNS metastases are eligible if they are 
asymptomatic, have no requirement for steroids, no requirement for 
anticonvulsants, and stable CNS radiographic study showing no significant 
vasogenic edema ≥ 4 weeks since completion of radiation and ≥ 2 weeks since 
discontinuation of steroids. 
9. History of known allergic reaction to paclitaxel  
10. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator. 


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11. Is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit through 120 
days after the last dose of study treatment. Pregnant women are excluded from 
this study because paclitaxel is an agent with the potential for teratogenic or 
abortifacient effects.  Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with paclitaxel, 
breastfeeding should be discontinued if the mother is treated with paclitaxel.  
These potential risks also apply to pembrolizumab being used in this study. 
12. Has a known history of Human Immunodeficiency Virus (HIV) or known 
acquired immunodeficiency disorder (AIDS). HIV-positive patients on 
combination antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interactions with paclitaxel and pembrolizumab.  In addition, 
these patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy.  
13. Has known active infection with hepatitis B or hepatitis C. 
14. Has an active autoimmune disease that has required systemic treatment in past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs).   
o Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. 
15. Has a known additional malignancy that progressed or required active treatment 
within the last 5 years.  
o Note: Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy, or 
in situ cervical cancer. 
16. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
17. Has an active infection requiring systemic therapy. 
18. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
19. Has received a live vaccine within 30 days of Cycle 1 Day 1 of study therapy.  
o Note:  Seasonal influenza vaccines for injection are generally inactivated 
flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., 
Flu-Mist®) are live attenuated vaccines, and are not allowed. 
 
4. INVESTIGATIONAL PLAN 
 
4.1. Milestone Date Definitions 


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Eligibility date:  the date of the last documented criterion that confirmed subject 
eligibility. 
Enrollment date:  the date subject is randomized to one of the study treatment arms. 
Treatment discontinuation date: Date investigator decides to discontinue subject from 
study treatment.  
• For subjects who have received pembrolizumab study treatment, this date 
is the date the investigator decides to discontinue subject from 
pembrolizumab. 
• For subjects in cohort A who have not yet received pembrolizumab, this 
date is the date the investigator decides to discontinue subject from 
paclitaxel.  
 
4.2. Overall Study Design 
This is an open-label, randomized pilot study designed to evaluate the safety and 
feasibility of the following two regimens: Cohort A) phased regimen of pembrolizumab 
in which paclitaxel is followed by paclitaxel plus pembrolizumab and Cohort B) 
concurrent regimen of paclitaxel plus pembrolizumab. Following informed consent and 
eligibility check, subjects will be randomized to either Cohort A or Cohort B. 
 
Data from this study will be collected on electronic case report forms (eCRFs) and 
stored in the CTMS. 
 
4.3. Randomization/Registration/Enrollment 
Following informed consent and eligibility check per standard operating procedures, 
subjects will be randomized in a 1:1 fashion to either Cohort A (phased) or the Cohort B 
(concurrent) and assigned a Study ID number. This will be accomplished utilizing the 
CTMS whereby a list of Study IDs and associated study treatment arm assignments 
randomly generated prior to study activation will be uploaded by a member of the Levine 
Cancer Institute Biostatistics Core. The Study ID will be a four digit randomly generated 
ID number, ranging from 0001 to 9999. A stratified block randomization will be utilized 
including hormone receptor status (positive versus negative) to reduce confounding of 
comparisons between the study treatment arms. 
 
4.4. Pre-Treatment 
4.4.1. Informed Consent 
No protocol-related assessments may be performed prior to obtaining informed consent. 
Baseline assessments will be conducted according to the Study Calendar.  The 


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investigator or qualified designee must obtain documented consent from each potential 
subject prior to participating in a clinical trial per standard operating procedures.  
 
4.4.2. Medical History 
Demographic information, medical history and baseline conditions will be obtained by 
the investigator or qualified designee.  Medical history will include all active conditions, 
and any condition diagnosed within the prior 10 years that are considered to be clinically 
significant by the Investigator. Details regarding the subject’s MBC will be recorded 
separately and not listed as medical history.   
 
4.4.3. Prior and Concomitant Medications 
All medication that is considered necessary for the subject’s welfare, and which is not 
expected to interfere with the evaluation of the study treatment, may be given at the 
discretion of the Investigator. All medications taken from the time of informed consent 
and during study treatment will be recorded in the medical record per standard clinical 
practice. 
 
4.4.4. Prior Treatment Details for Breast Cancer 
The investigator or qualified designee will review and record all prior cancer treatments 
including systemic treatments, radiation and surgeries. If applicable, documentation of 
clinical and/or radiographic disease progression on the most recent therapy will be 
collected.   
 
4.4.5. Baseline Procedures 
Physical exam, ECOG performance status, vital signs, clinical laboratory tests, baseline 
adverse event assessment, and ECG should be performed during screening within the 
timeframe defined in Section 5.  
 
  
 
4.4.5.1. 
Radiology and Tumor Measurements 
Imaging tests, including CT scan of chest, abdomen, and pelvis with contrast or MRI 
aimed at defining the extent of existing disease must be performed and documented 
within the timeframe defined in Section 5. A bone scan will be done at Baseline within 
the timeframe defined in Section 5 to document presence or absence of bone metastasis.  
  
4.4.6. Correlatives 
4.4.6.1. 
Tissue Biopsies 
It will be mandatory to obtain a tissue biopsy during screening before study treatment 
initiation in all subjects and then within 5 days prior to study treatment on Cycle 3, 


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Day 1. Bone tissue is not acceptable for research biopsies. See Section 3.2 (Inclusion 
#8) for possible exceptions to tumor biopsy. Optional time points include within 5 
days prior to study treatment on Cycle 5, Day 1 and within 21 days following 
documented disease progression. Subsequent biopsies ideally will be obtained from 
the same site used at Baseline, but this is not a requirement. Research biopsies may be 
obtained even if the subject has discontinued study treatment. 
 
An effort should be made to ask subjects in Cohort A if they can undergo the biopsy 
prior to study treatment on Cycle 5 Day 1 as this would be after 2 cycles of paclitaxel 
combined with pembrolizumab, and this would provide important information 
regarding PD-L1 expression and effect on TILs in the tumor after combined 
chemotherapy and immunotherapy. The overall goal of the trial would be to obtain 
paired pre-treatment and on-treatment tumor biopsy in at least 10 subjects in each 
cohort.  
Biopsies will be obtained only if they can be performed under local anesthesia. 
General anesthesia will not be used to obtain biopsies that are to be used only for 
research purposes. Biopsies may be obtained with the assistance of either a surgical 
consultant or designee, a dermatological consultant or designee, or a member of the 
interventional radiology staff.  
 
Biopsies performed for research purposes will only be obtained after the procedure 
has been explained to the subject, and per institution policy, the clinic specific 
informed consent has been secured. Subjects will have the opportunity to consent or 
refuse the use of their tumor samples to be banked at the CHS BioSpecimen 
Repository for additional unplanned future studies. 
 
4.4.6.2. 
Archived Tumor Tissue 
Tumor tissue samples will be collected (if available) for each subject on-study to 
evaluate the expression of, but not limited to, PD-L1 and TILs. This includes the 
following: 
 
1) Sample of tissue from time of original diagnosis (breast cancer primary) 
2)  Sample of tissue from initial metastatic diagnosis (any site of metastases) 
 
Subjects will have the opportunity to sign the consent form or refuse the use of any 
archival specimens collected to be banked at the Atrium Health BioSpecimen 
Repository for any desired unplanned future analyses. 
 
4.4.6.3. 
PD-L1 Expression in Tumor 


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Recent data suggests that inducible PD-L1 expression may be important for responses 
to PD-1 blockade therapy.  PD-L1 is expressed in about 20% of TNBCs in tumor 
samples from constructed tissue microarrays.36  In hormone receptor-positive breast 
cancer, PD-L1 expression has been reported at 6%, a smaller incidence compared to 
TNBC, while still suggestive that checkpoint inhibitors may have a role in luminal 
breast cancer.37   
 
An archived sample or core or punch biopsy (fine needle aspirate not adequate) 
collected during screening should be submitted to the CHS BioSpecimen Repository 
for characterization of PD-L1 expression if it can be safely obtained.  Tumor tissue 
collected during screening should be submitted in formalin or as formalin-fixed 
paraffin embedded tumor tissue blocks (preferred).   
 
 
Additionally, if available, archived tumor tissue specimens from prior biopsies will be 
collected for determination of PD-L1 tumor status to compare biomarker expression 
in archived specimens against the newly obtained tumor tissue that is collected as a 
requirement for entry into the trial.  Tumor tissue collected may also be used to 
support analysis of additional exploratory biomarkers. Details regarding time points 
for collection of tumor tissue are outlined in the Study Calendar (Section 5). 
 
4.4.6.4. 
Tissue Infiltrating Lymphocytes (TILs) in Tumor 
TILs have been shown to provide prognostic and predictive value, particularly in 
TNBC.38,39 H&E-stained slides will be evaluated for TILs according to standardized 
methodology described by Salgado et al.40  Additionally, there is recent data 
suggestive that the subset of breast cancer tumors with the highest potential to benefit 
from checkpoint inhibitors may be those breast tumors that have both high TILs and 
high PD-L1 expression.41 
 
4.4.6.5. 
Genomic Analysis 
The application of new technologies such as next generation sequencing has provided 
the opportunity to define certain tumor types at the genetic level as being 
“hypermutated.” It is possible that the hypermutated states may be correlated with 
response to pembrolizumab in HER2-negative breast cancer. Recent data in a group 
of patients with progressive metastatic carcinoma, with or without mismatch repair 
deficiency and treated with pembrolizumab, showed that mismatch-repair status 
predicted clinical benefit with pembrolizumab42.  
 
If tissue not previously sent for genomic analysis, FFPE tumor will be sent for 
genomic analysis by next-generation sequencing panel (≥400 genes). At least 50 


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mm2, or the equivalent of 4 core biopsies using an 18 gauge needle, is required for 
testing.  
 
 
4.4.6.6. 
Patient-Derived Xenografts (PDX) Models 
Cancer research and drug development have historically relied upon the use of in 
vitro cell lines and in vivo models such as genetically-engineered mice and cell line-
injected mice (i.e., cell line xenografts).  These models lack critical elements such as 
tumor heterogeneity and its associated microenvironment and therefore do not 
provide an accurate representation of a patient’s tumor.   
 
PDX models have been established by implanting a fragment of a patient’s fresh 
tumor tissue into immune-deficient mice.  Tumors are allowed to engraft and grow 
before they are resected and subsequently implanted into a second generation of mice.  
Once growth is observed in the second generation of mice, the PDX model is 
considered successfully established and can be maintained and passaged into 
subsequent generations of mice or cryopreserved for future use.  Extensive 
characterization of PDX models with regard to histopathology, gene expression and 
genomic sequence has shown high fidelity of the molecular characteristics of the 
original patient tumor. Therefore, these models have a distinct advantage over other 
models and have become an important in vivo model for oncology research and drug 
development.   
 
The use of PDX models as a robust research platform for optimizing oncology drug 
development efforts has been well recognized; however, until recently data was 
lacking to support the accuracy of these models to predict clinical response.  
Champions Oncology and many academic researchers have data sets that highlight 
the high degree of accuracy of personalized PDX models in predicting response of 
individual patients across a variety of tumor types. 
 
For this study, the objective is to collect tumor tissue in metastatic triple-negative 
breast cancer subjects to create patient-derived xenograft mouse models for 
translational research purposes.  This will give potential insight to mechanisms of 
response and resistance, pre- and post-treatment, with this combination regimen.    
 
Fresh tumor tissue will be obtained through a biopsy during screening. To maximize 
the success of tumor engraftment in the immune-deficient mouse, it is requested that 
approximately 0.5 cm3 or a minimum of 3 core biopsies using an 18 gauge needle (or 
equivalent) be obtained.  


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Freshly acquired specimens will be placed into one to two 50-ml vials containing 
transport medium that will be provided by Champions and labeled with a unique 
subject number identifier.   Vials containing the tissue specimen will be packaged in 
an insulated container with coolant blocks.  Transportation of the specimen to the 
designated implantation site will be arranged in advance with Champions Clinical 
Operations Staff. Ideally, the time from tumor extraction to placement in media 
should be immediately but can be up to 30 minutes. Exact times will be recorded.  
 
A whole blood sample will also be collected and submitted at the time of tumor 
biopsy to Champions Oncology.  This will enable a comparison of normal DNA 
profile to tumor DNA for PDX genomic analysis.  Lavender-topped, EDTA-
containing tubes will be used for collection.  Once collected, whole blood samples 
will be included with tissue specimen collection in an insulated container for transport 
to the designated implantation site.  Exact collection times will be recorded. 
 
Upon receipt of the tumor specimen at the designated implantation site, tumor tissue 
will be implanted into immune-deficient mice following the standard operating 
procedures (SOPs). Evaluation for tumor growth will occur as follows: tumor 
dimensions will measured twice weekly by digital caliper and data, including 
individual and mean estimated tumor volumes are recorded for each group. Tumor 
volume will be calculated using the formula: TV= width2 x length x π/2. 
Monthly reports of tumor growth status will be provided by Champions to the PI and 
designated individuals. 
 
Genomic sequencing (whole exome and RNA sequence) will be performed by 
Champions (or it’s designate) on successfully generated PDX models and provided to 
the Sponsor-Investigator for research purposes.   
 
4.4.6.7. 
Correlative Studies in the Tissue 
A priority ranking of studies on tumor tissue samples are listed below 
1) PD-L1 
2) TILS 
3) Genomic analysis 
4) Patient-derived xenografts for metastatic triple-negative breast cancer subjects 
only 
Tissue does not need to be sent for genomic analysis if already performed on 
previously collected tissue. 
Other exploratory biomarkers may also be measured in the tissues. 
 


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4.4.6.8. 
Blood Correlatives 
4.4.6.8.1. 
Circulating Tumor DNA 
Circulating tumor DNA (ctDNA) could serve as an early biomarker of therapeutic 
response to checkpoint inhibitors.43  Blood (20 ml; 2 BCT or equivalent tubes) 
will be drawn from the subject and submitted for isolation of ctDNA and analysis 
by next generation sequencing methods by a panel (≥40 genes).  This will be 
collected pre-treatment and at the timepoints as defined in Section 5. 
 
4.4.6.8.2. 
BRCA Mutations 
A phase II study identified the first genomic marker—mismatch repair 
deficiency—to predict clinical benefit of immune checkpoint blockade with the 
anti–PD-1 antibody pembrolizumab. Among 28 patients with colorectal cancer, 
40% of the 10 patients with mismatch repair–deficient tumors responded to 
pembrolizumab, but no responses were seen among the 18 mismatch repair–
proficient patients. The difference in disease control rates (response plus stable 
disease) was even greater: 90% in the mismatch repair–deficient group and only 
11% in the mismatch repair–proficient group.42 Mismatch repair deficiency leads 
to an accumulation of genetic mutations in a tumor. It is hypothesized that 
immune checkpoint inhibitors would work particularly well against mismatch 
repair-deficient tumors. For breast cancer subjects, the determination of BRCA 
status will be recommended, if they have not had germline testing performed. 
 
4.4.6.8.3. 
Biomarkers in the Blood 
A pre-treatment blood sample will be collected with additional blood collected at 
subsequent time points according to the study calendar in Section 5, using one 
serum separator tube (SST) and two cell preparation tubes (CPT) for blood cells 
separation and storage.  Samples will be delivered to the CHS BioSpecimen 
Repository to be processed and stored for batch analysis at the end of the study. 
The analysis will include but not be limited to immunotyping and cytokine 
profiling in Dr. David Foureau’s LCI Immune Monitoring Core Laboratory. 
 
4.4.6.8.4. 
Optional and Future Studies 
All study participants will be invited to provide blood samples for future 
unplanned studies.  Participation will be optional for all subjects entering the 
study. A subject’s acceptance of unplanned future analyses will not be a 
requirement of their participation in the main study.  Subjects will have the 
opportunity to consent or refuse the collection of these samples for additional 
unplanned studies. If the subject agrees to this collection, two 10 ml tubes of 
blood will be collected pre-treatment and other timepoints as defined in Section 5, 


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one red top (for serum) and a heparinized green top (for plasma) and frozen at -70̊ 
C to -80̊ C and stored in the CHS BioSpecimen Repository for future research. 
 
 
 
4.5. Treatment 
4.5.1. Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for any new or 
worsening AEs as specified in the Study Calendar and more frequently if clinically 
indicated.  Adverse events will be graded and recorded throughout the study from 
randomization through 30 days after last administration of study treatment, using 
CTCAE Version 4.0.  Toxicities will be characterized by seriousness, causality, toxicity 
grading, and action taken with regard to study treatment and recorded in the CTMS.   
 
4.5.2. Vital Signs 
The investigator or qualified designee will take vital signs prior to the administration of 
each dose of study treatment as specified in the Study Calendar.  Vital signs include 
temperature, pulse, respiratory rate, and blood pressure.   
 
4.5.3. ECOG PS 
The investigator or qualified designee will assess ECOG status at the timepoints 
specified in the Study Calendar in Section 5. 
 
4.5.4. Physical Exam 
The investigator or qualified designee will perform a complete physical exam including 
weight at the timepoints specified in the Study Calendar in Section 5. New clinically 
significant abnormal findings should be recorded as AEs. Height will be measured at 
screening only.   
 
4.5.5. Laboratory Procedures and Assessments 
Laboratory tests for hematology and chemistry at the timepoints specified in the Study 
Calendar in Section 5. 
Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of study treatment. 
 
4.5.6. On Study Tumor Imaging and Assessment of Disease 
Post treatment tumor imaging assessments should be performed at the timepoints 
specified in the Study Calendar in Section 5.  The same modality used at screening 
should be used at all follow-up imaging assessments.  


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If no bone lesions were identified at Baseline, bone scans will only be repeated as 
clinically indicated (i.e. showing signs or symptoms of new or progressing bone 
metastases). Subjects with bone metastasis present at Baseline will have bone scans at 
the same time point as study tumor imaging (CT/MRI), based on how long subjects have 
been on study as defined in Section 5.  
 
Imaging should follow calendar days and not be delayed for any dose interruptions that 
may occur. Imaging should continue to be performed until disease progression, the start 
of new anticancer treatment, withdrawal of consent for study participation, death, or 
notification by the Sponsor-Investigator, whichever occurs first.   
 
 
Radiographic disease progression must be confirmed at least 4 weeks after the first 
tumor imaging indicating progressive disease in clinically stable subjects.  Subjects in 
Cohort A will not require confirmatory imaging if radiographic disease progression is 
identified at the first follow-up imaging time-point (prior to pembrolizumab). 
Pembrolizumab-treated subjects who have unconfirmed radiographic disease progression 
may continue on treatment until progression is confirmed (or possibly even later) 
provided they have met the conditions detailed in irRECIST (Table 10). 
 
For subjects with new symptoms of osseous metastasis [e.g., new bone pain and/or new 
persistently elevated alkaline phosphatase (AP)] a bone scan should be obtained.   
 
4.6. End of Treatment 
An end of treatment visit should be completed after study treatment is discontinued. End 
of treatment visit is outlined in the Study Calendar.   
 
Subjects will be tracked for at least 30 days following cessation of study treatment to 
monitor for adverse events and any other unanticipated problems. If the end of treatment 
visit occurs prior to 31 days from last dose, subjects will be contacted by telephone on 
day 31 or next business day for monitoring. Subjects will be followed until all treatment-
related toxicities have resolved, returned to baseline, stabilized, or are deemed 
irreversible according to standard of care.  
 
Note: In the event a subject is discontinued from pembrolizumab, but is experiencing 
benefit (in the investigator’s opinion) from the paclitaxel, continuation of paclitaxel will 
not be considered protocol-directed therapy or start of new or subsequent anticancer 
therapy. 


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4.7. Follow-Up 
Subjects will be contacted approximately every 6 months from treatment discontinuation 
date, until death, lost to follow-up, or until the criteria defined for the final analysis 
(Section 12.4.1) are reached.  However, in the event the criteria for the final analysis are 
met, and there are subjects who have not yet been discontinued from study treatment, 
subjects in follow up will continue to be followed until all subjects have discontinued 
study treatment (see Section 6.6) and completed the required 30 day safety monitoring 
period (see Section 4.5.1).  Subjects will be contacted by telephone, in writing, or during 
clinic visits after treatment discontinuation for collection of follow-up information. 
Follow-up clinical information may also be obtained through chart reviews.  Death 
information from public sources i.e. death registry, obituary listing, etc. can also be used 
when available and verifiable. 
 
4.8. Subject Withdrawal and Off Study 
Subjects may withdraw consent at any time for any reason or be removed from the trial 
at the discretion of the investigator should any untoward effect occur.   
 
In this trial, a subject may discontinue from study treatment but continue to participate in 
the regularly scheduled activities, as long as the subject does not withdraw consent for 
participation. 
 
A subject will be discontinued from the trial for any of the following reasons: 
• The subject withdraws consent for participation on the study 
• The subject is lost to follow-up 
• Investigator’s decision to withdraw the subject from study, which may 
include noncompliance with study treatment or procedure requirements  
• Subject death 
 
In all cases, the reason for withdrawal and/or subject going Off Study must be 
documented in the subject’s medical records and/or research record and recorded in the 
eCRF. 
 
4.9. Screen Failures/Subject Replacements 
A subject who, for any reason (i.e. failure to satisfy the eligibility criteria or withdraws 
consent), terminates their participation in the study before being randomized is regarded 
as a “screen failure.” 
 


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A subject who discontinues from the trial after randomization will not be replaced. 
 
 
5. STUDY CALENDAR 
The following tests and evaluations will be performed according to the schedule below. Baseline 
(i.e., pre-study) evaluations must be performed within 14 days prior to Cycle 1 Day 1, unless 
otherwise indicated in one of the footnotes below the table.  All imaging must be performed 
within 28 days prior to Cycle 1 Day 1.  A cycle is defined as an interval of 21 (+/- 3) days. 
Evaluation 
 
Pre-
Study 
Cycle 1 
Day 1 
(C1D1) 
C1D81 C2D1 C2D81 C3D1 C3D81 
C4 
and 
after; 
D1 
C4 
and 
after; 
D81 
Every 
6 
weeks 
(+/- 7 
days) 
End of 
Treatment 
(w/in 31 
days of 
last dose)  
Progression 
Follow 
Up21 
Informed 
consent 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
• History23 
• weight/ 
height3  
• physical 
exam 
• ECOG PS 
X 
X2 
 
X4 
 
X4 
 
X4 
 
 
X 
 
 
Vital signs24  
X 
X2 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Serum or 
urine 
pregnancy 
test in 
WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
differential, 
platelets 
X 
X2 
X7 
X6 
X7 
X6 
X7 
X6 
X7 
 
X 
 
 
PT/PTT/ 
INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
chemistries 
and LFTs8 
X 
X2 
 
X6 
 
X6 
 
X6 
 
 
X 
 
 
Thyroid 
function 
tests (TSH 
and free T4) 
X 
 
 
 
 
 
 
X9 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Paclitaxel10 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


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1. 
Day 8 visits are not applicable for subjects receiving pembrolizumab monotherapy. Day 8 paclitaxel treatment may 
have a + 2 day window (it may be given up to 2 days later than Day 8) but paclitaxel doses should not be 
administered any closer than 7 days apart. 
2. 
Physical exam, ECOG performance status, weight, vital signs, and clinical laboratory tests do not need to be 
repeated prior to Cycle 1 Day 1 unless the subject’s condition is deteriorating.  
3. 
Collect height at Screening only. 
4. 
Physical exam, weight, and ECOG PS within 7 days of Day 1 for Cycles 2 and beyond. 
5. 
Within 28 days prior to study treatment initiation). 
6. 
May be performed within 72 hours 
7. 
May be performed within 1 day on Day 8 for Cycle 1 and beyond. 
8. 
Includes: sodium, potassium, bicarbonate, chloride, glucose, BUN, creatinine, calcium, total protein, and albumin, 
alkaline phosphatase, total bilirubin, AST and ALT.  
9. 
Blood draws for thyroid function tests should be repeated every 4 cycles starting at Cycle 5 Day 1 (within 72 
hours). 
Pembro-
lizumab 
 
X11 
 
X11 
 
X 
 
X 
 
 
 
 
 
Tumor 
biopsy, if 
accessible 
X19 
 
 
 
 
X20 
 
X12 
 
 
 
X12 
 
Evaluation 
continued 
 
Pre-
Study 
Cycle 1 
Day 1 
(C1D1) 
C1D81 C2D1 C2D81 C3D1 C3D81 
C4 
and 
after; 
D1 
C4 
and 
after; 
D81 
Every 
6 
weeks 
End of 
Treatment 
(w/in 31 
days of 
last dose)  
Progression 
Follow 
Up21 
Archived 
tumor tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for 
circulating 
tumor DNA  
 
X 
 
 
 
X 
 
X13 
 
 
 
 
 
Optional 
Future 
research 
blood draw 
 
X 
 
 
 
X 
 
X14 
 
 
 
X14 
 
Blood for 
biomarkers   
 
X 
 
X 
 
X 
 
X15 
 
 
 
 
 
Blood for 
BRCA 
mutation16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging 
studies 
and/or tumor 
assessments 
X5 
 
 
 
 
 
 
 
 
X17,18 
 
 
 
Review 
adverse 
events25 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Survival 
status 
 
 
 
 
 
 
 
 
 
 
 
 
X22 


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10. If paclitaxel needs to be omitted for the subject due to a paclitaxel-related toxicity or the subject has received 
maximum benefit from paclitaxel as deemed by the treating physician and the Sponsor-Investigator, paclitaxel may 
be discontinued.  
11. ONLY subjects randomized to Cohort B will receive pembrolizumab on Cycle 1 Day 1 and Cycle 2 Day 1 before 
paclitaxel. 
12. Optional within 5 days of C5D1 (strongly encouraged for subjects in Cohort A). If subject discontinues treatment 
due to disease progression, a biopsy will be performed  within 21 days of confirmed progression. If subject has 
confirmed disease progression but remains on treatment, a biopsy will not be performed.  
13. This will be collected at pre-treatment and then within 72 hours prior to Day 1 of every 2 (odd-numbered) cycles 
starting with Cycle 3.  
14. Within 72 hours of C5D1and within 21 days of confirmed progression. 
15. Within 72 hours of C4D1only. 
16. If applicable as determined by the treating investigator and not previously obtained, can be drawn at any time while 
on study in conjunction with genetic consultation. 
17. The first follow-up imaging timepoint should be 6 weeks (+/- 7 days) from C1D1. Subsequent follow-up imaging 
frequency as referenced in the calendar and below (based on length of time the subject has been on the study) 
should be based on the timepoint of the previous scan, not C1D1. If a subject has been on study for ≥ 6 months, the 
treating physician may decide to lengthen the interval to every 9 weeks (63 days ± 7 days) from previous scan, or 
more frequently, if clinically indicated. The last scan performed at the 6 week internal must occur on or after the 6 
month on study date; subsequent scans can be scheduled at the 9 week interval. The last scan performed at the 9 
week interval must occur on or after the 12 month on study date; subsequent scans can be scheduled at the 12 week 
interval. After 12 months, imaging frequency can be reduced to every 12 weeks (84 ± 7 days) from previous scan, 
or more frequently if clinically indicated.  
18. Imaging should follow calendar days and not be delayed for any dose interruptions that may occur until 
progression. 
19. May be collected anytime during screening prior to study treatment initiation. Subjects for whom tumor biopsies 
cannot be obtained during screening due to inaccessible tumor or subject safety concern may submit an archived 
tumor specimen from primary tumor or metastatic biopsy collected within 12 months from consent. Bone tissue is 
not acceptable for research biopsies. 
20. Within 5 days of C3D1 
21. Subjects will be contacted approximately every 6 months from treatment discontinuation date, until death, lost to 
follow-up, or until the criteria defined for the final analysis (Section 12.4.1) are reached.   
22. For surviving subjects who receive subsequent anti-cancer therapy prior to documented disease progression, collect 
start date of first subsequent anti-cancer therapy. In the event a subject is discontinued from pembrolizumab, but is 
experiencing benefit from the paclitaxel, continuation of paclitaxel will not be considered protocol-directed therapy 
or start of new or subsequent anticancer therapy. 
23. To include baseline conditions present at the time of study treatment initiation 
24. VS to include temperature, pulse, respiratory rate, and blood pressure 
25.  Adverse events will be followed for 30 days after last administration of study treatment. 
 
6. TREATMENT PLAN 
 
6.1. Drug Dosage and Administration 
6.1.1. General Considerations 
Trial treatment should begin on the day of or within 72 hours of randomization. 
Study treatment should be administered after all procedures/assessments have been 
completed as detailed in the Study Calendar.  A cycle is defined as an interval of 21 
(+/- 3) days (delays due to holidays, weekends and bad weather will be permitted 
and will not be counted as a protocol deviation). No investigational or commercial 


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agents or therapies intended to treat the subject’s malignancy may be administered 
while the subject is receiving study therapy, other than those described below. 
 
6.2. Paclitaxel 
Subjects will receive paclitaxel 80 mg/m2 as an IV infusion over 60 minutes on 
Days 1 and 8 every 21 days. However, given the variability of infusion pumps from 
site to site, a window of -5 minutes and +10 minutes is permitted.  In the event of a 
dosing delay, a make-up dose of paclitaxel may be given as outlined in Section 7.2. 
A window of +/- 3 days is allowed for the Day 1 dose and a + 2 day window is 
allowed for the Day 8 dose (it may be given up to 2 days later than Day 8) but 
paclitaxel doses should not be administered any closer than 7 days apart. 
Paclitaxel is commercially available. Anaphylaxis precautions should be observed 
during administration. 
Premedications for possible hypersensitivity reactions involving paclitaxel and/or 
its components will be given approximately 30 to 60 minutes prior to paclitaxel.  
The following is suggested: 
• Dexamethasone 8 mg IV (or equivalent)* 
• Diphenhydramine 25 mg IV (or equivalent) 
• Famotidine 20 mg IV (or equivalent) 
*A suggested regimen to taper dexamethasone is the following: dexamethasone 8 
mg IV 30 to 60 minutes prior to each paclitaxel infusion during cycle 1 and then 
dexamethasone 4 mg IV 30 to 60 minutes prior to each paclitaxel infusion during 
cycle 2, and then discontinued for subsequent infusions, if tolerated. 
The dose of paclitaxel will be calculated each cycle using the subject’s most recent 
weight during screening (baseline weight). If the subject’s weight changes >10% 
from baseline weight, recalculate that total dose per standard clinical practice.  
 
6.2.1. Treatment Criteria 
On Cycle 1 Day 8 and beyond, paclitaxel can be administered provided that the 
subject meets the following criteria: 
• ANC ≥ 1,000/l 
• Platelets ≥ 75,000/l 
 
If paclitaxel is held, follow guidelines for dosing pembrolizumab. It is possible for 
subjects to continue on pembrolizumab even if paclitaxel is held, when appropriate. 
 


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6.3. Pembrolizumab 
Subjects will receive 200 mg pembrolizumab as an IV infusion over 30 minutes on Day 1             
of every 21 days (+/- 3 days).  
 
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. 
 
A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of 
polyethersulfone (PES) must be used during administration of pembrolizumab to remove 
any adventitious particles.  If the infusion set does not contain 0.2 to 5 µm in-line filter, it 
is recommended to use 0.2 to 5 µm add-on filter which may contain an extension line 
(Note: the materials of the extension line and filter should be as mentioned above). 
 
Pembrolizumab 100 mg/ 4mL solution for injection will be supplied by Merck.  
 
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 study treatments in accordance with the protocol and any applicable laws and 
regulations. 
 
6.4. Treatment Administration 
6.4.1. Cohort A, Phased Pembrolizumab 
For subjects randomized to Cohort A, paclitaxel will be administered per Section 
6.2 during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. 
Starting with cycle 3 and subsequent cycles, pembrolizumab will be administered 
per Section 6.3 before paclitaxel on day 1 every cycle. 
 
6.4.2. Cohort B, Concurrent Pembrolizumab 
For subjects randomized to Cohort B, pembrolizumab will be administered per 
Section 6.3 on day 1 before paclitaxel every cycle.  Paclitaxel will be administered 
per Section 6.2, on days 1 and 8 every cycle.  
 
6.4.3. Pembrolizumab Monotherapy 
If paclitaxel needs to be omitted for the subject due to a paclitaxel-related toxicity 
(e.g., subject develops a hypersensitivity reaction or grade 3 or grade 4 neuropathy), 
the subject may be allowed to continue on protocol with single-agent 
pembrolizumab.   
 


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If the subject has received maximum benefit from paclitaxel as deemed by the 
treating physician, and in consultation with the Sponsor-Investigator, which could 
include a situation of complete response, partial response, or stable disease ≥ 6 
months, paclitaxel can be discontinued, and treatment with pembrolizumab alone 
may be continued.  Safety assessments, including physical exam, vital signs, 
laboratory assessments, and monitoring for the occurrence of adverse events will be 
performed according to Section 5.  The dosing of pembrolizumab will be given 
once every 3 weeks as described above.  
 
 
6.4.4. Table 1: Trial Treatment 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Pembrolizumab 
None 
200 mg 
IV over 30 
minutes before 
paclitaxel 
Day 1 
21 (+/- 3) 
days  
(3 weeks) 
 
 
 
Paclitaxel 
Dexamethasone* 
Famotidine 
Diphenhydramine 
80 mg/m2 IV over 60 
minutes; give 
after 
pembrolizumab 
Days 1  
and 8 
*Dexamethasone 8 mg IV will be given 30 to 60 minutes before each paclitaxel administration 
during cycle 1. If tolerated, dexamethasone should then be tapered to 4 mg at Cycle 2 and 
discontinued at Cycle 3 and beyond for subsequent infusions. 
 
 
6.5. Concomitant Medications 
6.5.1. 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 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 recorded. All concomitant medications used within 28 days before 
the first dose of  study treatment should be recorded.   
 
6.5.2. Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the screening and 
treatment phase of this trial: 


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• 
Immunotherapy not specified in this protocol  
• 
Chemotherapy not specified in this protocol  
• 
Investigational agents other than pembrolizumab  
• 
Radiation therapy  
• 
Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, intranasal 
influenza, rabies, BCG, and typhoid vaccine. 
• 
Glucocorticoids for any purpose other than to modulate symptoms from an event 
of suspected immunologic etiology or as premedication for paclitaxel.   
o Note: The use of physiologic doses of corticosteroids may be approved 
after consultation with the Sponsor-Investigator. 
o Note: Inhaled steroids are allowed for management of asthma.  
o Note:  Use of prophylactic corticosteroids to avoid allergic reactions (i.e., 
to IV contract dye) is permitted. 
 
6.6. Definition of Pembrolizumab Overdose 
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. 
 
6.7. Duration of Therapy 
In the absence of treatment delays due to adverse event(s), study treatment will 
continue until one of the following criteria applies: 
• Disease progression in subjects who have not yet received pembrolizumab 
(Cohort A)  
• Confirmed disease progression in subjects receiving pembrolizumab 
• Disease progression if clinically unstable 
• Unacceptable adverse event(s) 
• Subject decides to withdraw from study treatment or protocol 
• General or specific changes in the subject’s condition render the subject 
unacceptable for further study treatment in the judgment of the Investigator. 
 
Note: In the event the criteria for the final analysis are met, and there are subjects who 
have not yet been discontinued from study treatment, they will continue to receive 


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therapy beyond the date the criteria for the study final analysis are met and until one of 
the above criteria applies. 
 
6.8. Drug Accountability 
All investigational study drugs will be stored at the investigational site in accordance 
with Good Clinical Practice (GCP) and Good Manufacturing Practices (GMP) 
requirements and will be inaccessible to unauthorized personnel.  
 
An adequate record of receipt, distribution, destruction, or return of all investigational 
study drugs must be kept in the form of a Drug Accountability Form. The Investigator, 
or responsible party designated by the Investigator, will maintain a careful record of the 
inventory using the Drug Accountability Form. 
 
6.9. Destruction 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, including 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 according to LCI IDS pharmacy 
policies. It is the Investigator’s responsibility to arrange for 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. 
 
7. DOSE MODIFICATIONS 
 
7.1. Pembrolizumab 
Pembrolizumab dose reductions are not applicable to this study.  However, pembrolizumab 
must be withheld for drug-related toxicities and severe or life-threatening AEs as described 
in Table 2 below. Held doses will not be replaced.  When pembrolizumab is restarted, this 
dose would be considered Day 1 of the subsequent cycle and should be in alignment with the 
new schedule. If pembrolizumab is held, paclitaxel may continue, when appropriate. 
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of study treatment. See Section 8 for supportive 
care guidelines, including use of corticosteroids, for treatment-related adverse events. 


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Table 2: Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated with 
Pembrolizumab Monotherapy and IO Combinations 
 
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs 
are not controlled by corticosteroids. 
2. 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. 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0 
v4.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids (initial dose of 
1 to 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 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or mucus 


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Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 
 
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 
AST or ALT 
Elevation or 
Increased Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids (initial dose of 
0.5 to 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 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure 
Withhold d 
•  Initiate insulin replacement therapy for 
participants with T1DM 
•  Administer antihyperglycemic in 
participants with hyperglycemia 
 
•  Monitor participants for hyperglycemia or other signs and 
symptoms of diabetes 
Endocrine disorders-
other (Hhypophysitis) 
Grade 2 
Withhold 


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Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
•  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
•  Monitor for signs and symptoms of hypophysitis (including 
hypopituitarism and adrenal insufficiency) 
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 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
•  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care 
•  Monitor for signs and symptoms of thyroid disorders 
Nephritis: 
grading according to 
increased creatinine 
or acute kidney injury 
Grade 2 
Withhold 
•  Administer corticosteroids (prednisone 1 
to 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 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
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 


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All Other irAEs 
Persistent Grade 2 Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology or exclude 
other causes 
Grade 3 
Withhold or 
discontinue based 
on the event e  
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash with 
Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; 
TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a 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, subject vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor-Investigator. The reason for 
interruption should be documented in the patient's study record. 
See Section 8.1 for supportive care measures to be taken for potential immune-related 
toxicities associated with pembrolizumab. 
  
7.2. Paclitaxel 
Each paclitaxel cycle is defined as two paclitaxel treatments given during a 21-day period.  If 
paclitaxel is held for ≥ 2 weeks, the following instructions apply:  
 
If paclitaxel is held, resume with the missed treatment dose, e.g., if day 1 paclitaxel is held 
for 7 days, treatment will resume with the "day 1" paclitaxel dose on calendar day 8 and the 
"day 8" paclitaxel dose will be given on day 15.  (In this case, there is no break in therapy 
during the last week of the cycle. Paclitaxel doses should be given at least 7 days apart.)  
 
If two paclitaxel treatments have not been given by day 21 (+/- 3 days), proceed with 
treatment day 1 of the next cycle (if toxicities have resolved according to requirements in the 
dose modification sections/tables). 
 
If paclitaxel is discontinued for neuropathy or musculoskeletal pain or other toxicity, 
pembrolizumab may continue.  
 
Table 3:  Dose levels for paclitaxel 
 
Dose Level 0 
Starting Dose 
Dose Level −1 
Dose Level −2 
Dose Level −3 
Paclitaxel 
80 mg/m2 
70 mg/m2 
60 mg/m2 
Discontinue 
 
Table 4:  Dose Modifications for paclitaxel 
Note: dose modifications listed below are only for paclitaxel-related toxicities, do not 
modify dose if toxicity is not related to paclitaxel. 
 
Toxicity 
Paclitaxel  
No toxicity 
Maintain dose level  
Febrile Neutropenia 
Grade 3  
 
Hold until resolved, then  1 dose level 


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Grade 4 
Hold until resolved, then  1 dose level 
Neutropenia* 
Grade 1  
Grade 2  
Grade 3 
Grade 4 
 
Maintain dose level  
Maintain dose level 
Hold until resolved to ≥1,000/l, maintain dose level 
Decrease one dose level when resolved to ≤ Grade 2 
Thrombocytopenia* 
Grade 1 
Grade 2  
Grade 3 
Grade 4 
 
Maintain dose level 
Hold until resolved to ≥75,000/l, maintain dose level 
Hold until resolved to ≥75,000/l, maintain dose level 
Hold until resolved to ≥75,000/l, then  1 dose level 
Clinically Significant Non-
Hematologic Toxicities 
(excluding neuropathy and 
musculoskeletal pain) 
Grade 1 
Grade 2  
Grade 3 
Grade 4 
 
 
 
Maintain dose level 
Hold until resolved to ≤ Grade 1, maintain dose level 
Hold and then decrease one dose level when resolved to ≤ Grade 1 
Hold and then decrease one dose level when resolved to ≤ Grade 1 
*Only if present on the scheduled treatment day 
 
Table 5:  Dose Modifications for paclitaxel-related neuropathy 
Paresthesias/Dysesthesias 
1–7 Days Duration 
Persistent for  7 Days or 
Caused a Dose Delay 
Grade 1 – 
Paresthesias/dysesthesias that 
do not interfere with function 
Maintain paclitaxel dose 
Grade 2 – 
Paresthesias/dysesthesias 
interfering with function, but 
not activities of daily living 
Maintain paclitaxel dosea 
 
Decrease paclitaxel one dose 
levelb 
Grade 3 – 
Paresthesias/dysesthesias with 
pain or with function 
impairment that also interfere 
with activities of daily living 
First episode: 
Decrease paclitaxel one dose 
levelb 
Second episode: 
Discontinue study therapy 
First episode: 
Decrease paclitaxel one dose 
levelb or discontinue 
Second episode: 
Discontinue study therapy 


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Grade 4 – Persistent 
paresthesias/dysesthesias that 
are disabling or life-
threatening 
Discontinue study therapy 
a Must be resolved to  grade 1 to receive treatment. 
b Hold paclitaxel for persistent grade >2 neuropathy.  When  grade 1, resume treatment with 
dose modification.  If grade >2 toxicity persists after 2 weeks of delay, discontinue paclitaxel.  
 
Table 6:  Dose Modifications for paclitaxel-related musculoskeletal pain 
Note: Use of narcotics and NSAIDs is encouraged to maintain the paclitaxel dose if possible. 
Musculoskeletal Pain 
1–7 Days Duration 
Persistent for  7 Days or  
Caused a Dose Delay 
Grade 1 
(despite analgesics) 
Maintain paclitaxel dose 
Grade 2 
(despite analgesics) 
Maintain paclitaxel dose 
Maintain paclitaxel dose 
or 
Decrease paclitaxel one dose 
level* 
Grade 3 
(despite analgesics) 
First episode: 
Decrease paclitaxel one dose 
level 
 
Second episode:  
Discontinue study therapy 
First episode: 
Decrease paclitaxel one dose 
or 
Discontinue study therapy 
Second episode: 
Discontinue study therapy 
Grade 4 
(despite analgesics) 
Discontinue study therapy 
* Hold paclitaxel for persistent grade 2 or 3 musculoskeletal pain.  (Targeted therapy can be 
continued while paclitaxel is held.)  When  grade 1, resume treatment with paclitaxel dose 
modification.  If grade 2 or grade 3 toxicity persists after 2 weeks of delay, discontinue study 
therapy. 
 
8. TREATMENT-RELATED ADVERSE EVENTS 
 
8.1. Adverse Events Related to Pembrolizumab 
8.1.1. General Considerations 
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. Where appropriate, these guidelines include treatment with oral or 


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intravenous 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 does not need to follow the treatment guidance as outlined below. Refer 
to Section 7 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.  
 
8.1.2. Pneumonitis 
• 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.  
• For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed.  
• Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.  
 
8.1.3. Diarrhea/Colitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(e.g., diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and 
of bowel perforation (e.g., peritoneal signs and ileus). 
   
• 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 gastrointestinal (GI) consultation and 
endoscopy to confirm or rule out colitis.  
• For Grade 2 diarrhea/colitis administer oral corticosteroids.  
• For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high 
dose oral steroids.  
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 


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8.1.4. Type 1 Diabetes (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
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 subjects with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide 
 
8.1.5. Hypophysitis 
• 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. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
• 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.  
 
8.1.6. Hyperthyroidism and Hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor subjects 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.  
 
• Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):  
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.  
• Grade 3-4 hyperthyroidism  
o Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids.  
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  
o Replacement of appropriate hormones may be required as the steroid dose 
is tapered. 
 
8.1.7. Hepatic 


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• For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
o Treat with IV or oral corticosteroids 
• For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
8.1.8. Renal Failure or Nephritis 
• For Grade 2 events, treat with corticosteroids.  
• For Grade 3-4 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. 
 
8.1.9. 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 7 
below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. Subjects who experience an 
infusion reaction associated with administration of paclitaxel should be treated per 
institutional policy. 
 
Table 7: Pembrolizumab 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 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the treating 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 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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. 
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 
 
 
8.1.10. Reproductive Risks 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if 
they have azoospermia (whether due to having had a vasectomy or due to an 
underlying medical condition).   
 
Female subjects will be considered of non-reproductive potential if they are either:  
1) postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle 
stimulating hormone (FSH), luteinizing hormone (LH), and estradiol levels 
in the postmenopausal range may be used to confirm a post-menopausal 
state in women not using hormonal contraception or hormonal replacement 
therapy.  
OR  
2) have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion. 
OR  
3) has a congenital or acquired condition that prevents childbearing. 
 


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Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study  treatment 
and for 120 days after the last dose of study treatment by complying with one of the 
following: 
   
1) practice abstinence from heterosexual activity;  
OR  
2) use (or have their partner use) acceptable contraception during heterosexual 
activity.   
 
Acceptable methods of contraception are: 
  
Single method (one of the following is acceptable): 
• Intrauterine device (IUD) 
• Vasectomy of a female subject’s male partner  
• Contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
• Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• Cervical cap with spermicide (nulliparous women only)   
• Contraceptive sponge (nulliparous women only)  
• Male condom or female condom (cannot be used together) 
• Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
 
Note: Abstinence (relative to heterosexual activity) can be used as the sole 
method of contraception if it is consistently employed as the subject’s 
preferred and usual lifestyle and if considered acceptable by local regulatory 
agencies and IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-
thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  
 
Subjects should be informed that taking the study therapy may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study.  In 
order to participate in the study subjects of childbearing potential must adhere to the 
contraception requirement (described above) from the day of study medication 
initiation (or 14 days prior to the initiation of study therapy for oral contraception) 
throughout the study period up to 120 days after the last dose of study therapy.  If 


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there is any question that a subject of childbearing potential will not reliably comply 
with the requirements for contraception, that subject should not be entered into the 
study. 
 
9. DATA AND SAFETY MONITORING PLAN 
 
9.1. Safety Monitoring 
This protocol will be monitored according to the processes in effect for all Levine Cancer 
Institute investigator-initiated studies and the protocol-specific monitoring plan, and will 
abide by standard operating procedures set forth by both the Atrium Health Office of Clinical 
and Translational Research and the Levine Cancer Institute Clinical Trials Office.  It is the 
responsibility of the Sponsor-Investigator to monitor the safety data for this study.  The 
Sponsor-Investigator, Statistician, and other team members as needed will meet regularly to 
monitor subject consents, enrollment and retention, safety data for all subjects [including 
adverse events (AEs) for all grades and attributions, serious adverse events (SAEs)], study  
treatment administration, and validity/integrity of the data.  Documentation of these meetings 
will be kept with study records.  SAEs will be reported to the Food and Drug Administration 
(FDA) and the IRB per their requirements.  Major protocol deviations that result in a threat to 
subject safety or the integrity of the study will be reported to the FDA and IRB per their 
requirements.  The Sponsor-Investigator will submit data to the LCI Data and Safety 
Monitoring Committee according to the overarching LCI Data and Safety Monitoring Plan. 
 
9.2. Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the study protocol, 
standard operating procedures (SOPs) of the Levine Cancer Institute and Atrium Health 
Office of Clinical and Translational Research, the FDA, and other applicable regulations and 
guidelines (e.g. GCP). 
 
Subject data will be monitored by Levine Cancer Institute Research Monitors routinely for 
data quality.  This monitoring will be done by comparing source documentation to the 
eCRFs.  Any variation between the two data sets will be discussed with the Sponsor-
Investigator and/or appropriate research personnel. 
 
The study database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries 
requiring clarification will be generated and addressed by the appropriate study team member 
and/or Sponsor-Investigator.  Only authorized personnel will make corrections to the study 
database and all corrections will be documented in an electronic audit trail. 
 


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9.3. Communication Between Sites 
Investigational sites will be required to report applicable AEs, SAEs, deviations or any other 
problem that could affect the validity/integrity of the study data to the Sponsor-Investigator.    
AEs will be reported within 10 business days of the investigator learning of the event.  SAEs 
will be reported within 1 business day of the investigator learning of the event.  Drug 
administration or any other problem affecting subject safety or the integrity of the data 
should be communicated to the Sponsor-Investigator in writing as soon as possible but within 
2 business days of learning of the event.  
 
10. SAFETY DATA COLLECTION, RECORDING AND REPORTING 
 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, regular monitoring of hematology, blood chemistry and liver function test 
values, regular measurement of vital signs, and performance of history and physical 
examinations.  These assessments should be performed per the study calendar. Adverse 
events will be evaluated continuously throughout the study. Safety and tolerability, 
relationship to study treatment and intensity will be assessed according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. All adverse events (Grades 1 
– 5) will be documented in subject study charts, and recorded in the eCRF. 
 
10.1. 
Unanticipated Problem Definition 
An UAP is any incidence, experience or outcome that is unexpected, given the information 
provided in research-related documentation (e.g., Investigator’s brochure, informed consent) 
and the study population characteristics that is related or possibly related to participation in 
the research study and places the participant at an increased risk.   
 
10.2. 
Adverse Event 
10.2.1. Adverse Event Definition 
An adverse event or adverse experience is any untoward medical occurrence in a study 
subject who is administered a study drug that does not necessarily have a causal 
relationship with this study treatment.  An adverse event can therefore be any unfavorable 
and unintended sign, symptom, or disease temporally associated with the use of the study 
drug, whether or not considered related to the study drug.  Pre-existing conditions that 
increase in frequency or severity or change in nature during or as a consequence of use of 
a drug in human clinical trials are also considered adverse events.   
 
Any continuing medical condition or clinically significant laboratory abnormality with an 
onset date before the first date of study treatment administration should be considered 


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pre-existing and should be documented in the subject’s medical records and/or in the 
study chart at baseline. If the medical condition or clinically significant laboratory 
abnormality worsens while the patient is on study, it should be documented as an adverse 
event. 
 
10.2.2. An Adverse Event does not include 
An AE does not include:  
• 
relapse or progression of the underlying malignant disease; however, the 
associated signs, symptoms, or diagnoses should be recorded as adverse 
events (e.g., “jaundice” due to new or increasing liver metastases, or “tumor 
pain” or “bone pain” due to progressive disease);  
• 
medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion).  The condition that leads to the procedure is the adverse event;  
• 
situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions);  
• 
overdose of paclitaxel or concomitant medication without any signs or 
symptoms unless the subject is hospitalized for observation 
 
 
Laboratory abnormalities are usually not recorded as adverse events; however, signs 
and/or symptoms that are associated with laboratory findings requiring study 
withdrawal, dose modification, or medical intervention (e.g., anemia requiring 
transfusions or hyperglycemia requiring treatment) or other abnormal assessments 
(e.g., ECG, radiographs, vital signs) must be recorded as adverse events if they meet 
the definition of an adverse event.  In addition, laboratory abnormalities marked as 
clinically significant by the investigator should also be recorded as adverse events in 
the eCRF.  The investigator will record all clinically significant grades for laboratory 
abnormalities and will evaluate their relationship to the study treatment and subject’s 
clinical condition if/when a clinically significant laboratory abnormality occurs. 
 
10.2.3. Relationship to Study  Treatment 
The relationship to study treatment therapy should be assessed using the following 
definitions:   
 
Not Related:  Evidence exists that the AE has an etiology other than the study  treatment 
(i.e., pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication).  This includes events that are considered remotely or unlikely related to 
study treatment. 
 


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Related:  A temporal relationship exists between the event onset and administration of the 
study treatment.  It cannot be readily explained by the subject’s clinical state, intercurrent 
illness, or concomitant therapies.  In the case of cessation or reduction of the dose, the 
event abates or resolves and reappears upon rechallenge.  It should be emphasized that 
ineffective study treatment should not be considered as causally related in the context of 
AE reporting.  This includes events that are considered possibly, probably, or definitely 
related to study treatment. 
 
All adverse events (including event name, grade, start/stop date and attribution) will be 
documented in the medical record and on the case report form for this protocol. 
 
The Investigator is responsible for verifying and providing source documentation for all 
adverse events and assigning the attribution for each event for all subjects enrolled on the 
trial. 
 
10.3. 
Suspected Adverse Reaction Definition 
A SAR is an adverse event in which there is reasonable possibility that the study treatment 
caused the adverse event as defined by 21 CFR 312.32.  The Investigator is responsible for 
judging whether it is a reasonable possibility that the study  treatment caused the adverse 
event. 
 
10.4. 
“Unexpected” Definition 
An AE or SAR is to be considered unexpected if the event is not listed in the current 
Investigator Brochure, package insert or label or is not listed in the severity or specificity 
observed. 
 
10.5. 
Serious Adverse Event Definition 
Adverse events may also be considered serious adverse events. Serious adverse event or SAE 
shall mean any untoward medical occurrence in a study subject who is administered the study 
treatment that results in:  
• Death;  
• Life-threatening situation (subject is at immediate risk of death);  
• Inpatient hospitalization or prolongation of an existing hospitalization (excluding 
those for study  treatment administration, protocol-related procedures, palliative or 
hospice care, or placement of an indwelling catheter, unless associated with other 
serious events);  
• Persistent or significant disability/incapacity;  


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• Congenital anomaly/birth defect in the offspring of a patient who received study 
treatment;  
• A new cancer if the cancer is the condition of the study; or 
• Other:  Important medical events that may not result in death, be immediately life-
threatening, or require hospitalization, may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.    
o Examples of such events are:  
▪ Intensive treatment in an emergency room or at home for allergic 
bronchospasm;  
▪ Blood dyscrasias or convulsions that do not result in hospitalization; 
▪ Development of drug dependency or drug abuse.   
 
The following events do not meet the criteria for seriousness per ICH definition, but must be 
reported in the same manner as SAEs. Therefore, these events are considered serious for 
collection purposes: 
• Pregnancy or lactation 
• Overdose of pembrolizumab, as defined in Section 6.6 
 
10.6. 
Safety Reporting to the Sponsor-Investigator 
SAEs must be reported to the Sponsor-Investigator within 1 business day of awareness.  
SAEs will be captured from the time of study treatment initiation through 90 days after the 
date of the last study  treatment administration or 30 days following cessation of treatment if 
the subject initiates new anti-cancer therapy, whichever is earlier. Events that meet the 
definition of an SAE that are determined to be related and unexpected to a research 
procedure or study treatment are reportable starting with informed consent throughout the 
duration of the subject’s participation. In addition, once study treatment is initiated, SAEs 
that are determined to be related to pembrolizumab or a study procedure (regardless of 
expectedness) are reportable through the duration of the subject’s participation on the trial 
(treatment and follow-up). SAEs will be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, until progression has been stabilized, or until there 
has been acceptable resolution of the event. This may at times cause the follow-up period for 
SAEs to be greater than 90 days.  Similarly, the Sponsor-Investigator is responsible for 
following the subject during the required follow-up period even if the subject lives elsewhere 
or has been released from his or her care and is being treated under another service at LCI. 
10.7. 
Safety Reporting to the FDA 


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For investigator-initiated studies where the Sponsor-Investigator holds an IND, safety 
reporting requirements for the FDA apply in accordance with the guidance set forth in 21 
CFR312.32. The Sponsor-Investigator, or research designee, will be responsible for notifying 
FDA (using a MedWatch form) and all participating Investigators of any unexpected fatal or 
life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 
calendar days after the Sponsor's initial receipt of the information. For all other serious and 
unexpected safety events, the Sponsor-Investigator, or research designee, will notify the FDA 
within 15 calendar days. 
 
It is the responsibility of the Sponsor-Investigator, Investigators and the Protocol Team to 
ensure SAEs are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, Institutional Review Board, and FDA policy. 
 
Planned protocol deviations will be submitted to the FDA for prior approval only if the 
deviation affects the scientific validity of the study and/or the rights, safety, or welfare of 
subjects. 
 
10.8. 
Safety Reporting to the IRB 
All UAPs, protocol deviations and SAEs occurring during the conduct of a protocol will be 
reported to the IRB per IRB reporting requirements. 
 
10.9. 
Safety Reporting to Merck 
All SAEs meeting the definition of an SAE in Section 10.5 will be reportable to Merck.   
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 of study treatment initiation through 90 days following cessation of study treatment, 
or 30 days following cessation of study treatment if the subject initiates new anti-cancer 
therapy, whichever is earlier, whether or not related to pembrolizumab, will be reported 
within 2 working days of Sponsor-Investigator awareness to Merck Global Safety by the 
Sponsor-Investigator.  
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to pembrolizumab that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor-Investigator and to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to Merck by the 
Sponsor-Investigator to Global Safety facsimile number:  +1-215-993-1220 


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If the Sponsor-Investigator holds an IND, a copy of all 15 Day Reports and Annual Progress 
Reports are to be submitted as required by the FDA 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 the appropriate 
regulatory agency. 
 
10.9.1. Evaluating Adverse Events 
The treating investigator or qualified designee 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. 
 
11. MEASUREMENT OF EFFECT 
 
11.1. 
Anti-tumor Effect – Solid Tumor 
Response and progression will be evaluated in this study using the revised response 
evaluation criteria in solid tumors (RECIST) guideline version 1.1. 
 
11.1.1. Disease Parameters 
For the purposes of this study, subjects should be reevaluated for response per section 
4.5.6. In addition to the baseline scan(s), confirmatory scans should also be obtained 
not less than 4 weeks following initial documentation of objective response. Changes 
in the largest diameter (unidimensional measurement) of the tumor lesions, or shortest 
axis for lymph nodes, are used in the RECIST criteria.  
Note:  Lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used because it 
does not provide additional meaning or accuracy.  
 
Target lesions:  When more than one measurable lesion is present at baseline, all 
lesions up to a maximum of five lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and 
will be recorded and measured at baseline. Target lesions should be selected on the 


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basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. Lymph nodes merit special 
mention since they are normal anatomical structures which may be visible by imaging 
even if not involved by tumor. Pathological nodes, which are defined as measurable 
and may be identified as target lesions, must meet the criterion of a short axis of ≥ 15 
mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge 
if a node is involved by solid tumor. Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane). The smaller of these measures is the short axis. All other 
pathological nodes (those with short axis ≥ 10 mm but <15 mm) should be considered 
nontarget lesions. Nodes that have a short axis <10 mm are considered 
nonpathological and should not be recorded or followed. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 
be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.  
 
Non-target lesions: All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be followed as 
‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. 
 
11.1.2. Methods 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of study treatment and never more than 4 weeks before the beginning of 
study  treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the anti-tumor effect of a treatment.  The 
Sponsor-Investigator or designee will be responsible for performing tumor 
measurements.  The tumor measurements will be recorded on the eCRF. 
 
11.1.3. Response Criteria 


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Response will be evaluated using RECIST 1.1 Criteria. 
 Complete Response: 
• Target lesion: Disappearance of all target lesions. Any pathological lymph  
 
 
nodes (whether target or non-target) must have reduction in short axis to  
 
 
<10 mm. 
• Non-target lesion: Disappearance of all non-target lesions. All lymph nodes   
 
must be non-pathological in size (<10 mm short axis). 
 
Partial Response: 
• Target lesion: At least a 30% decrease in the sum of diameters of target, 
 
taking as reference the baseline sum diameters. 
• Non-target lesion: Not applicable 
 
Stable Disease: 
• Target lesion: Neither sufficient shrinkage to qualify for a partial response,  
 
 
nor sufficient increase to qualify for progressive disease, taking as reference   
 
the smallest sum diameters while on study. 
• Non-target lesion: Not applicable. 
 
Progressive Disease: 
• Target lesion: At least a 20% increase in the sum of diameters of target  
 
 
lesions, taking as reference the smallest sum on study (this includes the  
 
 
baseline sum if that is the smallest on study). In addition to the relative  
 
 
increase of 20%, the sum must also demonstrate an absolute increase of at 
 
least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
• Non-target lesion: Unequivocal progression (as described in RECIST version   
 
1.1) of existing non-target lesions. (Note: the appearance of one or more new   
 
lesions is also considered progression). 
 
Non-Complete Response / Non-Progressive Disease: 
• Target lesion: Not applicable 
• Non-target lesion: Persistence of one or more non-target lesion(s) 
 
 
 
Table 8: Summary of RECIST 1.1 (Subjects with measurable disease) 


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Table 9: Summary of RECIST 1.1 (Subjects with non-target disease only) 
 
RECIST 1.1 will be adapted as follows to account for the unique tumor response seen in 
this class of therapeutics, irRECIST.   
 
If imaging shows PD, tumor assessment should be repeated ≥4 weeks later in order to 
confirm PD with the option of continuing treatment for clinically stable subjects as 
discussed below in Table 10.   
 
Clinically stable is defined by the following criteria:   
• Absence of signs and symptoms indicating disease progression  
• No decline in ECOG performance status  
• Absence of rapid progression of disease  
Target 
Lesions 
Non-target Lesions 
New Lesions 
Overall 
Response 
Best Response for this 
Category also requires 
CR 
CR 
No 
CR 
Documented at least once 
 4 weeks from baseline 
CR 
Not-evaluated 
No 
PR 
NA 
CR 
Non-CR/Non-PD 
No 
PR 
Documented at least once 
 4 weeks from baseline 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Documented at least once 
 4 weeks from baseline 
Not all 
evaluated 
Non-PD 
No 
NE 
NA 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in nontarget lesions may be accepted as disease progression. 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/ Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 


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• Absence of progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention 
       
Table 10: irRECIST: Imaging and Treatment after 1st Radiologic Evidence of PD  
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging at > 4 
weeks at site to 
confirm PD 
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting confirmatory 
scan by site 
N/A 
Discontinue treatment 
Repeat scan confirms 
PD 
No additional imaging 
required 
Discontinue treatment 
(exception is possible 
upon consultation 
with Sponsor). 
N/A 
No additional imaging 
required 
N/A 
Repeat scan shows 
SD, PR or CR 
Continue regularly 
scheduled imaging 
assessments  
Continue study 
treatment at the 
Investigator’s 
discretion 
N/A 
N/A 
 
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 study 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 study 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 as outlined in Section 4.5.6 to monitor 
disease status. If radiologic progression is confirmed by subsequent tumor imaging, then the 
subject will be discontinued from study treatment.  
 
NOTE: If a subject with confirmed progression by tumor imaging (i.e. two 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 study treatment upon consultation with the Sponsor. Subjects exhibiting intolerable 
toxicity from trial therapy may NOT continue to receive trial therapy.  
 
NOTE:  In subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging as 


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outlined in Section 4.5.6 until (1) the start of new anti-cancer treatment, (2) disease progression 
(3) death, or (4) the end of the study, whichever occurs first. The same imaging modality (i.e., 
CT or MRI), acquisition and technical parameters should be used throughout the study for a 
given subject. 
 
12. STATISTICAL CONSIDERATION 
 
12.1. 
Sample Size 
This is an open-label randomized pilot study designed primarily to evaluate the safety and 
feasibility of the two regimens described earlier (Cohort A [phased regimen] and Cohort B 
[concurrent regimen]), in subjects with metastatic HER2-negative breast cancer who have 
received no more than three prior lines of chemotherapy for metastatic disease.  Based on the 
Bayesian stopping rules described in Section 12.4.4, 20 subjects per arm will enable an 
assessment for each regimen regarding whether or not evidence suggests the overall grade 3 
or 4 study treatment-related adverse event rate convincingly exceeds 0.35 (the reported rate 
for weekly paclitaxel).  Randomization to this study will continue until at least 20 subjects 
per arm have been randomized and begin study therapy. 
 
12.2. 
Endpoint Definitions  
12.2.1. Grade 3 or 4 Treatment-Related Adverse Event 
Grade 3 or 4 study treatment-related adverse events will be determined for each 
subject as a binary variable indicating whether or not the subject experienced any 
grade 3 or 4 study treatment-related adverse events according to the NCI Common 
Terminology for Adverse Events, version 4.0.  An adverse event will be considered 
study treatment related if it is determined that the event is at least possibly related to 
either paclitaxel, pembrolizumab, or both. 
 
12.2.2. Overall Survival 
Overall survival (OS) is defined as the duration of time from randomization to death 
from any cause. Subjects who are alive or lost to follow-up at the time of the 
analysis will be censored at the last known date they were alive. 
 
12.2.3. Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from 
randomization to first occurrence of either progressive disease or death. Disease 
progression must be objectively determined as per Section 11, where the date of 
progression is the date of the radiologic assessment that identified progressive 
disease.  If the subject died without documented disease progression, the date of 
progression will be the date of death. For surviving subjects who do not have 


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documented disease progression, PFS will be censored at the date of last radiologic 
assessment. For subjects who receive subsequent anti-cancer therapy prior to 
documented disease progression, PFS will be censored at the date of last radiologic 
assessment prior to the commencement of subsequent therapy. Subjects who have 
an initial PFS event immediately following 2 or more consecutive missed 
assessments will be censored at the date of the last assessment prior to those missed 
assessments. For participants with only one missed assessment, the documented 
progressive disease status and assessment date will be used.  PFS will be determined 
for each subject using the RECIST 1.1 criteria.  For subjects treated with 
pembrolizumab, PFS will also be calculated using the irRECIST criteria as an 
exploratory endpoint. 
 
12.2.4. Objective Response 
Objective response will be determined for each subject as a binary variable 
indicating whether or not the subject achieved a best overall response of CR or PR 
as determined by criteria described in Section 11.  Objective response will be 
determined for each subject using the RECIST 1.1 criteria.  For subjects treated with 
pembrolizumab, objective response will also be calculated using the irRECIST 
criteria as an exploratory endpoint. 
    
12.2.5. Duration of Response 
Duration of Response (DoR) is defined as the duration of time from the first 
assessment that determined a CR or PR to the date of the first occurrence of 
progressive disease or death.  Progression events and the censoring mechanism for 
DoR will be the same as described for PFS in Section 12.2.3.  DoR will be 
determined for each subject using the RECIST 1.1 criteria.  For subjects treated with 
pembrolizumab, DoR will also be calculated using the irRECIST criteria as an 
exploratory endpoint. 
 
12.2.6. Disease Control  
Disease control will be determined for each subject as a binary variable indicating 
whether or not the subject achieved a best overall response of CR, PR, or SD (for 
at least 24 weeks), as determined by the criteria described in Section 11.  Disease 
control will be determined for each subject using the RECIST 1.1 criteria.  For 
subjects treated with pembrolizumab, disease control will also be calculated using 
the irRECIST criteria as an exploratory endpoint.  
 
12.2.7. Safety Endpoints 
Safety endpoints will include study treatment administration (total number of 
doses taken, and total doses taken as a percent of total number of intended doses), 


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AEs, SAEs, deaths while on study therapy, and selected laboratory 
determinations. 
 
12.3. 
Analysis Populations 
The intent-to-treat (ITT) population will consist of all randomized subjects.  The ITT 
population will be used for the purposes of the subject disposition summary.  The 
evaluable population will consist of all randomized subjects who begin study therapy.  
OS, PFS, and all safety analyses will be conducted on the evaluable population. 
Analyses of objective response, DoR, and disease control will be conducted on those 
subjects in the evaluable population who have measureable disease at baseline. 
 
12.4. 
Analysis Methods 
12.4.1. Timing of Analysis 
Analyses on this study will be conducted on a continuous basis in order to assess the 
Bayesian stopping rules for toxicity described in Section 12.4.4.  An analysis of all 
endpoints will occur after the best overall response for each subject has been determined.  
A final analysis of the study will be conducted after the PFS censoring rate reduces to 
20% or when all subjects have been on study for at least two years (whichever occurs 
first). 
 
12.4.2. Subject Disposition 
An accounting of all consenting subjects will be provided at the end of the study. This 
will include a breakdown of subjects who consented, were randomized, treated, 
discontinued study treatment, died, and were lost to follow-up or withdrew consent. 
 
12.4.3. Baseline Patient and Disease Characteristics 
A summary of subject demographics and disease-related characteristics will be completed 
and subject medical history will be assessed. 
 
12.4.4. Primary Analysis 
This study is planned to enroll approximately 20 subjects in each study treatment arm. 
The primary objective is to evaluate the overall grade 3 or 4 study treatment related 
adverse event rate for each study arm.  It is not anticipated that the addition of 
pembrolizumab to standard chemotherapy will increase the grade 3 or 4 toxicity rate.  It 
has been reported that the rate of any grade 3 or 4 toxicity with weekly paclitaxel is 0.35 
[Budd, ASCO abstract 2013, CRA1008].  If it becomes evident that the grade 3 or 4 
toxicity rate on either arm convincingly exceeds 0.35, the study arm will be halted. The 
stopping rule will hold enrollment if the posterior probability of grade 3 or 4 toxicity risk 
exceeding 0.35 is 0.50 or higher.  The prior distribution for this monitoring rule is beta 


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(7,13).  This means that our prior assumption regarding the proportion of grade 3 or 4 
toxicity is 0.35, and there is 90% probability that this proportion is between 0.188 and 
0.530.  The operating characteristics of the stopping rule are given in the following table 
and are based on 5000 simulations. 
 
Table 11: Operating Characteristics of the Stopping Rule 
Number of grade 3 or 
4Toxicities 
Max. Denominator Cutoff for Early 
Stopping 
Posterior Probability 
Pr(Risk>0.35|Data) 
1 
2 
0.5352 
2 
5 
0.5302 
3 
8 
0.5216 
4 
11 
0.5148 
5 
14 
0.5040 
6 
16 
0.5438 
7 
19 
0.5334 
 
 
12.4.5. Secondary Analyses 
Overall survival and PFS will be analyzed by study arm using Kaplan Meier 
techniques.  Medians, 25th, and 75th percentiles will be estimated.  Selected landmarks 
for OS and PFS rates will be obtained from the Kaplan Meier estimates.  Differences 
between the arms will be assessed qualitatively using a stratified Cox proportional 
hazards model, including hormone receptor status as the stratification variable.  An 
estimate of the hazard ratio and 95% confidence interval will be provided.  Duration 
of response will be analyzed in a similar fashion as described for OS and PFS.  
Objective response rate and disease control rate will be estimated for each arm along 
with corresponding 95% Clopper-Pearson confidence intervals.  Differences between 
the arms will be assessed qualitatively using a stratified logistic regression, including 
hormone receptor status as the stratification variable.  Estimates of the odds ratios and 
95% confidence intervals will be provided.   
 
12.4.6. Safety Analyses 
Incident rates for treatment-emergent adverse events, SAEs, and deaths while on study 
therapy will be summarized.  Treatment-emergent adverse events are defined as follows: 
• An adverse event that occurs after study treatment start that was not present at the 
time of study treatment start; or 


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24 
 
• An adverse event that increases in severity after study treatment start if the event 
was present at the time of study treatment start. 
 
 
12.4.7. Exploratory Analyses 
Cox proportional hazards models and logistic regression will be used to assess the 
correlation between additional baseline biomarkers with clinical outcomes.  The 
biomarkers identified in Section 1.4 will be assessed qualitatively as deemed appropriate. 
 
12.5. 
Interim Analyses 
No formal interim analysis for efficacy is planned for this study.  However, results will 
be continuously monitored for safety using the Bayesian stopping rules described in 
Section 12.4.4. 
 
13. STUDY COMPLETION 
 
13.1. 
Completion  
The study will be considered complete when one or more of the following conditions is 
met: 
• 
All subjects have completed all study visits. 
• 
All subjects have discontinued from the study. 
• 
The IRB, FDA, LCI DSMC, Sponsor-Investigator discontinues the study because 
of safety considerations. 
• 
The Sponsor-Investigator defines an administrative or clinical cut-off date. 
 
13.2. 
Termination 
The study will be terminated when one or more of the following conditions occur: 
If risk-benefit ratio becomes unacceptable owing to, for example: 
• Safety findings from this study (e.g. SAEs) 
• Results of any interim analysis 
• Results of parallel clinical studies 
• Results of parallel animal studies (e.g. toxicity, teratogenicity,  
       carcinogenicity or reproduction toxicity). 
• If the study conduct (e.g. recruitment rate; drop-out rate; data quality; 
protocol compliance) does not suggest a proper completion of the trial 
within a reasonable time frame. 
The Sponsor-Investigator has the right to close the trial at any site and at any time. 


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For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties. 
• All affected institutions must be informed as applicable according to local 
law.   
• In case of a partial study closure, ongoing subjects, including those in 
follow-up, must be taken care of in an ethical manner. 
 
 
 
14. RETENTION OF RECORDS 
 
Essential documentation (e.g. adverse events, records of study drug receipt and dispensation), 
including all IRB correspondence, will be retained for at least 2 years after the investigation 
is completed.  Documentation will be readily available upon request. 
 
15. ETHICAL AND LEGAL ISSUES 
 
15.1. 
Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and  
documentation of this study, are designed to ensure that the Investigator abide by Good 
Clinical Practice (GCP) guidelines and under the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). 
 
Documented approval from appropriate agencies (e.g. DSMC, IRB, FDA) will be obtained 
for all participating centers before start of the study, according to GCP, local laws, 
regulations and organizations.  When necessary, an extension, amendment or renewal of IRB 
approval must be obtained and forwarded to Merck (if applicable). 
 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the Investigators may not modify or alter the procedures described in this 
protocol.   
 
Modifications to the study protocol will not be implemented by the Sponsor-Investigator 
without discussion and agreement by Merck (if applicable).  However, the Investigators may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior approval from applicable agencies.  As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the appropriate agencies.  Any deviations from the 
protocol must be explained and documented by the Investigator. 


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26 
 
 
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Sponsor-Investigator is responsible for personally overseeing the treatment of 
all study subjects.  The Sponsor-Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol and 
all applicable regulations and guidelines regarding clinical trials both during and after study 
completion. 
 
The Sponsor-Investigator will be responsible for assuring that all the required data will be 
collected and properly documented. 
 
15.2. 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. 
 
 
 
16. PUBLICATION POLICY 
 
The Investigator must send a draft manuscript of the publication or abstract to Merck Sharp 
& Dohme Corp, prior to submission of the final version for publication or congress 
presentation. All relevant aspects regarding data reporting and publication will be part of the 
contract between Merck Sharp & Dohme Corp and the Investigator. 
 
The Investigator will ensure that the information regarding the study be publicly available on 
the internet at www.clinicaltrials.gov.  
 
 


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Seidman AD, Tiersten A, Hudis C, et al: Phase II trial of paclitaxel by 3-hour 
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Seidman AD, Berry D, Cirrincione C, et al: Randomized phase III trial of weekly 
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Mauri D, Kamposioras K, Tsali L, et al: Overall survival benefit for weekly vs. 
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Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in 
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Kantoff PW, Higano CS, Shore ND, et al: Sipuleucel-T immunotherapy for 
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Pedoeem A, Azoulay-Alfaguter I, Strazza M, et al: Programmed death-1 pathway 
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Sheppard KA, Fitz LJ, Lee JM, et al: PD-1 inhibits T-cell receptor induced 
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FEBS Lett 574:37-41, 2004 
 
12. 
Yao S, Chen L: PD-1 as an immune modulatory receptor. Cancer J 20:262-4, 
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Keir ME, Butte MJ, Freeman GJ, et al: PD-1 and its ligands in tolerance and 
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14. 
Sanmamed MF, Chen L: Inducible expression of B7-H1 (PD-L1) and its selective 
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15. 
Topalian SL, Drake CG, Pardoll DM: Immune checkpoint blockade: a common 
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16. 
Pembrolizumab Investigator's Brochure. Edition 9.  
 
17. 
Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 
treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised 
dose-comparison cohort of a phase 1 trial. Lancet 384:1109-17, 2014 


Protocol Number:  LCI-BRE-H2N-PEPP-001 
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18. 
Ribas A, Puzanov I, Dummer R, et al: Pembrolizumab versus investigator-choice 
chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, 
phase 2 trial. Lancet Oncol 16:908-18, 2015 
 
19. 
Robert C, Schachter J, Long GV, et al: Pembrolizumab versus Ipilimumab in 
Advanced Melanoma. N Engl J Med 372:2521-32, 2015 
 
20. 
Nanda R, Chow Q, Dees C, et al. Pembrolizumab in patients with advanced triple-
negative breast cancer: Phase Ib KEYNOTE-012 study. J Clin Oncol. 2016:Published online on 
May 2, 2016. 
 
21. 
Chen G, Emens LA: Chemoimmunotherapy: reengineering tumor immunity. 
Cancer Immunol Immunother 62:203-16, 2013 
 
22. 
National Comprehensive Cancer Network Clincal Practice Guidelines in 
Oncology.  Breast.  Version 1.2016.  
 
23. 
DeNardo DG, Brennan DJ, Rexhepaj E, et al: Leukocyte complexity predicts 
breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1:54-
67, 2011 
 
24. 
Zhang L, Dermawan K, Jin M, et al: Differential impairment of regulatory T cells 
rather than effector T cells by paclitaxel-based chemotherapy. Clin Immunol 129:219-29, 2008 
 
25. 
Nizar S, Copier J, Meyer B, et al: T-regulatory cell modulation: the future of 
cancer immunotherapy? Br J Cancer 100:1697-703, 2009 
 
26. 
Chan OT, Yang LX: The immunological effects of taxanes. Cancer Immunol 
Immunother 49:181-5, 2000 
 
27. 
Kaufmann DE, Walker BD: Programmed death-1 as a factor in immune 
exhaustion and activation in HIV infection. Curr Opin HIV AIDS 3:362-7, 2008 
 
28. 
Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat 
Rev Cancer 12:252-64, 2012 
 
29. 
Lynch TJ, Bondarenko I, Luft A, et al: Ipilimumab in combination with paclitaxel 
and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a 
randomized, double-blind, multicenter phase II study. J Clin Oncol 30:2046-54, 2012 
 
30. 
Reck M, Bondarenko I, Luft A, et al: Ipilimumab in combination with paclitaxel 
and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a 
randomized, double-blind, multicenter phase 2 trial. Ann Oncol 24:75-83, 2013 
 
31. 
Rhen T, Cidlowski JA: Antiinflammatory action of glucocorticoids--new 
mechanisms for old drugs. N Engl J Med 353:1711-23, 2005 
 
32. 
Sparano JA, Wang M, Martino S, et al: Weekly paclitaxel in the adjuvant 
treatment of breast cancer. N Engl J Med 358:1663-71, 2008 
 
33. 
Markman M, Kennedy A, Webster K, et al: An effective and more convenient 
drug regimen for prophylaxis against paclitaxel-associated hypersensitivity reactions. J Cancer 
Res Clin Oncol 125:427-9, 1999 
 
34. 
Berger MJ, Vargo C, Vincent M, et al: Stopping paclitaxel premedication after 
two doses in patients not experiencing a previous infusion hypersensitivity reaction. Support 
Care Cancer 23:2019-24, 2015 
 
35. 
Quock J, Dea G, Tanaka M, et al: Premedication strategy for weekly paclitaxel. 
Cancer Invest 20:666-72, 2002 
 
36. 
Mittendorf EA, Philips AV, Meric-Bernstam F, et al: PD-L1 expression in triple-
negative breast cancer. Cancer Immunol Res 2:361-70, 2014 


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37. 
Basu GD, Ghazalpour A, Vader R,  et al. Expression of novel immunotherapeutic 
targets in luminal breast cancer patients. Presented at San Antonio Breast Cancer Symposium. 
December 9-13, 2014. San Antonio, TX. Abstract P5-04-08.  
 
38. 
Loi S, Sirtaine N, Piette F, et al: Prognostic and predictive value of tumor-
infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive 
breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based 
chemotherapy: BIG 02-98. J Clin Oncol 31:860-7, 2013 
 
39. 
Adams S, Gray RJ, Demaria S, et al: Prognostic value of tumor-infiltrating 
lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast 
cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32:2959-66, 2014 
 
40. 
Salgado R, Denkert C, Demaria S, et al: The evaluation of tumor-infiltrating 
lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 
2014. Ann Oncol 26:259-71, 2015 
 
41. 
Schalper KA: PD-L1 expression and tumor-infiltrating lymphocytes: Revisiting 
the antitumor immune response potential in breast cancer. Oncoimmunology 3:e29288, 2014 
 
42. 
Le DT, Uram JN, Wang H, et al: PD-1 Blockade in Tumors with Mismatch-
Repair Deficiency. N Engl J Med 372:2509-20, 2015 
 
43. 
Lipson EJ, Velculescu VE, Pritchard TS, et al: Circulating tumor DNA analysis as 
a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with 
immune checkpoint blockade. J Immunother Cancer 2:42, 2014 
 


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APPENDICES 
APPENDIX 1: ECOG PERFORMANCE SCALE 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but fully ambulatory, restricted in physically 
strenuous but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours. 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead 
 
 

ICF_001.pdf: 
Official Title: LCI-BRE-H2N-PEPP-001: A Pilot Study of Paclitaxel Plus Pembrolizumab in 
Patients with Metastatic HER2-Negative Breast Cancer 
NCT03018080 
IRB-Approved Date: 6/9/2021 


Levine Cancer Institute / Protocol Number LCI-BRE-H2N-PEPP-001 
Page 1 of 18 
 
 
Antoinette Tan, MD 
 
Advarra IRB Approved Version 9 Jun 2021 
 
 
 
 
 
ATRIUM HEALTH 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
 
Sponsor / Study Title: 
  
Levine Cancer Institute/ A Pilot Study of Paclitaxel Plus 
Pembrolizumab in Patients with Metastatic HER2-Negative 
Breast Cancer  
 
Protocol Number: 
 
 
LCI-BRE-H2N-PEPP-001 
Principal Investigator: 
 
Antoinette Tan, MD 
Telephone: 
 
 (24 Hours) 
 (24 Hours) 
 
Address: 
Levine Cancer Institute 
 
 
 
INTRODUCTION 
 
Dr. Antoinette Tan and her associates (the investigators) are asking you to participate in a research 
study at Levine Cancer Institute (LCI) and Atrium Health (AH). The purpose of this study is to 
determine if the research study drug, pembrolizumab, in combination with chemotherapy, is 
successful at treating metastatic breast cancer and if it is safe.  You are being asked to take part in 
this study because you have been diagnosed with metastatic breast cancer.   
 
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. 
Clinical trials include only people who choose to take part. Please take your time to make your 
decision about taking part. You have also been told that you have the option not to participate. You 
may discuss your decision with your friends and family. You can also discuss it with your health care 
team. If you have any questions, you can ask your study doctor for more explanation.  
 
This study is being carried out under the sponsorship of Levine Cancer Institute (LCI).  Merck is the 
pharmaceutical company that makes the research drug, pembrolizumab, which will be used in this 
study. 
 
WHY IS THIS STUDY BEING DONE? 
 
This is a research study to determine if the study drug, pembrolizumab (KEYTRUDA), is safe to 
use in combination with a chemotherapy drug called paclitaxel. Other goals in this study are to learn 
about the effect of combining paclitaxel and pembrolizumab on tumor growth, and to understand if 
there is a difference when giving paclitaxel and pembrolizumab on different study treatment 
schedules.  
 


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Antoinette Tan, MD 
 
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We will compare giving the chemotherapy paclitaxel alone for 2 cycles (6 weeks) followed by giving 
pembrolizumab and paclitaxel during future cycles to giving pembrolizumab and paclitaxel starting 
with the first cycle. We also want to collect information to learn about DNA (the genetic material in 
the cells in the body that serve as blueprints for making proteins) and proteins in the blood and 
tumor that may predict or show an effect of pembrolizumab.  
 
Pembrolizumab has been approved by the Food and Drug Administration (FDA) in the United 
States to treat several different cancers to include locally recurrent unresectable or metastatic triple 
negative breast cancer (TNBC) in combination with chemotherapy and whose tumor express PD-L1 
as determined by an FDA approved test. Paclitaxel is an FDA-approved anticancer drug. Paclitaxel 
is a standard chemotherapy used to treat metastatic breast cancer.   
 
Subjects in this study will be randomized to one of the two study treatment schedule groups. 
Randomized means you have a 50:50 chance, the same as a flip of a coin, of being assigned to either 
study treatment group.  You or your study doctor will not be able to pick which study treatment 
group you will be in on this study.  
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
About 40 subjects will take part in this study at Levine Cancer Institute and associated sites. About 
20 subjects will be randomized into each of the Cohorts, A and B.  
 
HOW THE STUDY WORKS 
 
Before you begin the study (Baseline): 
In order to participate in this study, you will need to review, sign and date this consent form. By 
doing so, you are giving us permission to determine if you are eligible to participate in this study. To 
determine if you are eligible, we will need to collect important information from your medical record 
about your demographics (for example age, race, etc.), medical history, your current disease, any 
anti-cancer treatments you are receiving or have received before, and any medications you are taking 
or have recently taken.  We will also need to perform some tests, and a complete physical exam to 
make sure that you are eligible for the study. Some of these tests may need to be repeated if they are 
done more than 14 days before the first day you receive the study drug(s). We will also need to 
collect blood for laboratory tests. 
 
If not already done within 28 days before the first day you receive the study drug(s), you will have a 
scan of the chest, abdomen, and pelvis. The scan will be done using an x-ray machine that uses a 
computer to take pictures or computerized tomography (CT) scan, or a scan that takes pictures of 
the body using magnetic waves to look at soft tissue, called magnetic resonance imaging or MRI. We 
will also ask that you have a bone scan within 28 days of the first day you receive the study drug(s) 
to determine the presence or absence of disease in your bones at baseline. 
 
A blood or urine pregnancy test will be done for women who can have children, within 14 days of 
the first day you receive the study drug(s) on this trial.  
 


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The results of the pregnancy test must be negative in order to be in the study. An ECG must also be 
performed within 14 days of the first day you receive the study drug(s). 
 
We would like to test your tumor for tumor markers or certain types of tumor cells. We will need to 
collect a fresh tumor biopsy before you receive your first day of study drug(s). However, if your 
study doctor determines that a new or fresh biopsy is not possible due to difficulty getting to a 
tumor site or a safety concern, then we may be able to use an archived (previously collected) tumor 
tissue sample as long as it was collected no more than 12 months prior to this consent being signed.  
However, if an archived tissue sample is not available, not large enough, or was collected more than 
12 months ago, you will not be eligible to participate in this study.  
 
If we are able to collect a fresh tumor sample, we will ask to do a core needle biopsy or a punch 
biopsy of some of the cancerous tumor.  A core needle biopsy is when a needle is inserted into the 
body from a small surgical cut and into the tumor. The needle is hollow on the inside and removes a 
small amount of tissue from the tumor. A punch biopsy is when a small round piece of tissue about 
the size of a pencil eraser is removed using a sharp, hollow, circular instrument.  The biopsy will be 
performed as an outpatient procedure using a local anesthetic.  
 
You may be required to sign a separate non-study related consent that is standard procedure for 
performing surgical procedures to have the biopsy. 
 
We would also like to collect and test archived tumor tissue samples available from storage. This 
may include tissue from your first diagnosis and from your diagnosis of metastatic disease. We 
would like to compare these earlier samples to the samples collected for this study. We would also 
like to store your archived tissue samples for future, currently unplanned research. We will ask your 
permission to do this at the end of the consent form. 
 
Blood samples will be collected prior to study treatment initiation, for research purposes to look at 
certain features in your blood that may be related to your disease. We would also like to test your 
blood for the BRCA 1 and BRCA 2 mutations if you have not previously been tested for these. The 
BRCA1 and BRCA2 mutations are changes in the genes that help control a cell’s normal growth. If 
you have not been tested for BRCA 1 and 2 and do not want to be tested for it, you may still be 
eligible to be in the study. 
 
If you qualify for the study and agree to participate, you will be randomized and enrolled to the 
study, and we will make arrangements to for you to begin receiving study treatment on the study.  
 
During the study (Intervention; number of visits/cycles): 
Cycles on this study are scheduled to last 21 (+/-3) days. You will be scheduled to receive study 
drug(s) on Days 1 and 8 of each cycle.  
 
The study treatment cohort that you have been assigned will determine the schedule in which you 
receive the study drug(s). 
 
Cohort A: Phased Regimen 
Subjects randomized into cohort A will receive paclitaxel on Days 1 and 8 of each cycle.  


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However, they will not receive their first dose of pembrolizumab until Cycle 3 Day 1. 
Pembrolizumab will be administered on Day 1 of each cycle starting at Cycle 3 and until the final 
dose of study treatment on study. 
 
Cohort B: Concurrent (at the same time) Regimen 
Subjects randomized into cohort B will receive pembrolizumab on Day 1 of each cycle starting with 
Cycle 1, and paclitaxel on Days 1 and 8 of each cycle. Pembrolizumab will be administered on Day 1 
of each cycle and until the final dose of study treatment on study.  
 
In both cohorts, subjects will be given a dose of pre-medication steroids before the paclitaxel 
(chemotherapy) infusion to prevent possible allergic or hypersensitivity reactions. If you do not have 
allergic reactions and tolerate the chemotherapy regimen well over time, the investigator may decide 
to reduce and then remove the steroid pre-medication from the regimen.  Also, if a scheduled study 
treatment of paclitaxel is delayed or missed, you may be rescheduled by your investigator to receive a 
replacement dose on a later date, within the same cycle. Finally, if you have a side effect to the 
paclitaxel chemotherapy or if the investigator believes you have received maximum benefit from 
paclitaxel, he/she may reduce or remove the paclitaxel from your study treatment regimen.  
 
Some assessments will be scheduled to occur on each day that you receive study drug(s) on this 
study, including vital signs and blood draws. Other assessments and procedures will occur on set 
intervals. Scans to monitor your disease will occur at least every 6 weeks on this study and may occur 
less frequently after you have received 6 months of study treatment. Other assessments will occur 
on specific days and sometimes only on a specific cycle. Several procedures and assessments will 
occur only on Day 1 of each cycle, including documentation of any changes in medical history, 
physical exam, and collection of blood to test your liver’s function, other organ function, and other 
blood levels of importance. 
 
We will also schedule an additional biopsy to take a tumor sample as described above ideally from 
the same site biopsied at baseline (if possible), within 5 days of Cycle 3 Day 1 if your disease can be 
safely biopsied. 
 
After you complete the intervention (Post-intervention; one visit and follow-up): 
After you receive your final dose of study drug(s) on trial, we will schedule an end of study treatment 
visit to take place within 31 days from the last day of study treatment. We will update any changes in 
your medical history, perform a physical exam, collect vital signs and blood samples, and review any 
symptoms you have or have had. You will continue to have scans at the scheduled described above 
to monitor your disease until your disease worsens or you start new cancer therapy. We will check 
back with you by phone, in writing, or during clinic visits every 6 months thereafter. 
 
Optional collections 
We will also ask if you would be willing to provide additional samples of blood or additional samples 
of your tumor for additional research. This includes additional blood collections (explained in detail 
at the end of this consent), and additional tumor biopsies within 5 days of Cycle 5 Day 1 and at the 
time of disease progression (if your disease progresses). We will further explain the optional tumor 
biopsies at the end of this consent form. 


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RISKS 
 
If you decide to take part in this study, study drugs used may cause all, none or some of the 
following side effects listed.  Also, there is always the risk of developing very uncommon or 
previously unknown side effects.  There may be other side effects or risks that are not known at this 
time. There also is a risk of death.  
 
Pembrolizumab: 
Pembrolizumab works by helping your immune system to fight your cancer. 
However, pembrolizumab can also cause your immune system to attack normal organs and tissues 
in your body and can affect the way they work, which can result in side effects. These side effects 
may be serious (for example, causing hospitalization or be life-threatening), may result in death, 
and/or may occur after you stop taking pembrolizumab. These side effects can affect more than 
one of your normal organs and tissues at the same time. 
 
Very common side effects, some may be serious (for example, causing hospitalization, life-
threatening or where noted, may cause death); seen in 20% or more of subjects treated with 
pembrolizumab include the following: 
 
• Diarrhea (loose or watery stools) 
• Itching of the skin 
• Cough 
• Nausea 
• Fatigue 
 
Common side effects, some may be serious; seen in 5% to less than 20% of subjects treated with 
pembrolizumab include the following: 
 
• Joint pain 
• Fever 
• Back pain 
• Rash 
• Pain in your belly 
• Loss of skin color 
• Not enough thyroid hormone so you may feel tired, gain weight, feel cold, 
and/or have infrequent or hard stools (hypothyroidism) 
• Low levels of salt in the blood that may cause you to feel tired, feel confused, 
have a headache, have muscle cramps, and/or feel sick to your stomach 
(hyponatremia) 
 
Uncommon side effects, some may be serious; seen in 1% to less than 5% of subjects treated with 
pembrolizumab include the following: 
 


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• Too much thyroid hormone so you may feel anxious, feel angry, have trouble sleeping, feel 
weak, tremble, sweat, feel tired, and/or have loose or watery stools (hyperthyroidism) 
• Inflammation of the lungs, so you may feel short of breath and cough (pneumonitis)  
• Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or 
watery stools, and black, tarry, sticky stools or stools with blood or mucus (colitis) 
• Inflammation of the skin so you may have peeling of the skin, itchiness, and/or skin 
redness. The skin inflammation (for example, peeling, itching and redness) could also be 
widespread throughout your body. More severe skin reactions may involve the inside of 
your mouth, the surface of your eye and genital areas, and/or may cause the top layer of 
your skin to peel from all over your body which can cause severe infection (Severe skin 
reactions, including Stevens-Johnson syndrome/or toxic epidermal necrolysis, which may 
be serious or potentially life-threatening)  
• Infusion reaction, where you may feel dizzy or faint, feel flushed, get a rash, have a fever 
and/or feel short of breath, experience a decrease in your blood pressure at the time of 
receiving your infusion (IV) or just after, or have pain at the site of infusion. 
 
Rare side effects, some may be serious; seen in less than 1% of subjects treated with 
pembrolizumab include the following: 
 
• Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like 
not eating, feel tired, have a mild fever, have a pain in the right side of your belly, yellow 
eyes and skin, and dark urine (hepatitis) 
• Inflammation of the pituitary gland (a gland in the head), which may cause you to feel sick 
to your stomach or have headaches, changes in your behavior, double vision, few to no 
menstrual cycles, weakness, vomiting and dizziness, or fainting (hypophysitis) 
• Adrenal glands (glands on top of the kidneys) may not make enough hormone, which could 
cause tiredness, weight loss, muscle weakness, feeling faint, having joint, muscle and belly 
aches, nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes darkening 
of the skin like a suntan (adrenal insufficiency)  
• Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, 
swelling and low back pain (nephritis) 
• Inflammation of the muscles so you may feel weak or have pain in the muscles (myositis) 
• Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you 
may have severe pain in the top part of your belly that may move to your back, feel sick to 
your stomach, and have vomiting that gets worse when you eat (pancreatitis) 
• Inflammation of the eye so you may have eye redness, blurred vision, sensitivity to light, eye 
pain, see floaters or have headaches (uveitis) 
• Type 1 Diabetes, a condition that can cause too much sugar in your blood, feeling thirstier 
than usual, frequent urination and weight loss. You are likely to need regular insulin shots 
• Inflammation of the nerves that may cause pain, weakness or tingling in your hands and 
feet, and may spread to your legs, arms and upper body leading to severe muscle weakness 
and possible temporary paralysis (inability to move) (Guillain-Barré syndrome) 
• Inflammation of the middle layer of your heart wall (myocarditis) that may cause your heart 
to have difficulty pumping blood throughout your body, which can cause chest pain, 


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shortness of breath and swelling of the legs. You may experience a fast or irregular 
heartbeat that may cause dizziness or fainting (myocarditis) 
• Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. This 
condition may lead to change in your heart rate, blood pressure, body temperature, and the 
rate at which food is converted into energy (thyroiditis) 
• A condition that may make you feel weak and tired and may cause drooping of the eyelids, 
blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and 
legs, or difficulty breathing (myasthenic syndrome/myasthenia gravis including 
exacerbation) 
• The formation of small clusters of immune cells (called granulomas) in parts of your body 
such as your lymph nodes, eyes, skin or lungs (sarcoidosis) 
• Inflammation of the brain (encephalitis) with confusion and fever. This may also include: 
disorientation, memory problems, seizures (fits), changes in personality and behavior, 
difficulty speaking, weakness or loss of movement in some parts of your body, and loss of 
consciousness 
• Inflammation of the spinal cord (myelitis) with pain, numbness, tingling, or weakness in the 
arms or legs, bladder or bowel problems including needing to urinate more frequently, 
urinary incontinence, difficulty urinating, and constipation  
• Inflammation of the blood vessels 
 
Additionally, since pembrolizumab was approved in September 2014, the following side effects have 
been reported by people receiving pembrolizumab. These side effects were voluntarily reported 
from a group of people of unknown size. It is not possible to estimate the frequency of this side 
effect: 
• Inflammation of the joints which may include joint pain, stiffness and/or swelling (arthritis) 
• Severe responses of the immune system that cause the body to attack its own blood cells, 
spleen, liver, lymph nodes, skin and brain. This may include fever, rash, inflammation of the 
liver, yellowing of the skin, an enlarged liver and spleen, low blood counts, and enlarged 
lymph nodes. The nervous system may also be affected and cause confusion, seizures, and 
even coma (hemophagocytic lymphohistiocytosis) 
• Changes in eyesight, eye pain, whitish patches on the skin and hearing loss (Vogt-Koyanagi-
Harada syndrome) 
• Inflammation and scarring of the bile ducts (tubes that carry digestive fluid that is made in 
the liver). This can cause symptoms similar to those seen with inflammation of the liver 
(hepatitis) such as pain in the right side of your belly, yellow eyes and skin, feeling tired, and 
itching 
 
If you have had an allogeneic stem cell transplant (a procedure in which a person receives blood-
forming stem cells from a donor), you may experience graft versus host disease (GvHD), which may 
include diarrhea, skin rashes, and liver damage, after receiving pembrolizumab. Sometimes this 
condition can lead to death. 
 
If you have had a solid organ transplant (for example, if you have received a kidney or heart 
transplant), you may experience rejection of the transplanted organ. Your doctor will monitor you 


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and should tell you what signs and symptoms you should report depending on the type of organ 
transplant that you have had. 
 
Paclitaxel: 
 
Paclitaxel is an FDA-approved and standard anticancer drug for the treatment of metastatic breast 
cancer. Therefore, the risks and side effects of receiving paclitaxel in the treatment of metastatic 
breast cancer have been studied extensively. 
 
Tell your healthcare provider right away if you have: 
 
• Severe stomach pain 
• Severe diarrhea 
 
The most common side effects include:  
 
• Low red blood cell count (anemia) feeling weak or tired 
• Hair loss 
• Numbness, tingling, or burning in your hands or feet (neuropathy) 
• Joint and muscle pain 
• Nausea and vomiting 
• Hypersensitivity reaction – trouble breathing; sudden swelling of your face, lips, tongue, 
throat, or trouble swallowing; hives (raised bumps) or rash 
• Diarrhea 
• Mouth or lip sores (mucositis) 
• Infections – if you have a fever (temperature above 100.4°F) or other sign of infection, tell 
your healthcare provider right away 
• Swelling of your hands, face, or feet 
• Bleeding events 
• Irritation at the injection site 
• Low blood pressure (hypotension) 
 
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. 
These are not all of the possible side effects of paclitaxel. For more information, ask your 
healthcare provider or pharmacist. 
 
Allergic Reaction Risks 
 
As with taking any drug, there is a risk of allergic reaction.  If you have a very serious allergic 
reaction, you may be at risk of death.  Some symptoms of allergic reactions are:   
 
• Rash 
• Wheezing and difficulty breathing  
• Dizziness and fainting 


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• Swelling around the mouth, throat or eyes 
• A fast pulse 
• Sweating 
 
Please seek treatment immediately and tell the study doctor and study staff if you have any of these 
symptoms, or any other side effects, during the study. 
 
Other Risks: 
 
Electrocardiogram (ECG) procedure may cause minimal discomforts during the attachment and 
removal of the ECG leads to and from the skin. 
 
Tumor Biopsy:  Having biopsies performed may cause pain, bruising, bleeding, redness, low blood 
pressure, swelling and/or infection at the site of the biopsy, shortness of breath from lung collapse 
and rarely, death.  An allergic reaction to the anesthetic may occur. A scar may form at the biopsy 
site.  Other potential risks will be described to you and discussed with you by physicians who 
conduct these biopsies. 
 
CT Scan: CT scans are used to create images of internal bones and organs using radiation.  The 
effect of exposure to radiation adds up over a lifetime.  The amount of radiation exposure involved 
in this trial will not be significantly greater than for subjects with your disease who do not take part 
in the trial.   
 
In rare cases, the contrast solution that may be given for a CT scan may cause an allergic reaction.  
Severe allergic reactions can be life threatening.  CT contrast solution can cause kidney damage, 
especially if you are diabetic, dehydrated (lost body water) or elderly. 
 
Magnetic Resonance Imaging (MRI): Risks of MRI include claustrophobia, discomfort due to 
lying still for a prolonged period of time, and other factors which will be described to you and 
discussed with you at the MRI center.   
 
Blood Drawing Risks: During this study, blood will be drawn from a vein to perform tests that 
allow your study doctors to see how you are doing. Drawing blood may cause pain where the needle 
is inserted, and there is a small risk of bruising and/or infection at the place where the needle is 
inserted. Some people experience dizziness, upset stomach, or fainting when their blood is drawn. 
 
Pregnancy Precautions:  
 
Female:  
It is not known if the study drug(s) may affect an unborn or nursing baby. If you are pregnant, trying 
to become pregnant or breast-feeding, you may not be in the study.  The study doctor will perform a 
blood or urine pregnancy test before the start of the study, if you are able to have a baby. 
 
If you are able to have a baby, you must avoid having sex (abstinence) or use reliable birth control 
methods during the study and for a period of 120 days after your last dose of study drug.  If you 


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become pregnant during the study you must notify the study doctor right away.  The study drugs will be 
stopped and you will be taken out of the study.  
 
Male: 
There may be risks if you are male and your partner is pregnant or trying to become pregnant.  If you 
are male and your partner is able to have a baby, you and your partner must avoid having sex 
(abstinence) or use reliable birth control methods during the study and for a period of 120 days after 
your last dose of study drug pembrolizumab.   
 
If your partner becomes pregnant during the study, you must notify the study doctor right away.  If 
your partner is already pregnant when you begin the study, you must use a condom (male) during 
the study and for a period of 120 days after your last dose of pembrolizumab.  You must also agree 
to not donate sperm during the study and for a period of 120 days after your last dose of study drug. 
 
Male and Female: 
The following birth control methods for subjects who are able to conceive a child or a subject’s partner 
are allowed during the study as per local regulations or guidelines: 
 
Two (2) of the following barrier methods in combination: 
 
• Diaphragm with spermicide (cannot be used with cervical cap/spermicide) 
• Cervical cap with spermicide (women who’ve never had a child)   
• Contraceptive sponge (women who’ve never had a child)  
• Male condom or female condom (cannot be used together) 
• Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection 
 
OR 
 
One (1) of the following: 
 
• Intrauterine Device (IUD) 
• Vasectomy of a female subject’s male partner  
• Contraceptive rod implanted into the skin 
Privacy Risks 
 
If your genetic research data are shared with unauthorized users, you may be at risk of loss of the 
privacy of your health data.  This risk is minimized by protections described in the Confidentiality 
section below. 
 


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WILL I BENEFIT FROM PARTICIPATING IN THIS STUDY? 
 
If you agree to take part in this study, there may or may not be direct medical benefit to you. 
Information learned from this study may help other people in the future.  The Sponsor will not 
provide you with ownership or any financial benefits that may result from this study. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
 
Instead of being in this study, you have other options including: 
 
• Receiving treatment without participation on this study 
• Treatment with other anti-cancer drugs 
• No therapy with comfort care only 
 
Please talk to your study doctor about these and other options along with their risks and benefits. 
Please ask any questions you may have and take as much time as you need to make your decision. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
 
You will not receive payment for taking part in this study. For more information on clinical trials 
and insurance coverage, you can visit the National Cancer Institute’s web site at 
http://cancer.gov/clinicaltrials/understanding/insurance-coverage   You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this web site.  Another way to get the 
information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.  
 
Some of the tests or treatments used in this study may be part of standard care used to maintain 
your health and would be recommended even if you did not take part in this study.  You or your 
insurance company will be responsible for the cost of this standard care.  Pembrolizumab, tests, 
and procedures done for the sole purpose of the study, including tumor biopsies and blood drawn 
for research will be provided at no cost to you. If you have a biopsy as part of your standard care 
during any of the time-points when a research biopsy is required, the cost of the biopsy will be 
billed to you or your insurance. After tissue has been collected during a biopsy, a portion of the 
tissue will be used for the purposes of the study. If you do not require a biopsy as part of your 
standard care during the time-point when a research biopsy is required, you will have a biopsy for 
research purposes only, and the cost of the biopsy will not be billed to you or your insurance. 
 
You may wish to discuss coverage with your insurance company before agreeing to participate in 
this research study. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
 
If you become ill or are hurt while you are in the study, get the medical care that you need right 
away. 
 
In the event that you are harmed as a result of your participation in this study, inform your study 
doctor immediately so you can access medical treatment.  


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You and/or your health plan will be charged for this treatment in the usual manner. The study will 
not pay for standard medical treatment.  
 
You still have the right to make a claim through the legal system even if you sign and date this form, 
accept medical care, or accept payment for medical expenses. 
 
WHAT IF I WANT TO QUIT THE STUDY LATER ON? 
 
Your participation in this study is completely voluntary. You should feel under no pressure to be in 
the study.  If you decide not to be in the study, your decision to not participate will not in any way 
harm your relationship with your doctors or with Atrium Health.  You are free to stop being in the 
study if you change your mind after entering it.  This would not harm your relationship with your 
doctors or Atrium Health.   
 
If you choose to withdraw from the study, please notify the study doctor in writing at: 
 
Antoinette Tan, MD 
 
 
 
The study doctor may choose to involuntarily withdraw you from the study for any reason. 
 
We will tell you about new medical findings that may affect your willingness to continue in the 
study. 
 
CONFIDENTIALITY 
 
The records of this study will be kept private.  In any sort of report we might publish, we will not 
include any information that will make it possible to identify a patient.  Your record for this study 
may, however, be reviewed and/or photocopied by the sponsor, by Atrium Health, or by 
representatives of the Food and Drug Administration or other government agencies.  To that extent, 
confidentiality is not absolute. 
 
To ensure that your information collected for this study will be kept private, your name will not be 
used whenever possible.  A code will be used instead of your name.  All of your study data will be 
kept in a secure location. 
 
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans and most employers to discriminate against 
you based on your genetic information. 
 
This law generally will protect you in the following ways: 
 
• Health insurance companies and group health plans may not request your genetic information 
that the sponsor will get from this research. 


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• Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums. 
• Employers with 15 or more employees may not use your genetic information that the sponsor 
will get from this research when making a decision to hire, promote, or fire you or when setting 
the terms of your employment. 
 
All health insurance companies and group health plans and all employers with 15 or more people must 
follow this law. 
 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
If you wish to take part in this clinical study, you will be asked to sign this consent form.  It allows 
the study sponsor and the study investigator to collect, process and pass on to the sponsor 
organizations any relevant personal health information collected from you during the study.  These 
are activities routinely carried out during all clinical studies. 
 
You have been told that personal information about you (including sensitive personal health 
information, such as your medical history and your racial/ethnic origin if relevant to the study) will 
be reviewed, collected on a computer database, stored in electronic or manual files, audited, and/or 
otherwise processed by: 
 
• the study doctor and study staff, 
• the study sponsor and/or its associated companies, Levine Cancer Institute, 
• regulatory or other governmental authorities of the United States and other countries, 
• other persons authorized by the study sponsor, 
• Atrium Health employees, 
• Caris Life Sciences employees (de-identified clinical data), 
• Inivata Limited employees (de-identified clinical data) 
• other persons or agencies as required by law or allowed by federal regulations. 
 
You have been told that your personal data are being collected and processed to: 
 
• check your suitability to take part in the study, 
• monitor your treatment with the study drug, 
• compare and pool study treatment results with those of other subjects in clinical studies, 
• support the development of the study drug, 
• support the licensing application for regulatory approval of the study drug in the world  
• support the marketing, distribution, sale and use of the study drug anywhere in the world.    
 
You have been told that your personal information may be processed within the U.S. or elsewhere in 
the world or transferred to or from the U.S. for review, processing and/or storage by an associated 
company or a carefully selected third-party organization.  By signing this document, you explicitly 
consent to the transfer of your personal information, including sensitive personal information, 
collected during this clinical study, for review, processing and/or storage.  Your personal health 


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information may be further shared by the groups above.  If shared by them, the information will no 
longer be covered by the Privacy Rule.  However, the groups are committed to keeping your 
personal health confidential. 
 
You may refuse this authorization to transfer your personal information.  If you choose not to agree 
to this authorization, you might be ineligible to participate in the study.  If you decide not to sign 
this authorization, that will not harm your relations with your doctors or with Atrium Health.  
 
You have the right to inspect your medical record at any time. Your research record may be 
unavailable until the conclusion of the study. At that point, it will be available.  Please speak with the 
study doctor if you desire to access your record. 
 
You have been told whenever your personal information is processed; it will be kept confidential 
and secure, to the best of our ability.  It will be used only for the purpose for which it was collected. 
 
This Authorization does not have an expiration date. You have been told that according to the 
guidelines for good clinical practice, the study investigator and sponsor will keep your personal 
information for at least 6 years. If you do not withdraw this Authorization in writing, it will remain 
in effect indefinitely.  If you wish to revoke authorization to use your personal information, you will 
notify the study doctor in writing at the address and telephone number listed on the first page of this 
form. Some of the data obtained from your record prior to your revocation may still be used if 
considered necessary for the study.   
 
FINANCIAL DISCLOSURE  
 
None of the doctors asking you to participate in this study has received or will receive money or 
other benefits for personal use from Merck Sharp & Dohme Corp, that developed pembrolizumab 
used in this study. 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or have 
questions, concerns or complaints about the study, please contact the Investigator at the telephone 
number listed on the first page of this consent document.  If you seek emergency care, or 
hospitalization is required, alert the treating physician that you are participating in this research 
study.   
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects.  If you have any questions about your rights as a research subject, and/or 
concerns or complaints regarding this research study, contact: 
 
• By mail: 
Study Subject Adviser 
 
 
 


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• or call toll free:        
 
• or by email:              
 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00019078. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
OPTIONAL TUMOR BIOPSIES 
 
The study doctor and her associates (the investigators) are asking you to allow additional biopsies of 
your tumor to be collected at specific time points and used for the purposes of research. All 
information for the main study’s informed consent form, still applies to this part of the informed 
consent.  
 
Your study doctor would like to collect additional tumor biopsies within 5 days of Cycle 5 Day 1 and 
at the time of disease progression, if your disease progresses. Regardless of your decision to allow 
additional tumor biopsies to be taken, you may still participate in the main study, if you choose to. 
However, you must participate in the main study in order to be eligible for the additional biopsies. 
 
The samples from your tumor biopsy will be stored at the Levine Cancer Institute Bio Specimen 
Repository, a place where human samples are securely stored and where any of your remaining 
archived and/or freshly collected samples will be stored.   
 
If you decide, at a later date to withdraw your consent for any reason, you have the option not to 
allow Levine Cancer Institute to use your tumor samples for testing by contacting the study doctor 
at the telephone number or address listed on the first page of this form. At your request, tumor 
samples will be destroyed, only if they have not already been tested. 
 
Do you give permission to have optional tumor biopsies for the purposes of research? Participation 
in these collections are optional, and refusing to participate will not affect your eligibility for the 
study or the study treatment given. 
 
 
Yes____________________ No____________________ Initials____________________ 


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OPTIONAL AND FUTURE STUDIES – BIO SPECIMEN COLLECTION 
 
The study doctor and her associates (the investigators) are asking you to allow your blood to be 
collected and used for the purposes of research. In addition, the study doctor is also asking you to 
allow your tissue (including previously collected tissue and tissue collected as part of your 
participation in the study) to be stored for future, currently unplanned research after research testing 
on your tissue has been completed. All information for the main study’s informed consent form, still 
applies to this part of the informed consent. Regardless of your decision to participate in this 
optional blood collection and/or tissue storage, you may still participate in the main study, if you 
choose to. However, you must participate in the main study in order to be eligible for participation 
in this optional blood collection and/or tissue storage.  
 
If you agree to participate in the optional and future research - blood collection, we will ask to 
collect approximately 20 mL or about a tablespoon and a half of blood at each collection time point. 
We would like to collect blood before the first day of study treatment on this study, before cycle 3 
day 1 of this study, before cycle 5 day 1 on this study, and after your study doctor has confirmed 
disease progression (if your disease progresses). 
 
If you agree to participate in tissue banking for future research, we will store a portion of previously 
collected tissue and any tissue collected as part of your participation on this study to store for future, 
currently unplanned research. 
 
If you agree to donate samples, they will be stored at the Levine Cancer Institute Bio Specimen 
Repository, a place where human samples are securely stored and where any of your remaining 
archived and/or freshly collected samples will be stored.   
 
If you decide, at a later date to withdraw your consent for any reason, you have the option not to 
allow Levine Cancer Institute to use your blood samples and/or tissue for testing by contacting the 
study doctor at the telephone number or address listed on the first page of this form. Blood and 
tissue samples will be destroyed only if they have not already been tested. 
 
Participation in these collections are optional, and refusing to participate will not affect your 
eligibility for the study or the study treatment given. 
 
Do you give permission to have optional blood collections for the purposes of storage for 
future research?  
 
Yes____________________ No____________________ Initials____________________ 
 
Do you give permission to have a portion of your previously collected tissue and any tissue 
collected during the study to be stored for future research?  
 
Yes____________________ No____________________ Initials____________________ 


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TRIPLE NEGATIVE BREAST CANCER SUBJECTS ONLY: SUBJECT DERIVED 
XENOGRAFT 
You are being asked to take part in this assessment, because you have different disease 
characteristics than some of the other subjects on this study, and have been diagnosed with triple 
negative breast cancer.  Triple negative breast cancer means you do not express any of three 
common hormones (progesterone, estrogen) or protein (human epidermal growth factor receptor 2 
– Her2/neu) receptors in your breast cancer. These receptors are proteins that detect specific 
hormones to signal cellular growth. By choosing to participate on this study, you are agreeing to 
allow part of your pre-study treatment tumor sample and blood to be used for the purposes of 
research. All of the above information, for the main part of the study, still applies to this part of the 
informed consent. 
 
If you have triple negative breast cancer, and you still have enough remaining tumor sample after 
testing your tumor for cellular characteristics and biomarker expression, we will take a portion of the 
collected pre-study treatment tumor specimen and a blood sample and send it to an external 
laboratory, Champions Oncology Inc. laboratory. Your name and other personal identifying 
information will not be provided to this external lab, and your specimens will be labeled with a 
unique identifier code that is assigned to you. De-identified clinical information will be provided to 
Champions. 
 
A part of your tumor will be injected and regrown in mice that are immune deficient. Immune 
deficient means that the immune system isn’t strong enough to fight disease or is absent. Your blood 
sample will be used to compare to the regrown tumor sample. Through this process, a model of 
your disease can be maintained and tested for translational or laboratory purposes. The goal is to 
evaluate tumor response and resistance to treatment, and to sequence (determine the order of) the 
tumor DNA structure and the regular DNA blood sample for comparison. 
 
If you decide, at a later date to withdraw your consent for any reason, you have the option not to 
allow Levine Cancer Institute to use your tumor sample for testing by contacting the study doctor at 
the telephone number or address listed on the first page of this form. Tumor and/or tissue samples 
will be destroyed, only if they have not already been tested. 
 
Participation in this study is optional, and refusing to participate will not affect your relationship 
with your doctors, Levine Cancer Institute, or Atrium Health. 
 
If you have any additional questions, you can ask your study doctor for more explanation. 
 
Do you give permission to use your tumor sample for the purposes of research? 
 
 
Yes____________________ No____________________ Initials____________________ 


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STATEMENT OF CONSENT   
 
I have read this form and its contents were explained to me.  I agree to be in this research study for 
the purposes listed above.  All of my questions were answered to my satisfaction.  I will receive a 
signed and dated copy of this form for my records.  I am not giving up any of my legal rights by 
signing and dating this form. Dr. Tan, one of her associates, or her designee, will give me a copy of 
this signed and dated form.  
 
___________________________________ 
____/____/____  _________ 
Signature of Research Subject 
 
Date 
 Time 
 
___________________________________ 
Printed Name of Research Subject 
 
 
STATEMENT OF PERSON EXPLAINING CONSENT  
 
I have carefully explained to the subject the nature and purpose of the above study.  There has been 
an opportunity for the subject to ask questions about this research study.  I have been available to 
answer any questions that the subject has about this study. 
 
___________________________________ 
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Signature of Person Explaining Consent 
Date 
 Time 
 
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Printed Name of Person Explaining Consent