Phase II Study of Pembrolizumab and Capecitabine for Advanced Triple Negative and Hormone-Refractory Breast Cancer
Phase: PHASE2
Conditions: Estrogen Receptor Negative, HER2/Neu Negative, Progesterone Receptor Negative, Recurrent Breast Carcinoma, Stage III Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer, Triple-Negative Breast Carcinoma
Sponsor: Northwestern University

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Phase II Study of Pembrolizumab and Capecitabine for Advanced Triple Negative and Hormone- 
Refractory Breast Cancer
Principal Investigator:
William John Gradishar, MD, FACP, FASCO 
Professor
Department of Medicine
Division of Hematology & Oncology
Feinberg School of Medicine
676 N. St. Clair St. – Suite 850
Chicago, IL 60611 
(312) 695-4541
w-gradishar@northwestern.edu
Sub-Investigator(s):
Northwestern University Feinberg School of Medicine
William Gradishar, MD 
Lisa Flaum, MD
Massimo Cristofanilli, MD
Northwestern Lake Forest Hospital
Valerie Nelson, MD
Biostatistician:
Alfred Rademaker, PhD
rademaker@northwestern.edu
Study Intervention(s):
Pembrolizumab (MK-3475; Keytruda) and Capecitabine (Xeloda)
IND Number:
132860
Funding Source:
Drug support from Merck
Version Date:
Amendment 7   9 .13.2018
Coordinating Center:
Clinical Research Office
Robert H. Lurie Comprehensive Cancer Center
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL 60611 
www.cancertrials.northwestern.edu
CONFIDENTIAL
This material is the property of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Do not disclose or use except as authorized in writing by the study sponsor.
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS ............................................................................................................... 3
STUDY SCHEMA ............................................................................................................................... 5
STUDY SUMMARY ......................................................................................................................... …6
1.0
INTRODUCTION – BACKGROUND & RATIONALE...........................................................8
2.0
OBJECTIVES .................................................................................................................... …12
3.0
PATIENT ELIGIBILITY ...................................................................................................... …. 13
4.0
TREATMENT PLAN ............................................................................................................  17
5.0
STUDY PROCEDURES.....................................................................................................30
6.0
ENDPOINT ASSESSMENT.................................................................................................. 31
7.0
ADVERSE EVENTS ............................................................................................................. 34
8.0
DRUG INFORMATION ........................................................................................................ . 42
9.0
CORRELATIVES/SPECIAL STUDIES................................................................................48
10.0
STATISTICAL CONSIDERATIONS ...................................................................................49
11.0
STUDY MANAGEMENT.....................................................................................................50
REFERENCES ................................................................................................................................. .53
APPENDICES.................................................................................................................................... 54
History of Protocol Amendments………………………………………………………………………59
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CNS
Central Nervous System 
CR
Complete Response 
CrCL
Creatinine Clearance
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board
D5W
Dextrose % in Water
DNA
Deoxyribonucleic acid
ECOG
Eastern Cooperative Oncology Group
EMR
Electronic Medical Record
eCRF
Electronic Case report form
FOCBP
Females of Child-Bearing Potential
5-FU
5-Fluorouracil
HER2
Epidermal Growth Factor receptor 2
IV (or iv)
Intravenously
ITIM
Immunoreceptor Tyrosine –based Inhibition Motif
IHC
Immuno-Histochemical
INR
International Normalized ratio
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
LLN
Low Limit of Normal
MTD                
Maximum Tolerated Dose 
MBC                
Metastatic Breast Cancer 
MEL                 Melanoma3
mAB
Monoclonal Antibody
NCI
National Cancer Institute
NS
Normal Saline
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PD-1
Programmed Death -1-Ligand
PD
Progressive Disease
PFS
Progression Free Survival
PK
Pharmacokinetics
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response 
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PT
Prothrombin Time 
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase 
SPGT
Serum Glutamic Pyruvic Transaminase 
TNBC
Triple Negative Breast Cancer
TILs
Tumor Infiltrating Lymphocytes
Q2W
Every 2 weeks
Q3W
Every 3 weeks
ULN
Upper Limit of Normal
UPIRSO
Unanticipated problem involving risk to subjects or others
WBC
White Blood Cells
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STUDY SCHEMA
Metastatic
TNBC
& Hormone 
refractory 
breast cancer
Pembrolizumab
200mg IV Day 1 
of 21 day cycle
+ 
Capecitabine
1000mg/m2 PO 
BID Days1-14 of
21 day cycle
Response Assessment after 3 
cycles
Toxicity assessment every 
cycle
Treatment will continue until:
-Disease progression
-Unacceptable toxicity
-Death
-Withdrawal from study
Follow-up 3 months up to 2 year after discontinuation of the 
study drugs for PFS with visits and/or phone calls
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STUDY SUMMARY
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Title
Phase II study of Pembrolizumab and Capecitabine for advanced triple 
negative and hormone-refractory breast cancer.
Study Design
This is an open-label, single arm, Phase II study of the combination of 
pembrolizumab and capecitabine in locally advanced or metastatic Triple 
Negative (TNBC) and hormone-refractory Breast Cancer.
Study Center(s)
Northwestern University – Robert H. Lurie Comprehensive Cancer
Center.(RHLCCC)
Objectives
Primary objective(s):
To evaluate the median progression-free survival (median PFS) for 
participants receiving pembrolizumab with capecitabine for the treatment 
of locally advanced or metastatic TNBC and hormone-refractory MBC.
Secondary Objectives:
-The objective response rate (ORR) for participants receiving 
pembrolizumab with capecitabine for the treatment of locally advanced or 
metastatic TNBC and hormone-refractory MBC.
-To assess Safety and tolerability for the combination of pembrolizumab 
and capecitabine for the treatment of locally advanced or metastatic 
TNBC and hormone-refractory MBC.
Diagnosis & Key
Eligibility Criteria
Key Inclusion criteria:
1)The target population for this study is:
 
Patients( both female and male).with triple negative locally 
advanced or metastatic (stage IV) breast cancer
 
Patients with hormone refractory negative locally advanced or 
metastatic (stage IV) breast cancer.
 
Patients must be ≥18 years and have a life expectancy of ≥ 90 
days.
 
Patients with central nervous system (CNS) involvement may 
participate if they meet all the following criteria:
 
At least 4 weeks from prior therapy completion 
(including radiation and/or surgery) to starting 
the study treatment,
 
Clinically stable with respect to the CNS tumor at 
the time of screening
Key Exclusion criteria:
 
Patients with documented HER2-positive metastatic disease are 
not eligible, even if their primary breast cancer was HER2- 
negative.
 
History of autoimmune disease, including but not limited to 
myasthenia gravis, myositis, autoimmune hepatitis, systemic 
lupus erythematosus
 
Patients who have evidence of active, noninfectious pneumonitis 
or have a history of severe pneumonitis that required treatment 
with steroids are not eligible for this study.
 
Patients with impaired GI function or GI disease that may 
significantly alter absorption of oral capecitabine.
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Treatment Plan
This will be an open-label, single-arm, II study of the combination of 
pembrolizumab and capecitabine in locally advanced and metastatic triple 
negative and hormone-refractory breast cancer.
Pembrolizumab will be administered at 200mg IV on Day 1 of each cycle 
(1 cycle=21 days). Capecitabine will be administered at 1000 mg/m2 BID 
D1-14 q21d. Patients will be instructed to take the morning dose of 
capecitabine before coming to clinic for pembrolizumab infusion. Patients 
will continue to receive treatment until disease progression or 
unacceptable toxicity. After discontinuation of study drugs, patients will be 
assessed every 3 months up to 1 year for PFS, with visits and/or phone 
calls.
Statistical Methodology
For PFS, assumptions are that the addition of pembrolizumab will 
increase PFS to 5 months compared to historical control of 3 months. 
Assuming exponential survival, with 27 evaluable patients, there is 80% 
power to detect this difference using a one-tailed z test at p<0.05.
Recruitment will last approximately 30 months (2.5 years) and 
participants will be followed for a maximum of 2 years. The primary 
outcomes chosen is PFS based on mechanism of action. A total of 30 
patients may be accrued in order to achieve 27 evaluable patients.
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1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1 Disease Background
1.1.1
Overview on Breast Cancer
Approximately 231,840 women will be diagnosed with breast cancer in the 
United States in 2015 making it the most frequently diagnosed
cancer (excluding skin cancer) in women and ranking second as a cause of cancer 
death. Triple negative breast cancer (TNBC), defined as estrogen receptor 
negative, progesterone receptor negative and human epidermal growth factor 
receptor 2 (HER2) negative, accounts for 9-21% of newly diagnosed breast 
cancers1, 2. TNBC is associated with more aggressive disease both histologically 
and clinically. Patients with TNBC have a lower relapse free survival and 
decreased overall survival (OS) when compared to hormone receptor positive 
disease. In an observation study conducted by Pogoda(13), metastatic disease 
occurred in 35% of all TNBC patients within 6 years of diagnosis.
1.1.2
Treatment Options for Metastatic Triple Negative Breast Cancer and
Hormone-Refractory Metastatic Breast Cancer
Current treatment options for metastatic breast cancer (MBC) are not curative 
and therapy aims to prolong survival while minimizing toxicity to preserve or 
improve quality of life for patients. In TNBC, there are no approved biologic or 
targeted agents and chemotherapy is the standard of care. While combination 
chemotherapy can provide higher rate of objective response and longer time to 
progression, it is associated with higher toxicity and minimal survival benefit3. 
Current recommendations for single agent therapies include anthracyclines, 
taxanes, anti- metabolites and microtubule inhibitors. Ultimately, patients will 
develop resistance to these therapies. Similarly, patients with hormone-positive 
metastatic breast cancer eventually become resistant to endocrine therapy, and 
chemotherapy is the standard of care.
1.1.3
The Immune System and Breast Cancer
The importance of intact immune surveillance in controlling outgrowth of 
neoplastic transformation has been known for decades. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue 
and favorable prognosis in various malignancies. In particular, the presence of 
CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells 
seems to correlate with improved prognosis and long-term survival in many solid 
tumors.
The Programmed Death-1-Ligand (PD-1 receptor-ligand) interaction is a major 
pathway hijacked by tumors to suppress immune control. The normal function of 
PD-1, expressed on the cell surface of activated T- cells under healthy conditions, 
is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2). The structure of murine PD-1 has been resolved. PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type 
(V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling
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molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases
SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which 
are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-
1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 
as both molecules regulate an overlapping set of signaling proteins. PD-1 was 
shown to be expressed on activated lymphocytes including peripheral CD4+ and 
CD8+ T-cells,
B-cells, T regs and Natural Killer cells.  Expression has also been shown during 
thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells. The ligands for PD-
1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety 
of cell types, including non-hematopoietic tissues as well as in various tumors. 
Both ligands are type I transmembrane receptors containing both IgV- and IgC-
like domains in the extracellular region and contain short cytoplasmic regions 
with no known signaling motifs.
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through 
the T-cell receptor.  PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen- presenting cells found in 
lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to 
control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues. Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor. PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma (MEL). This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic 
intervention.
1.2
Intervention Background & Overview
1.2.1
Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal 
antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. KeytrudaTM 
(pembrolizumab; MK-3475) has recently been approved in the United 
States for the treatment of patients with unresectable or metastatic 
melanoma and disease progression following ipilimumab and a BRAF 
inhibitor, if BRAF V600 mutation positive.
In Oct. 2015, the U.S. Food and Drug Administration granted accelerated 
approval for Keytruda (pembrolizumab) to treat patients with advanced 
(metastatic) non-small cell lung cancer (NSCLC) whose disease has 
progressed after other treatments and with tumors that express a protein 
called PD-L1. Keytruda was approved for use with a companion 
diagnostic, the PD-L1 IHC 22C3 pharmDx test, the first test designed to 
detect PD-L1 expression in non-small cell lung tumors.
An open-label Phase I trial (Protocol 001) is being conducted to evaluate 
the safety and clinical activity of single agent MK-3475. The dose 
escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3
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mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors. All three dose levels were well tolerated 
and no dose-limiting toxicities were observed. This first in human study 
of MK-3475 showed evidence of target engagement and objective
evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and
10 mg/kg Q2W). No MTD has been identified to date. 10.0 mg/kg Q2W, 
the highest dose tested in PN001, will be the dose and schedule utilized 
in Cohorts A, B, C and D of this protocol to test for initial tumor activity. 
Recent data from other clinical studies within the MK-3475 program has 
shown that a lower dose of MK-3475 and a less frequent schedule may 
be sufficient for target engagement and clinical activity.
PK data analysis of MK-3475 administered Q2W and every 3 weeks 
(Q3W) showed slow systemic clearance (0.22L/day), limited volume of 
distribution (7.7L), and a long half-life (26 days) (refer to Package Insert). 
Pharmacodynamic data (IL-2 release assay) suggested that peripheral 
target engagement is durable (>21 days).  This early PK and 
pharmacodynamic data provides scientific rationale for testing a Q2W
and Q3W (dosing schedule.
A population pharmacokinetic analysis has been performed using serum 
concentration time data from 476 patients. Within the resulting population 
PK model, clearance and volume parameters of MK-3475 were found to 
be dependent on body weight. The relationship between clearance and 
body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights. MK-3475 has 
been found to have a wide therapeutic range based on the melanoma 
indication. The differences in exposure for a 200 mg Q3W fixed dose 
regimen relative to a 2 mg/kg Q3W body weight based regimen were
well within the established exposure margins of 0.5 – 5.0 for MK-3475 in 
the melanoma indication. The exposure margins are based on the notion 
of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. 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.
The KEYNOTE-012 trial is a phase Ib study of patients with metastatic 
triple-negative breast cancer with tumors positive for the expression of 
PD-L1. 32 patients were treated with pembrolizumab at 10mg/kg Q2W 
until progression of disease. Preliminary analysis of the data 
demonstrated an overall response rate of 18.5% including one complete 
response (3.7%), four partial responses (14.8%) and seven patients with 
stable disease (25.9%).
Embryofetal Toxicity:
Based on its mechanism of action, pembrolizumab can cause fetal harm 
when administered to a pregnant woman. Animal models link the PD-
1/PD-L1 signaling pathway with maintenance of pregnancy through 
induction of maternal immune tolerance to fetal tissue. If this drug is used 
during pregnancy, or if the patient becomes pregnant while taking this 
drug, apprise the patient of the potential hazard to a fetus. Advice
females of reproductive potential to use highly effective contraception 
during treatment with pembrolizumab and for 4 months after the last 
dose of pembrolizumab.
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1.2.2
Capecitabine
Capecitabine is an oral fluoropyrimidine approved for treatment of 
metastatic breast cancer. Capecitabine is metabolized to 5-FU by an 
enzymatic process catalyzed by thymidine phosphorylase which has 
higher activity in tumor tissue compared to normal tissue4. A phase II trial 
by Blum et al demonstrated safety and efficacy of capecitabine in
patients with paclitaxel refractory metastatic breast cancer with an overall 
response rate of 20% and a median duration of response of 8.1 months5. 
Another phase II study of capecitabine monotherapy in patients with both 
anthracycline and taxane pretreated metastatic breast cancer 
demonstrated an overall response rate of 28% and median time to 
progression of 4.9months6. Capecitabine has been associated with a 
favorable risk-benefit profile without having a negative impact on quality
of life in patients with metastatic breast cancer7. Given the favorable 
safety profile and relative ease of administration, capecitabine is an ideal 
agent for consideration of combination therapy for palliative management 
of metastatic triple negative breast cancer. Currently, there is no 
randomized control data suggesting survival benefit to combined 
chemotherapy with capecitabine and the added chemotherapy comes 
with the risk of additional toxicity.
1.3
Rationale for the Current Study
Metastatic TNBC and hormone-refractory MBC are responsible for a 
disproportionate number of breast cancer deaths. Therefore, there is a significant 
unmet need to advance the management of MBC. Moreover, there have been 
fewer advances in the treatment of triple negative breast cancer than have been 
seen with other subtypes. Interestingly, triple negative breast cancers respond 
better to chemotherapy, but can become chemotherapy resistant and have a 
higher recurrence rate compared with other breast cancer subtypes. One 
mechanism of chemoresistance in TNBC may be the tumors ability to evade the 
innate immune system. It has been demonstrated that programmed death-1- 
ligand 1 (PD-L1) expression in cancer cells contributes to immunoresistance8. 
TNBC and basal subtypes of breast cancer are associated with increased 
expression of PD-L19 and this is associated with poor clinical prognosis10. 
Combining chemotherapy with immunotherapy may allow for a better response to 
chemotherapy and the innate immune system, leading to improved outcomes. 
Recent data show safety of pembrolizumab in metastatic TNBC. Capecitabine is 
an FDA approved drug for metastatic breast cancer, which is effective in TNBC. 
Combining pembrolizumab with standard of care chemotherapy capecitabine
may improve upon survival outcomes for this patient population, whose median 
survival remains less than one year.
The standard dose used in clinical practice for capecitabine is 1000 mg/m2. 
Therefore it would not be necessary to repeat a dose finding phase I study. 
Furthermore, 2 studies have opened to date (one phase 2, one phase 3) that are 
evaluating this combination in gastrointestinal (GI) cancers. We do not feel it is 
necessary to repeat a phase I in only breast cancer patients.
Hence, we are proposing to do a Phase II study of the combination of 
pembrolizumab and capecitabine for Metastatic Triple Negative Breast Cancer 
(TNBC) and Hormone refractory breast cancer.
1.4
Exploratory Studies:
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1. PD-L1 immunohistochemical (IHC) assessment, baseline tissue biopsy of a 
metastatic will be obtained for PD-L1 immunohistochemical (IHC) assessment. 
QualTek developed and validated a PD-L1 IHC assay using Merck's proprietary
22C3 antibody, and this will be used for the study. The study site’s pathology core 
will be used to store, process, and ship samples to QualTek. The presence of PD- 
L1 expression will be correlated with response (PFS, RR) and other clinical- 
pathologic factors in an attempt to define a subset of patients that may benefit from 
pembrolizumab.
Note: The requirement for biopsy (fresh) may be omitted per treating physician’s 
discretion, if the biopsy would cause undue morbidity to the patient and if 
enough tissue from a prior metastatic lesion (archival biopsy) is not available.
2. ORR and median-PFS assessment will be done using the irRECIST criteria, 
which is now applied to immunotherapeutic drugs.
2.0
OBJECTIVES
2.1
Primary objective(s):
 
To evaluate the median progression-free survival (median PFS) for participants 
receiving pembrolizumab with capecitabine for the treatment of locally advanced 
or metastatic TNBC and hormone-refractory MBC. This will be assessed by using 
RECIST 1.1 criteria.
2.2
Secondary Objectives:
 To describe the objective response rate (ORR) for participants receiving 
pembrolizumab with capecitabine for the treatment of locally advanced or 
metastatic TNBC and hormone-refractory MBC. This will be assessed by using 
RECIST 1.1 criteria.
 To describe the safety and tolerability of the combination of pembrolizumab and 
capecitabine for the treatment of locally advanced or metastatic TNBC and 
hormone-refractory MBC. All adverse events will be assessed by NCI CTCAE
4.03 criteria
2.3

Exploratory Objectives
Analysis of expression of Programmed Cell death 1 Ligand 1 (PD-L1 ) through
immunohistochemical (IHC) analysis : A baseline tissue biopsy of a metastatic
site will be obtained for PD-L1 immunohistochemical (IHC) assessment, from all 
patients. An archived specimen may be used (metastatic tissue only) if
collected  no more than 2 months of registration. Otherwise fresh biopsy of 
metastatic lesion is mandatory at baseline and should be performed no more 
than 2 months prior to registration. 
Note: The requirement for biopsy (fresh) may be omitted per treating physician’s 
discretion, if the biopsy would cause undue morbidity to the patient and if 
enough tissue from a prior metastatic lesion (archival biopsy) is not available.
Note: PD-L1 IHC assay from QualTek will be used for the study. 
Please refer to section 9.1 and laboratory manual for more details.

To evaluate ORR and median-PFS using irRECIST:
To evaluate efficacy endpoint median-Progression Free survival (PFS), 
assessment will be done up to 1 year after discontinuation of the study drugs. 
Assessment will be done using irRECIST (see Table 6)
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ORR will be assessed every 3 cycles (every 9 weeks) with imaging (CT
chest/abdomen/pelvis and bone scan[if indicated]). Assessment will be done using 
irRECIST.
3.0
PATIENT ELIGIBILITY
The target population for this study is patients with locally advanced and metastatic TNBC and 
hormone-refractory MBC. This will be a single-center trial conducted at Northwestern University. 
Patients will be recruited by the clinical team at Lynn Sage Comprehensive Breast Center of 
Northwestern University. The investigators may also utilize the services of the Cancer Trial 
Recruitment Nurse Coordinator as needed to assist with recruitment.
A total of 30 subjects will be needed to obtain 27 evaluable patients on this trial. Approximately 
10 potentially eligible patients are seen per month, and it is anticipated that at least 1 per month will 
be accrued. Potential patients may be referred to the Principal Investigator (PI) at Northwestern 
University, Dr. William Gradishar, via the Clinical Research Office at (312) 695-1301.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer 
to Section 11 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have histologically-confirmed unresectable, locally advanced or 
metastatic breast cancer that meets one of the following:
 
Triple negative, defined as estrogen receptor (ER) negative, 
progesterone receptor (PR) negative, human epidermal growth factor 
receptor 2 (HER2) negative. HER2 negative defined as 
immunohistochemistry (IHC) 0 or 1+ or fluorescence in situ hybridization 
(FISH) negative.
 
Her2- negative hormone-refractory breast cancer which denotes 
progression on one or more endocrine therapies (e.g., tamoxifen, 
aromatase inhibitors, fulvestrant) unless contraindicated.
3.1.2
Patients must be age 18 years or older and may be male or female.
3.1.3
Patients must have an Eastern Cooperative Oncology Group (ECOG)
performance status ≤ 2(see appendix 1).
3.1.4
Patients must have a life expectancy of ≥ 90 days.
3.1.5
Patients with central nervous system (CNS) involvement may participate if they 
meet all the following criteria:
 
At least 4 weeks from prior therapy completion (including radiation and/or 
surgery) to starting the study treatment.
 
Clinically stable with respect to the CNS tumor at the time of screening
3.1.6  Patients must have baseline laboratory tests within the following parameters 
within 14 days prior to registration :
System
Laboratory Value
Hematological
Absolute neutrophil 
count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without 
transfusion or EPO dependency
Renal
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14
Serum creatinine 
OR Measured or 
calculateda 
creatinine clearance 
(GFR can also be 
used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN)
OR
≥60 mL/min for subject with 
creatinine levels > 1.5 X institutional 
ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects 
with total bilirubin levels > 1.5 ULN
AST (SGOT) and
ALT (SGPT)
≤ 2.5 X ULN  
Albumin
>2.5 mg/dL
Coagulation (required only for patients needing biopsy)
International 
Normalized Ratio 
(INR) or 
Prothrombin Time 
(PT)
Activated Partial 
Thromboplastin 
Time (aPTT)
≤1.5 X ULN unless subject is 
receiving anticoagulant therapy 
as long as PT or PTT is within
therapeutic range of intended use of 
anticoagulants
≤1.5 X ULN unless subject is 
receiving anticoagulant therapy 
as long as PT or PTT is within
therapeutic range of intended use of 
anticoagulants
aCreatinine clearance should be calculated per 
institutional standard.
3.1.7
Females of child-bearing potential (FOCBP) must have a negative serum or urine 
pregnancy test within 7 days prior to registration. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.
Note: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria:
 
Has not undergone a hysterectomy or bilateral oophorectomy
 
Has had menses at any time in the preceding 12 consecutive months (and 
therefore has not been naturally postmenopausal for > 12 months)
3.1.8 Female subjects of childbearing potential (FOCBP) must be willing to use an 
adequate method of contraception as outlined in Appendix 2. Contraception must be 
used for the course of the study through 120 days after the last dose of study 
medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
3.1.9 Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Appendix 2. Contraception must be used starting with 
the first dose of study therapy through 120 days after the last dose of study 
therapy.
Note: 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)
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
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3.1.10 Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study.
3.1.11Patients must be willing and able to comply with scheduled visits, treatment plan 
and laboratory tests.
3.1.12 Patient must be able to swallow and retain oral medication.
3.2
Exclusion Criteria
3.2.1 Patients with documented HER2-positive metastatic disease are not eligible, 
even if their primary breast cancer was HER2-negative.
3.2.2 Patients who have received prior anti-cancer therapy (e.g., biologic or other 
targeted therapy, chemotherapy) within 2 weeks prior to registration. Hormone 
therapy is permitted until registration.
Note: patients who received prior anti-PD-1, PD-L1 or PD-L2 agents are still 
eligible. A wash-out period of 2 weeks prior to registration is required.
3.2.3
Patients who have received prior capecitabine therapy are not eligible.
3.2.4
Patients who have not recovered from adverse events to Grade 1 severity or 
lower due to agents administered more than 2 weeks earlier than registration, are 
not eligible, except for stable sensory neuropathy (≤ Grade 2) and alopecia.
3.2.5
Patients who have received radiotherapy ≤ 4 weeks prior to registration, with the 
exception of palliative radiotherapy, who have not recovered from side effects of 
such therapy to baseline or grade ≤ 1 are not eligible for participation.
Note: any lesions treated with radiation therapy cannot be used in disease 
assessment.
3.2.6
Patients who have undergone major surgery ≤ 4 weeks prior to registration or 
have not recovered from side effects of such procedure are not eligible for 
participation.
3.2.7
Patients may not be receiving any other investigational agents.
Note: A wash-out period of 2 weeks prior to registration is required for any patient 
to be enrolled in the study.
3.2.8
Patients who have a history of allergic reactions or hypersensitivity reactions 
attributed to compounds of similar chemical or biologic composition to 
pembrolizumab and/or humanized antibodies are not eligible.
3.2.9
Known hypersensitivity to capecitabine, fluorouracil, or any component of the 
formulation.
3.2.10  History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, vascular thrombosis associated with 
antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, 
Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis.
 
Patients with history of autoimmune-related hypothyroidism on a stable 
dose of thyroid replacement hormone may be eligible for this study.
 
Patients with controlled Type I diabetes mellitus on a stable dose of 
insulin regimen for more than a month may be eligible for this study.
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 
Patients with auto immune disease that does not recur unless patient is 
exposed to an external trigger (i.e. gluten and celiac disease) may also be 
eligible.
3.2.11  Patients who have evidence of active, noninfectious pneumonitis or have a 
history of severe pneumonitis that required treatment with steroids are not 
eligible for this study.
(Note: Replacement physiologic dose of steroids (prednisone 10 mg daily or 
equivalent) are allowed)
3.2.12  Patients who have an uncontrolled intercurrent illness including, but not limited to 
any of the following, are not eligible:
 
Hypertension that is not controlled on medication (defined as ≥140/100 at 
rest, average of 3 consecutive readings)
     Ongoing or active infection requiring systemic treatment
     Symptomatic congestive heart failure
     Unstable angina pectoris
     Cardiac arrhythmia
 
Psychiatric illness/social situations that would limit compliance with study 
requirements
     Known positive test for HIV
 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected).
     Active tuberculosis
     Prior allogeneic bone marrow transplantation or solid organ transplant
 
Administration of a live, attenuated vaccine within 4 weeks before starting the 
study treatment or anticipation that a live attenuated vaccine will be required 
during the study.
 
Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety or 
study endpoints
3.2.13  Female patients who are pregnant or nursing (lactating) are not eligible.
3.2.14  Patients exhibiting any other condition that would, in the Investigator’s judgment, 
preclude patient’s participation in the clinical study due to safety concerns or 
compliance with clinical study procedures are not eligible for participation. This 
might include, but is not limited to, infection/inflammation, intestinal obstruction, 
and/or social/psychological complications.
3.2.15  Patients with impaired GI function or GI disease that may significantly alter 
absorption of oral capecitabine (e.g. ulcerative disease, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome or small bowel resection) are not 
eligible for participation.
3.2.16  Patients with a history of another malignancy that progressed or required 
treatment within the past year prior to registration are not eligible for participation. 
Note: the exceptions to this include non-melanoma skin cancer or excised 
carcinoma in situ of the cervix.
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4.0
TREATMENT PLAN
4.1
Overview
This will be an open-label, single-arm, phase II study of the combination of 
pembrolizumab and capecitabine in locally advanced and metastatic triple 
negative and hormone-refractory breast cancer.
Pembrolizumab will be administered at 200mg IV on Day 1 of each cycle (1 
cycle=21 days).Capecitabine will be administered at 1000 mg/m2 BID D1-
14q21d. Patients will be instructed to take the morning dose of capecitabine 
before coming to clinic for pembrolizumab infusion. (Refer to section 8.2.5 for 
details about drug intake). Patients will continue to receive treatment until 
disease progression or unacceptable toxicity. After discontinuation of study 
drugs, patients will be assessed every 3 months up to 1 year for PFS, with visits 
and/or phone calls.
4.2
Treatment Administration
Agent
Pre- 
medications
Dose
Route
Schedule
Cycle
Length
Pembrolizumab
n/a
200 mg
IV
Day1 of a
21 day 
cycle
Capecitabine
n/a
1000 
mg/m2
oral
BID on
Days
1-14 
every 21 
days
21 
days
4.2.1
Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal 
antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. KeytrudaTM 
(pembrolizumab; MK-3475) has recently been approved in the United 
States for the treatment of patients with unresectable or metastatic 
melanoma and disease progression following ipilimumab and, if BRAF 
V600 mutation positive, a BRAF inhibitor.
In this trial, pembrolizumab will be given at a dose of 200 mg IV every 21 
days (Day 1 of a 21-day cycle, can be administered +/- 3 days of Day 1) 
in a 30 minute IV infusion (-5 min/+10 min).
No pre-medications are required as part of this study.
See Section 4.9 for supportive care guidelines for pembrolizumab, 
including use of corticosteroids.
4.2.2
Capecitabine
Capecitabine is to be self-administered by patient, 1000 mg/m2 PO BID 
Days 1-14 every 21 days. It is to be taken preferably 12 hours apart (with 
minimum 8 hours between doses).It is to be ingested with food or within
30 minutes of eating with 8 oz glass of water (not fruit juices). Tablets are 
to be swallow whole and not crushed or cut. No supportive medications 
are required as part of this study.
If dose is missed and next dose would normally be in less than 8 hours, 
then dose should be skipped entirely and marked accordingly on the 
medication diary (available as stand-alone document).
Patients will also record doses taken, missed, or skipped, as well as any 
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occurrence of vomiting, diarrhea, increased stool frequency, or rashes on 
the Medication Diary. This Diary will be reviewed by a member of the 
study team at every study visit, and any issues with compliance will be 
addressed. Along with the diary, patients should bring the medication 
bottle and any remaining tablets with them on each study visit. The 
Coordinator and PI will monitor for compliance. If a patient misses more 
than 7 consecutive doses of capecitabine due to poor adherence, the 
patient will be removed from study treatment. If capecitabine doses are 
missed, and it is < 7 doses, they may be made up within the same cycle. 
Patients will be given 14 days of supply at the start of study treatment. 
Additional capecitabine tablets will be dispensed every 3 weeks. The 
consent form will also ask that patients agree to keep the capecitabine 
pills out of reach from children and other individuals in their home.
4.2.3
Continuation of Investigational Therapy after Radiographic
Progression (Pseudoprogression)
Treatment may be continued in the setting of pseudoprogression 
(radiographic increase or new lesions felt to be due to 
inflammation/immune response) as long as all of the following criteria 
are met:
 
Absence of clinical symptoms or signs indicating 
clinically significant PD.
 
No significant decline in Eastern Cooperative
Oncology Group (ECOG) performance status.
 
Absence of rapid PD or threat to vital organs/critical anatomical 
sites (eg, spinal cord compression) requiring urgent alternative 
medical intervention
 
Patients are made aware of the potential benefits and risks of 
continuing study therapy in the setting of Pseudo-Progression.
These patients will continue to be monitored for safety parameters. 
Patients continuing therapy in the setting of suspected 
pseudoprogression should continue with treatment according to protocol 
as long as the above criteria are met and clearly documented in the 
patient’s medical record.
4.3   Dose Modifications
4.3.1
Dose Modification
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 treatment. Pembrolizumab must be 
withheld for drug-related toxicities and severe or life-threatening AEs as 
per Table 1 below. Dose reductions for pembrolizumab are not 
permitted.
Capecitabine should be withheld/dose reduced for drug-related toxicities 
and AEs as per Table 2, 3, 4.
See Section 4.9 for supportive care guidelines for pembrolizumab, 
including use of corticosteroids.
Any patient who receives at least one dose of study therapy will be 
evaluable for toxicity endpoints. Each patient will be assessed for the
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development of toxicity according to the timeframe referenced in the 
Schedule of Events table). Toxicity will be assessed according to NCI’s 
CTCAE, version 4.03.
Dosing interruptions are permitted in the case of medical / surgical 
events or logistical reasons not related to study therapy (e.g., elective 
surgery, unrelated medical events, patient vacation, and/or holidays). 
Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption of capecitabine and 12 weeks of interruption of 
pembrolizumab, unless otherwise discussed with the Principal 
Investigator and QAM. The reason for interruption should be 
documented in the patient's study record.
If pembrolizumab is held for toxicity, participants are permitted to 
continue on protocol therapy with capecitabine alone. If capecitabine is 
held for toxicity, participants are permitted to continue on therapy with 
pembrolizumab alone.
If capecitabine doses are missed,and it is < 7 doses, they may be 
made up within the same cycle.
If one drug is permanently withdrawn for toxicity (i.e. the patient cannot 
dose reduce any further on capecitabine), then the patient should come 
off study completely.
Capecitabine Dose Reduction Table
Dose Level
Dose
1
1000 mg/m2
-1
800 mg/m2
-2
640 mg/m2
Stop
N/A
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Table 1 –Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 
or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 
weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for 
signs and symptoms of 
pneumonitis

Evaluate participants with 
suspected pneumonitis 
with radiographic imaging 
and initiate corticosteroid 
treatment

Add prophylactic 
antibiotics for 
opportunistic infections
Grade 2 or 3
Withhold
Diarrhea / Colitis 
Grade 4
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation 
(ie, peritoneal signs and 
ileus).

Participants with ≥ Grade 
2 diarrhea suspecting 
colitis should consider GI 
consultation and 
performing endoscopy to 
rule out colitis. 

Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  
If sufficient oral fluid 
intake is not feasible, fluid 
and electrolytes should be 
substituted via IV 
infusion.
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 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
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Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for participants with 
T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and 
symptoms of hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and 
symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care

Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal 
function
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue

Based on severity of AE 
administer corticosteroids

Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Intolerable/ 
persistent Grade 2
Withhold
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis
All other 
immune-related 
AEs
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab 
may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic 
control (in case of T1DM).  
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Capecitabine Dose Modifications:
Table 2: Hematologic Toxicities
ANC(/mm3)
Platelets (/mm3)
Modification
<1000/mm3
AND/OR
<100,000/mm3
Hold until 
ANC>=1000/mm3 
and PLt >=100,000 3 
resume at 20% dose 
reduction
>=1000/mm3
AND
>=100,000/mm3
No dose modification
Table 3: Mucositis, Diarrhea or Esophagitis
Grade
Toxicities/Symptoms
Modification
1
Mucositis, esophagitis, or diarrhea
No dose modification
2
Diarrhea
No dose modification
2
Mucositis, or esophagitis
Hold until <=grade1 and resume at 20%
dose reduction
3
Diarrhea
Hold until <=grade 1; resume at 20%
dose reduction
3/4
Mucositis or esophagitis
Hold until <=grade 1; resume at 20%
dose reduction
Table 4: Palmar-Plantar Erythrodysesia Syndrome (Hand and Foot Rash)
Grade
Modification
1
No dose modification
2
Hold until symptoms resolve to grade 0 or 1
Resume a 20% dose reduction (per treating physician’s discretion)
>=3
Hold until symptoms resolve to Grade 1 or lower. Resume with dose reduction of 1 
level (20% dose reduction). 
Non-hematologic Toxicity
For other non-hematologic toxicities, dose reductions of capecitabine will be at the discretion of 
the investigator. A 20% dose reduction must be performed with each subsequent reduction. A 
maximum of 2 dose reductions will be performed. 
4.4
Concomitant Medications/Treatments
Premedication: National Comprehensive Cancer Network (NCCN) approved 
prophylactic antiemetics may be given as appropriate
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial. If there is a clinical indication for one of these or 
other medications or vaccinations specifically prohibited during the trial,
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discontinuation from trial therapy or vaccination may be required. The 
investigator should discuss any questions regarding this with PI. The final 
decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician.
Acceptable concomitant medications:
All treatments that the investigator considers necessary for a subject’s welfare 
may be administered at the discretion of the investigator in keeping with the 
community standards of medical care. All concomitant medication will be 
recorded on the case report form (CRF) including all prescription, over-the- 
counter (OTC), herbal supplements, and IV medications and fluids. If changes 
occur during the trial period, documentation of drug dosage, frequency, route,
and date may also be included on the CRF. All concomitant medications received 
within 28 days before the first dose of trial treatment and 30 days after the last 
dose of trial treatment should be recorded. Concomitant medications
administered 30 days after the last dose of trial treatment should be recorded for
SAEs and ECIs as defined in Section 7.2 and 7.3.3.3
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening 
and Treatment Phase (including retreatment for post-complete response relapse) 
of this trial:
 
Antineoplastic systemic chemotherapy or biological therapy
 
Immunotherapy not specified in this protocol
 
Chemotherapy not specified in this protocol
 
Investigational agents other than pembrolizumab
 
Radiation therapy
Note: Radiation therapy to  symptomatic  lesions or to the brain may be 
allowed at the investigator’s discretion.
 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, 
rabies, BCG, and typhoid vaccine.
 
Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology.   
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the 
trial.  Subjects may receive other medications that the investigator deems to be 
medically necessary.
Concomitant Medications/treatments to be taken with precaution
Capecitabine is a strong CYP2C9 inhibitor. Caution should be exercised when 
capecitabine is co - administered with CYP2C9 substrates (see Section
8.2).Capecitabine may increase the serum concentration of vitamin K antagonists
(warfarin). Patients receiving concomitant capecitabine and oral warfarin-
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derivative anticoagulant therapy should have their anticoagulant response (INR 
or prothrombin time) monitored frequently in order to adjust the anticoagulant 
dose accordingly.
Pembrolizumab may be associated with Stevens-Johnson Syndrome (SJS) and 
Toxic Epidermal Necrolysis (TEN). Risk factors for SJS and TEN include certain 
medications such as anticonvulsants, sulfonamides, aminopenicillins, allopurinol, 
and NSAIDs. These should be taken after consultation with the treating
physician. Non-medication triggers include infection, contrast media, and 
vaccinations. Malignancy is associated with an increased mortality rate in 
patients with SJS and TEN
Certain medications such as anthracyclines, alkylating agents and checkpoint 
inhibitors as well as radiation may be risk factors for immune-mediated myocarditis. 
These should be taken after consultation with the treating physician.
Note: There are no prohibited therapies during the Post-Treatment Follow-up
Phase.
4.5
Duration of Therapy
Patients may continue to receive cycles of treatment until any of the following 
occur:
 
Disease progression
 
Development of an inter-current illness that prevents further administration of 
treatment
 
Unacceptable adverse event(s)
 
Patient decides to withdraw from either study treatment or the whole study
 
The treating investigator determines that the patient should be taken off 
treatment for any reason (i.e. changes in condition, inability to comply with 
study treatment or procedures)
4.6
Duration of Follow Up
   End of treatment visit is required approximately 30 days after the last dose of 
pembrolizumab for the purposes of adverse event assessment.
   Patients removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event.
 
Patients will be assessed every 3 months up to 2 year after discontinuation of 
the study drugs for PFS with visits and/or phone calls.
4.7
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study as a whole at any time 
at their own request, or they may be withdrawn at the discretion of the
investigator for safety, behavioral or administrative reasons. The reason(s) for 
discontinuation must be clearly documented on the appropriate electronic case 
report form (eCRF) and may include:
 
Patient voluntarily withdraws from treatment (follow-up permitted)
 
Patient withdraws consent (no follow-up permitted)
 
Patient is unable to comply with protocol requirements
 
Patient demonstrates disease progression
 
Patient experiences unacceptable toxicity
 
Treating physician determines that continuation on the study would not 
be in the patient’s best interest
 
Patient becomes pregnant
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 
Patient develops a second malignancy that requires treatment which 
would interfere with this study
 
Patient becomes lost to follow-up (LTF)
4.8
Patient Replacement
If a patient is withdrawn from the study prior to completing 21 days of therapy, for 
reasons other than adverse event or progression of disease, an additional patient 
may be added. If a patient discontinues treatment due to early progression prior
to completing 3 cycles of therapy, the patient will be evaluable for toxicity but not 
for efficacy endpoints; in this case an additional patient may be added. (Note:
any patient receiving 1 dose of pembrolizumab is evaluable for toxicity but not for 
primary objective of PFS).
Patients missing 14 or more doses of capecitabine due to toxicity will not be 
replaced.
4.9
Supportive Care Guidelines & Toxicity Management
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 the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.  Note 
that several courses of steroid tapering may be necessary as symptoms may 
worsen when the steroid dose is decreased. For each disorder, attempts should 
be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. Toxicity will be
attributed to either or both drugs per physician's clinical judgement, and dose 
modifications/delays will be made accordingly.
Note: if after the evaluation the event is determined not to be related, the 
investigator is instructed to follow the treatment guidance (as outlined below)
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event. Refer section
4.3 for dose modification.
4.9.1
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.
4.9.2
Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) 
and of bowel perforation (such as peritoneal signs and ileus).
 All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.     For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis.
 For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.
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
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, 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.
4.9.3
Type 1 diabetes mellitus (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  patients  with  serum  glucose  and  a  metabolic  panel,  urine 
ketones, glycosylated hemoglobin, and C-peptide.
4.9.4
Hypophysitis:

For Grade 2 events, treat with corticosteroids. When symptoms improve to
Grade 1 or less, steroid taper should be started and continued over no less than
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

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.
4.9.5
Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during
treatment, and as indicated based on clinical evaluation) (see section 5.0) and for 
clinical signs and symptoms of thyroid disorders.
 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):
 
In  hyperthyroidism,  non-selective  beta-blockers  (e.g.  propranolol)  are 
suggested as initial therapy.
 
In    hypothyroidism,    thyroid    hormone    replacement    therapy,    with 
levothyroxine or liothyroinine, is indicated per standard of care.

Grade 3-4 hyperthyroidism
 
Treat   with   an   initial   dose   of   IV   corticosteroid   followed   by   oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.
4.9.6
Hepatic:
 For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
 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.
4.9.7
Renal Failure or Nephritis:
 For Grade 2 events, treat with corticosteroids.
 For Grade 3-4 events, treat with systemic corticosteroids.
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When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
4.9.8 Stevens-Johnson Syndrome(SJS) and Toxic Epidermal Necrolysis(TEN)
 For signs or symptoms of SJS or TEN, withhold pembrolizumab and refer the 
patient for specialized care for assessment and treatment.
  If SJS or TEN is confirmed, permanently discontinue pembrolizumab.
4.9.9   Immune-mediated myocarditis
 For suspected immune-mediated myocarditis, ensure adequate evaluation to 
exclude other etiologies, and administer corticosteroids as appropriate.
4.9.10  Management of Infusion Reactions:
Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  Table 5 
below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
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Table 5 Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion interruption not 
indicated; intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for
< =24 hrs
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further trial 
treatment administration.
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po
(or equivalent dose of antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration.
4.10 Restrictions during pregnancy and lactation
Based on its mechanism of action, KEYTRUDA can cause fetal harm when 
administered to a pregnant woman.
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study. The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed 
or terminated. The outcome of the pregnancy will be reported to the Sponsor and to 
Merck without delay and within 24 hours to the Northwestern University and within 2
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working days to Merck if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to Northwestern
University.  If a male subject impregnates his female partner the study personnel at the 
site must be informed immediately and the pregnancy reported to the Northwestern 
University and to Merck and followed as described above and in Section 7.0
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
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5.0
STUDY PROCEDURES
Screening
(-28 days)
On Treatment 10
Off Treatment
Time Period
Baseline
Cycle 1+ 
(+/- 3days)
After 
Every 3 
cycles
End of
Treatment
Follow- 
up11
Assessment or
Activity
Informed Consent
X
Medical history (H)
X
X
Concomitant
Medications12
X
X
X
X12
Vitals,
Physical 
exam1 (PE)1
X
X
X
ECOG status
X
X
X
Toxicity 
assessment14
X
X
X15
Tumor
Measurements2
X
X2
X
Biopsy/archival 
tissue3
X
CBC with diff 4
X
X
X
Chemistry panel 5
X
X5
X
PT/PTT/INR 6
X
Thyroid function 
tests13
X
X13
Pregnancy test7
X
Pembrolizumab8
X
Capecitabine9
X
Survival status
X
1 Every physical exam will be a full physical exam and is standard of care. It will include vital signs (pulse, temperature, 
and blood pressure) and height (baseline only) and weight.
2 CT c/a/p AND bone scan. In place of bone scan, a PET/CT may be used. If CT is contraindicated, MRI may be used.
Any additional imaging such as MRI can be completed at the physician's discretion. The same modality should 
be used throughout the study. The baseline procedure is to be performed within 28 days prior to registration. 
Subsequently, it will be done prior to the start of the next treatment cycle e.g 4, 7, 10 etc. For patients who are 
unable to obtain scans at the designated time points, a window of 7-10 days is allowed. This exception is not 
applicable to the screening period. Bone scans are to be repeated at each time point ONLY if the patient has 
bone metastasis or if it is clinically indicated. If the original bone scan during screening is negative, then bone 
scans are not required in subsequent visits. 
3 A baseline tissue biopsy of a metastatic site will be obtained for PD-L1 immunohistochemical (IHC) assessment, from 
all patients. An archived specimen may be used (metastatic tissue only) if collected no more than 2 months prior to 
registration. Otherwise fresh biopsy of metastatic lesion is mandatory at baseline and should be performed no more 
than 2 months prior to registration. The requirement for biopsy (fresh) may be omitted per treating physician’s 
discretion, if  the biopsy would cause undue morbidity to the patient and if enough tissue from a prior metastatic 
lesion (archival biopsy) is not available.
PD-L1 IHC assay from QualTek will be used for the study.
Please refer to section 9.1 and laboratory manual for more details
4 Hematology will include white blood cells (WBC) with differential, platelet count, hematocrit, and hemoglobin. To be 
performed within 14 days before Day1
5 Serum Chemistry will include calcium, chloride, creatinine, sodium, potassium, blood urea nitrogen, bicarbonate, glucose, 
total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin, 
and total protein. To be performed within 14 days prior to registration. Patients with liver metastatis will have additional 
liver function testing done on C1D7 and C1D14, which can be done locally and sent to NU for review.
6 This is to be done if the patient is required to have a biopsy (in order to test for bleeding parameters before biopsy).
It is to be performed and resulted before the biopsy. (Also refer to footnote 14)
7Serum or urine test for females of child-bearing potential.
8 Pembrolizumab will be administered IV at the assigned dose, at Day 1 of every cycle (1cycle
=21 days)
9 Capecitabine will be self-administered orally by patients at a fixed dose daily on Days 1-14 twice daily, of each cycle.
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10 A cycle is defined as 21 days (+/- 3 days).
11 Patients will be assessed every 3 months up to 2 year after discontinuation of the study drugs for PFS with visits and/or 
phone calls.
12 concomitant medications to be recorded during screening, at the beginning of each cycle and for 30 days after end of 
treatment
13Thyroid function will be evaluated at baseline (performed within 14 days of Day1) and prior to the start of the next 
treatment cycle e.g. 4, 7, 10 etc. The tests included are TSH, freeT3, and freeT4.
14 Toxicity assessment to be done at the beginning of each cycle, at the end of treatment visit and for 30 days after end of 
treatment.
6.0
ENDPOINT ASSESSMENT
6.1
Disease Definitions
Patients with non-measurable and measurable disease are eligible for this study. 
Response to treatment will be assessed using RECIST1.1 guidelines (Appendix
3). Response and progression will be assessed in this study via physical exam 
and imaging. Lesions are defined as either measurable or non-measurable using 
the criteria provided below.
6.1.1
Measureable Disease
Measurable disease per RECIST 1.1 is defined as the presence of at least one 
measurable lesion. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by 
clinical exam. For irRC, measurable lesions are defined as as those that can be 
accurately measured in at least two dimensions as 10x10mm with CT scan. All 
tumor measurements must be recorded in millimeters.
6.1.2
Non-Measurable Disease
For both RECIST 1.1 and irRC, all other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 10 to
<15 mm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.
Evaluation of Overall Timepoint Response for Patients without Measurable 
disease at baseline
Non-target
New
Overall Response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Not all evaluated
No
NE
Unequivocal
Progression
Yes or No
PD
Any
Yes
PD
CR=Complete Response, PD=Progressive disease, NE=Inevaluable
6.1.3
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
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will be recorded and measured at baseline (this means in instances where 
patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded). Target lesions should be selected on the 
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.
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements 
(either by imaging techniques or clinically). A sum of the longest diameter (LD) 
for all target lesions will be calculated at baseline and used as the reference by 
which to characterize the objective tumor response.
6.1.4
Non-Target Lesions
All other lesions (or sites of disease) should be identified as non-target lesions 
and should also be recorded at baseline. Non-target lesions include measurable 
lesions that exceed the maximum numbers per organ or total of all involved 
organs as well as non-measurable lesions. Measurements of these lesions are 
not required.
6.2
Guidelines for Evaluation of Measureable Disease
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed within the timeframe 
noted in section 5.0. 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 antitumor 
effect of a treatment.
6.2.1
Clinical lesions
Clinical lesions will only be considered measurable when they are superficial and 
P10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of 
skin lesions, documentation by color photography including a ruler to estimate
the size of the lesion is suggested. As noted above, when lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the 
study.
6.3
Endpoints
6.3.1
Primary Endpoint(s):
To evaluate the median progression-free survival (median PFS) for participants 
receiving pembrolizumab with capecitabine for the treatment of locally advanced 
or metastatic TNBC and hormone-refractory MBC.  This will be assessed by 
using RECIST 1.1 criteria.
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to
<10 mm.
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Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD): 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).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study.
Please note patients with PD may stay on study with PD if they meet the critiera in 
section 4.2.3.
Any patient who has completed at least 3 cycles of pembrolizumab and 
capecitabine will be evaluable for this endpoint.
Note: the first set of scans is required to establish that the patient is evaluable for this 
endpoint.
6.3.2
Secondary Endpoints:
To describe the objective response rate (ORR) for participants receiving 
pembrolizumab with capecitabine for the treatment of locally advanced or 
metastatic TNBC and hormone-refractory MBC.
This will be assessed by using RECIST 1.1 criteria (appendix 3).
Any patient who has completed at least 3 cycles of this combination therapy are 
evaluable for this endpoint. Note: the first set of scans is required to establish that the 
patient is evaluable for this endpoint.
To describe the safety and tolerability of the combination of pembrolizumab and 
capecitabine for the treatment of locally advanced or metastatic TNBC and hormone- 
refractory MBC. All adverse events will be assessed by NCT CTCAE
4.03 criteria.
Any patient who has completed at least one dose of either pembrolizumab or 
capecitabine will be evaluable for this endpoint.
(NOTE: If a patient discontinues treatment due to early progression prior to completing 3 
cycles of therapy, the patient will be evaluable for toxicity but not for efficacy endpoints; in 
this case an additional patient may be added).
6.3.3
Exploratory Endpoint: PD-L1 assessment
A baseline tissue biopsy of a metastatic site will be obtained for PD-L1 
immunohistochemical (IHC) assessment, from all patients. An archived specimen may 
be used (metastatic tissue only) if collected no more than 2 months prior to 
registration. Otherwise fresh biopsy of metastatic lesion is mandatory at baseline and 
should be performed no more than 2 months prior to registration.
Note: The requirement for biopsy (fresh) may be omitted per treating physician’s 
discretion, if the biopsy would cause undue morbidity to the patient and if enough tissue 
from a prior metastatic lesion (archival biopsy) is not available.
Note: PD-L1 IHC assay from QualTek will be used for the study. 
Please refer to section 9.1 and laboratory manual for more details
QualTek developed and validated a PD-L1 IHC assay using Merck's proprietary
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22C3 antibody, and this will be used for the study. The study site’s pathology core will be
used to store, process, and ship samples to QualTek. The presence of PD-L1 expression 
will be correlated with response (PFS, RR) and other
clinical-pathologic factors in an attempt to define a subset of patients that may 
benefit from pembrolizumab.
PFS and ORR assessment (using irRECIST)
To evaluate efficacy endpoint median-Progression Free survival (PFS), 
assessment will be done up to 1 year after discontinuation of the study drugs. 
Assessment will be done using irRECIST (see table below)
ORR will be assessed every 3 cycles (every 9 weeks) with imaging (CT 
chest/abdomen/pelvis and bone scan [if indicated]). Assessment will be done 
using irRECIST (see table below)
Table No: 6 Tumor Response Evaluation: Comparison between RECIST 1.1 and 
irRECIST
Criteria
RECIST 1.1
irRECIST
New 
measurable 
lesions (≥10 
mm)
Always represents PD
Incorporated into tumor burden
New non- 
measurable 
lesions (< 10 
mm)
Always represents PD
Does not define progression but 
precludes irCR
Non-Target 
lesions
Changes contribute to defining BOR of CR, 
PR, SD, and PD
Contribute to defining irCR (complete 
disappearance required)
CR
Disappearance of all lesions
Disappearance of all lesions
PR
≥ 30% decrease in the sum of the longest 
diameter of all target lesions compared with 
baseline, in absence of new lesions or 
unequivocal progression of non-target 
lesions
≥ 30% decrease in tumor burden 
compared with baseline
SD
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, 
taking as reference the smallest sum 
diameters while on study
Neither a 30% decrease in tumor burden 
compared with baseline nor a 20% 
increase compared with nadir can be 
established
PD
At least 20% increase in sum of diameters 
of target lesions, taking as reference the 
smallest sum on study. In addition to the 
relative increase of 20%, the sum must also 
demonstrate an absolute increase of at
least 5mm. The appearance of one or more 
new lesions is also considered progression.
At least 20% increase in tumor burden 
compared with nadir (at any single time 
point)*
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
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(http://cancer.northwestern.edu/cro/data/DataandSafetyMonitoringPlanMay2014.pdf). The level of 
risk attributed to this study requires high intensity monitoring, as outlined in the DSMP. In
addition, the study will abide by all safety reporting regulations, as set forth in the Code of Federal
Regulations and as required by the NCI AdEERS Reporting Guidelines.
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 for timepoints). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care.
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until:
 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;
 
any abnormal laboratory values have returned to baseline;
 
there is a satisfactory explanation other than the study drug for the changes 
observed; or
 
death.
7.2
Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.
Any worsening (i.e., any clinically significant adverse change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of 
the Merck’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary 
significantly in frequency or severity from expected levels are not to be 
considered adverse events.  Examples of this may include, but are not limited to, 
teething, typical crying in infants and children and onset of menses or 
menopause occurring at a physiologically appropriate time.
Merck product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational 
(including placebo or active comparator medication) or marketed, manufactured 
by, licensed by, provided by or distributed by Merck for human use.
Adverse events may occur during the course of the use of Merck product in 
clinical trials, or as prescribed in clinical practice, from overdose (whether 
accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed but before
treatment allocation/randomization must be reported by the investigator if they 
cause the subject to be excluded from the trial, or are the result of a protocol-
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specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. 
Such events will be recorded at each examination on the Adverse Event case 
report forms/worksheets.  The reporting timeframe for adverse events meeting 
any serious criteria is described in section 7.3. The investigator will make every 
attempt to follow all subjects with non-serious adverse events for outcome.
Adverse events will not be collected for subjects during the pre-screening period 
(for determination of archival tissue status) as long as that subject has not 
undergone any protocol-specified procedure or intervention. If the subject 
requires a blood draw, fresh tumor biopsy etc., the subject is first required to 
provide consent to the main study and AEs will be captured according to 
guidelines for standard AE reporting.
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible. However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
Definition of Overdose according to Merck: 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.
7.2.2
Severity of AEs
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The 
CTCAE v4.03 is available at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf
If no CTCAE grading is available, the severity of an AE is graded as follows:
 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.
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 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.
 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.
 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.
 
Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 90 days after last dose of study medication (SM) or until start of new 
anticancer regimen, but for at least 30 days post last SM dose, whichever occurs first.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:
 
Results in death.
If death results from (progression of) the disease, the disease should be
reported as event (SAE) itself.
 
Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer to
an event that hypothetically might have caused death if it were more severe.
 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.
 
Results in persistent or significant disability or incapacity.
 
Is a congenital anomaly/birth defect.
 
Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event“.
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
 
Note: In addition to the above criteria, adverse events meeting either of the 
below criteria, although not serious per ICH definition, are reportable to the 
Merck in the same timeframe as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by Merck for collection 
purposes.
● Is a new cancer (that is not a condition of the study);
● Is associated with an overdose.
7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:
 
Is unanticipated in terms of nature, severity, or frequency
 
Places the research subject or others at a different or greater risk of harm
 
Is deemed to be at least possibly related to participation in the study.
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7.3
Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine AEs will 
be reviewed by the Data Monitoring Committee (DMC) according to the study’s 
phase and risk level, as outlined in the DSMP.
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 4.03.
2)
Grade the adverse event using the NCI CTCAE v 4.03.
3)
Determine whether the adverse event is related to the protocol therapy.
Attribution categories are as follows:
 
Definite: AE is clearly related to the study treatment.
 
Probable: AE is likely related to the study treatment.
 
Possible: AE may be related to the study treatment.
 
Unlikely: AE not likely to be related to the study treatment.
 
Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:
 
the current protocol
 
the drug package insert
 
the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
7.3.3.1 Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form is 
required (refer to NU template SAE Form available in NOTIS)
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:
 
Protocol description and number(s)
 
The patient’s identification number
 
A description of the event, severity, treatment, and outcome (if 
known)
 
Supportive laboratory results and diagnostics
 
The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
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7.3.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs.
 
Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification.
 
Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment)
 
Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 10 working days of notification.
 
All other deaths of NU subjects not previously reported, other non- 
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review.
7.3.3.3 Reporting to FDA
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life- 
threatening.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DMC).
All other SAEs will be reported on an annual basis as part of the annual
FDA report.
7.3.3.4 Reporting to Merck
For the time period beginning when the consent form is signed until 
treatment allocation/randomization, any serious adverse event, or follow 
up to a serious adverse event, including death due to any cause other 
than progression of the cancer under study (reference Section 7.2.3.5 for 
additional details) that occurs to any subject must be reported within 24 
hours to the NU QA and/or IRB (see section 7.3.3.1 and 7.3.3..2)r and 
within 2 working days to Merck Global Safety if it causes the subject to
be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization 
through 90 days following cessation of treatment, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression 
of the cancer under study (reference Section 7.2.3.5 for additional details 
whether or not related to the Merck product, must be reported within 24 
hours to the S and within 2 working days to Merck Global Safety.
Additionally, any serious adverse event, considered by an investigator 
who is a qualified physician to be related to Merck product that is brought
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to the attention of the investigator at any time following consent through 
the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the 
Sponsor and to Merck Global Safety.
All subjects with serious adverse events must be followed up for 
outcome.
SAE reports and any other relevant safety information are to be 
forwarded to the Merck Global Safety facsimile number: +1-215-993-
1220.
A copy of all 15 Day Reports and Annual Progress Reports is submitted 
as required by FDA, European Union (EU), Pharmaceutical and Medical 
Devices agency (PMDA) or other local regulators. Investigators will cross 
reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of 
submission. Additionally investigators will submit a copy of these reports 
to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-
1220) at the time of submission to FDA.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as 
Events of Clinical Interest (ECI) and must be reported within 24 hours to 
the Sponsor and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220).
For the time period beginning when the consent form is signed until 
treatment allocation/randomization, any ECI, or follow up to an ECI, that 
occurs to any subject must be reported within 24 hours to the Sponsor 
and within 2 working days to Merck Global Safety if it causes the subject 
to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization 
through 90 days following cessation of treatment, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Merck product, must be reported within 24 hours to the NU QA
/IRB (refer section 7.3.3.1 and 7.3.3.2) and within 24 hours to Merck
Global Safety.
Events of clinical interest for this trial include:
1. An overdose of Merck product, as defined in Section 7.2.1 - Definition 
of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor, that is not associated with clinical symptoms or abnormal 
laboratory results.
2. An elevated AST or ALT lab value that is greater than or equal to 3X 
the upper limit of normal and an elevated total bilirubin lab value that is 
greater than or equal to 2X the upper limit of normal and, at the same 
time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance 
documents. The purpose of the criteria is to specify a threshold of
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abnormal hepatic tests that may require an additional evaluation for an 
underlying etiology.
7.3.3.5  Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to 
Merck as described in Section 7.2.3(expedited reporting), unless there 
is evidence suggesting a causal relationship between the drug and the 
event. Any such event will be submitted to the Sponsor within 24 hours 
and to Merck Global Safety within 2 working days either by electronic or 
paper media.
Specifically, the suspected/actual events covered in this exception 
include any event that is disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint 
events and safety data to ensure the safety of the subjects in the trial. 
Any suspected endpoint which upon review is not progression of the 
cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression 
of the cancer under study
Hospitalization related to convenience (e.g. transportation issues etc.)
will not be considered a SAE.
7.3.3.6
Reporting of Overdose to Merck
If an adverse event(s) is associated with (“results from”) the overdose of 
a Merck product, the adverse event(s) is reported as a serious adverse 
event, even if no other seriousness criteria are met.
If a dose of Merck’s product meeting the protocol definition of overdose 
(refer section 7.2.1) is taken without any associated clinical symptoms 
or abnormal laboratory results, the overdose is reported as a non- 
serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be 
reported within 24 hours to the Sponsor and within 2 working days 
hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX
215 993-1220).
(Note: This does not apply to Northwestern University, because, as per 
NU IRB regulations, any amount of overdose will be reported as a 
reportable New Information [RNI])(Refer Section 11.7.2).
7.3.3. 7
Reporting of Pregnancy and Lactation to the Sponsor and to
Merck
Although pregnancy and lactation are not considered adverse events, it 
is the responsibility of investigators or their designees to report any 
pregnancy or lactation in a subject (spontaneously reported to them) 
that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be excluded from the trial, or are 
the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or
a procedure.
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Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of 
Sponsor’s product, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator. All reported pregnancies must be followed 
to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the 
pregnancy continues to term, the outcome (health of infant) must also
be reported.
Such events must be reported within 24 hours to the Sponsor and within
2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220)
8.0
DRUG INFORMATION
8.1
Pembrolizumab
8.1.1
Other Names
Keytruda (Pembrolizumab; MK-3475 [Anti-PD-1 Antibody MK-3475])
8.1.2
Classification
Humanized X PD-1_mAb (H409A11) IgG4
8.1.3
Mode of action
Highly selective anti-PD-1 humanized monoclonal antibody which inhibits 
programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T- 
cells to block PD-1 ligands (PD-L1 and PD-L2) from binding. Blocking the PD-1 
pathway inhibits the negative immune regulation caused by PD-1 receptor 
signaling (Hamid, 2013). Anti-PD-1 antibodies (including pembrolizumab) reverse 
T-cell suppression and induce antitumor responses.
8.1.4
Storage and Stability
Please refer to pharmacy manual for detailed instructions
Clinical supplies must be stored in a secure, limited-access location under the 
storage conditions specified on the label.
Store Pembrolizumab vials under refrigeration at 2 to 8 degrees Celsius (0C) or
36 to 46 degrees Fahrenheit (0F). Do not freeze; do not shake.
Prior to reconstitution, the vials of lyophilized powder can be out of refrigeration
(temperatures at or below 25°C (77°F)) for up to 24 hours.
Storage following reconstitution and dilution: Store at room temperature for a 
cumulative time up to 4 hours (this includes room temperature storage of the 
diluted infusion solution and the duration of infusion). IV bags and/or 
reconstituted vials can be also stored refrigerated at 2—8 degrees 0C (36—46 
degrees 0F) for up to 20 hours. If refrigerated, allow the vials and/or IV bags to 
come to room temperature prior to use. Do not freeze.
Receipt and dispensing of trial medication must be recorded by an authorized 
person at the trial site.
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Clinical supplies may not be used for any purpose other than that stated in the 
protocol.
8.1.5
Protocol dose specifics
200mg IV once every 3 weeks until disease progression or unacceptable toxicity. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 21 
days. A window of -5 minutes and +10 minutes is permitted (i.e., infusion time is
30 minutes: -5 min/+10 min).
8.1.6
Preparation
Please refer to pharmacy manual for detailed instructions. 
Pembrolizumab is provided as a white to off-white lyophilized powder (50
mg/vial) or as a liquid solution (100 mg/vial) in Type I glass vials intended for 
single use only. Pembrolizumab is formulated with L-histidine as buffering agent, 
polysorbate 80 as surfactant, sucrose as stabilizer/tonicity modifier, and 
hydrochloric acid (HCl) and/or sodium hydroxide (NaOH) for pH adjustment (if 
necessary).
Pembrolizumab Powder for Solution for Infusion is reconstituted with 2.3 mL 
sterile water for injection (SWFI) to yield a 2.4 mL solution containing 25 mg/mL 
of pembrolizumab prior to further dilution. Pembrolizumab vial contains an 
excess fill of 10 mg (equivalent to 0.4 mL of reconstituted solution) to ensure the 
recovery of label claim of 50 mg/2 ml pembrolizumab per vial.
The product after reconstitution with sterile water for injection and the liquid 
drug product is a clear to opalescent solution, which may contain extraneous and 
proteinaceous particulates. The reconstituted drug product solution and liquid 
drug product are to be further diluted with normal saline in polyvinyl chloride 
(PVC) or non-PVC IV bags to achieve final concentration between 1 mg/mL and
10 mg/mL.
Reconstituted vials and infusion solutions should be immediately administered 
after preparation. If not used immediately, reconstituted vials and/or IV bags may 
be stored at 2-8 °C for up to a cumulative time of 20 hours. If refrigerated, the 
vials and/or IV bags should be allowed to equilibrate to room temperature prior to 
subsequent use. Pembrolizumab solutions may be stored at room temperature
for a cumulative time of up to 4 hours. This includes room temperature storage of 
reconstituted drug product solution and liquid drug product in vials, storage of 
infusion solution in the IV bag and the duration of infusion.
8.1.7
Route of administration for this study
Intravenous (IV)
8.1.8
Incompatibilities
None known
Refer to pharmacy manual for list of infusion set materials compatible with 
pembrolizumab.
8.1.9
Availability & Supply
Merck will supply pembrolizumab (investigational / clinical supply) directly to the 
NU Investigational Pharmacy at no charge to subjects participating in this clinical 
trial. The contact for drug ordering will be Sloan Stribling
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(sloan_stribling@merk.com) or Tammy Moll (tammy.moll@merck.com). The 
Merck Drug Request Form, provided by Merck, should be completed and 
emailed to these contacts.
The treating investigator shall take responsibility for and shall take all steps to 
maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution, and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations.
8.1.10  Side effects
Pembrolizumab is generally well tolerated and demonstrates a favorable safety 
profile in comparison to chemotherapy. Pembrolizumab is an immunomodulatory 
agent, and based on this mechanism of action, immune mediated adverse events 
are of primary concern. Important identified risks for pembrolizumab are of an 
immune mediate nature, including: pneumonitis, colitis, thyroid disorders 
(hypothyroidism/hyperthyroidism), hepatitis, hypophysitis, Type I diabetes
mellitus, uveitis, and nephritis. After a recent review of data, events newly 
characterized as identified risks also include pancreatitis, myositis, and severe 
skin reaction; these are included in the reference safety information in the current 
IB. The majority of immune-mediated adverse events were mild to moderate in 
severity, were manageable with appropriate care, and rarely required 
discontinuation of therapy.
In addition to the previously noted identified risks, infusion-related reactions are 
a risk but are not considered immune mediated; these are also further described in 
the current IB.
Most common (seen in >10% of patients):
   Fatigue
   Headache
   Chills
   Difficulty sleeping
   Dizziness
   Leg swelling
   Itching and/or rash
   Elevated blood sugar level
   High triglycerides (type of cholesterol)
   Lower levels of calcium or sodium in the blood
   Nausea and/or vomiting
   Decreased appetite
   Diarrhea or constipation
   Pain in the abdomen
   Cough
   Shortness of breath
   Fever
Less common (seen in 1 to 10% of patients):
   Skin infection
   Abnormal thyroid function (decreased or increased)
   Colitis (inflammation or infection of the colon [large intestine]
   Sepsis (infection in the bloodstream)
   Kidney failure
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   Pneumonitis (inflammation of the lung) or pneumonia (infection in the lung)
Rare but serious or life-threatening (seen in <1% of patients)
 Immune system attacking adrenal gland (adrenocortical insufficiency), joints 
(arthritis), liver (hepatitis), kidneys (nephritis), skin (dermatitis) muscles (myositis), 
eyes (optic neuritis or uveitis), pancreas (pancreatitis), brain (partial epilepsy), heart 
(immune-mediated myocarditis) or other organs causing possibly irreversible damage 
to these organs.
 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis have also been 
identified as rare but serious life-threatening side-effects.
 Sarcoidosis is a clinically significant, immune-mediated adverse reaction that was 
reported in less than 1% of patients
 Encephalitis is a clinically significant, immune-mediated adverse reaction that was 
reported in less than 1% of patients
Please refer to the current version of the Investigator’s Brochure for a complete list 
of adverse events.
8.1.11  Nursing implications
Pembrolizumab will be administered at 200mg IV on Day 1 of each cycle (1 
cycle=21 days).Capecitabine will be administered at 1000 mg/m2 BID D1-14 
q21d. Patients will be instructed to take the morning dose of capecitabine before 
coming to clinic for pembrolizumab infusion (Refer to section 4.0 for details)
Pembrolizumab will be administered as an IV infusion ((section 8.1.6) over 
approximately 30 minutes Every effort should be made to target infusion timing 
to be as close to 30 minutes as possible. However, a window of -5 minutes and
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of 
polyethersulfone (PES) must be used during administration.
When an IV bag is used for the infusion, the IV line will be flushed with a volume 
of normal saline equal to the priming volume of the infusion set used after the 
contents of the IV bag are fully administered
Since the compatibility of pembrolizumab with other IV medications and 
solutions, other than normal saline (0.9% [w/v] sodium chloride for injection) and 
D5W , is not known, the Pembrolizumab solution should not be infused through 
an IV line in which other solutions or medications are being administered. The 
date, start time, interruption, and completion time of Pembrolizumab 
administration must be recorded in the source documents. Any unused solution 
for injection should not be used for another infusion of the same or different 
subject.
8.1.12  Return and Retention of Study Drug
The investigator is responsible for keeping accurate records of the clinical 
supplies received from Merck or designee, the amount dispensed to and returned 
by the subjects and the amount remaining at the conclusion of the trial.
Upon completion or termination of the study, all unused pembrolizumab vial(s)
shall be returned to the designated facility for destruction.
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Please refer to pharmacy manual for the address of the designated facility.
All used and/or partially used investigational product will be destroyed at the 
site per institutional policy. It is the Investigator’s responsibility to a r r a n g e f o r 
disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept.
8.2
Capecitabine
8.2.1
Other Names
Xeloda
8.2.2
Classification – Type of Agent
Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)
8.2.3
Mode of action
Capecitabine is a prodrug of fluorouracil. It undergoes hydrolysis in the liver and 
tissues to form fluorouracil which is the active moiety. Fluorouracil is a fluorinated 
pyrimidine antimetabolite that inhibits thymidylate synthetase, blocking the 
methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a 
lesser degree, RNA synthesis. Fluorouracil appears to be phase specific for the 
G1 and S phases of the cell cycle.
8.2.4
Storage and stability
Capecitabine is commercially available as 150 mg or 500 mg tablets. Physician 
may prescribe either 150mg or 500mg tablets based on calculation of patient’s 
BMI
Capecitabine tablets should be stored at room temperature (15° to 30°C) in the 
container in which they are provided.
Patient will keep medication in a cool, dry place out of reach of children and other 
individuals.
8.2.5
Protocol dose specifics
Patient to take capecitabine 1000mg/ /m2 BID D1-14 of a 21 day cycle. 
Capecitabine will be taken orally. It is self-administered by patient. Patients will 
be instructed to take the morning dose of capecitabine before coming to clinic for 
pembrolizumab infusion.
Capecitabine is to be taken preferably 12 hours apart (with minimum 8 hours 
between doses).
It is to be ingested with food or within 30 minutes of eating with 8 oz glass of water
(not fruit juices). Tablets are to be swallow whole and not crushed or cut.
If dose is missed and next dose would normally be in less than 8 hours, then 
dose should be skipped entirely and marked accordingly on the medication diary 
(available as stand-alone document).
8.2.6
Preparation
Film coated tablets
8.2.7
Route of administration for this study
Oral. Self-administered by patient.
8.2.8
Incompatibilities
Potential drug interactions: Capecitabine is a strong inhibitor of CYP2C9 and 
concomitant administration of CYP2C9 substrates should be avoided (ex: 
bosentan, cannabis, carvedilol, diclofenac, dronabinol, fosphenytoin, lacosamide, 
metronidazole, ospemifene, parecoxib, phenytoin, ramelteon, warfarin).
Warfarin: [US Boxed Warning]: Capecitabine may increase the anticoagulant
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effects of warfarin; bleeding events, including death, have occurred with 
concomitant use. Clinically significant increases in prothrombin time (PT) and 
INR have occurred within several days to months after capecitabine initiation (in 
patients previously stabilized on anticoagulants), and may continue up to 1 
month after capecitabine discontinuation. May occur in patients with or without 
liver metastases. Monitor PT and INR frequently and adjust anticoagulation
dosing accordingly. An increased risk of coagulopathy is correlated with a cancer 
diagnosis and age >60 years.
Leucovorin Calcium-Levoleucovorin: May enhance the adverse/toxic effect of
Capecitabine. Risk C: Therapy to be monitored.
Capecitabine may enhance the immunosuppressive effect of 
Immunosuppressants (ex: Leflunomide, Tacrolimus, etc.) concomitant 
administration is prohibited.
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of 
Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of 
Vaccines (Live). Management: Avoid use of live organism vaccines with 
immunosuppressants; live-attenuated vaccines should not be given for at least 3 
months after immunosuppressants.
Cimetidine: Since cimetidine can decrease the clearance of 5-FU, co- 
administration should be avoided. Ranitidine or a drug from another anti-ulcer 
class can be substituted for cimetidine if necessary.
For a complete and detailed list, please refer to FDA website:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources
/DrugInteractionsLabeling/ucm093664.htm
8.2.9
Availability & Supply
Capecitabine is standard of care treatment for metastatic breast cancer and will 
be provided through patient’s insurance. Patients will be given a 14 days supply 
of tablets at the start of study treatment (patients will collect the tablets from their 
respective pharmacies). Additional capecitabine tablets will be dispensed every 3 
weeks. The consent form will also ask that patients agree to keep the 
capecitabine pills out of reach from children and other individuals in their home.
8.2.10  Side effects
Frequency listed derived from monotherapy trials. Incidence reported for all 
indications and usage, unless otherwise noted. Frequency not always defined. 
Most common (seen in >10% of patients):
 
Fatigue
 
Diarrhea
 
Nausea and/or vomiting
 
Decreased appetite
 
Numbness or tingling
 
Weakness
 
Rash on the palms or soles
 
Leg swelling
 
Lowering of the white blood cell count or platelet count
 
Anemia
 
Higher levels of bilirubin in the blood
 
Eye irritation
 
Fever
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 
Less common (seen in 1 to 10% of patients):
 
Blood clot in the veins
 
Chest pain
 
Irregular heart rhythms
 
Fluid around the heart
 
Heart stopping
 
Heart attack
 
Headache
 
Dizziness
 
Depressed mood or mood changes
 
Difficulty swallowing
 
Feeling sleepy
 
Skin rash
 
Hair loss
 
Itching
 
Increased thirst
 
Hot flashes
 
Lowering of the potassium or magnesium levels in the blood
 
Weight gain
 
Pain in your belly/indigestion
 
Bleeding in the GI tract
 
Feeling bloated
 
Abnormal liver tests in the blood
 
Hypersensitivity (allergic) reaction
 
Back pain
 
Muscle and/or joint aches
 
Cough
 
Shortness of breath
 
Flu-like symptoms
 
Coughing up blood
 
Hoarse voice
 
Nose bleeds
Rare but serious or life-threatening (seen in <1% of patients)
  Kidney failure (usually reversible)
  Fluid buildup in the abdomen
  Bronchitis and/or pneumonia
  Stroke
  Confusion
  Passing out
  Blood clots
  Sepsis (infection in the bloodstream)
  Stevens-Johnson syndrome (allergic reaction)
9.0
CORRELATIVES/SPECIAL STUDIES
9.1
PD-L1 testing
A baseline tissue biopsy of a metastatic will be obtained for PD-L1 
immunohistochemical (ICH) assessment from all patients no more than 2 months 
prior to registration. An archived specimen may be used (metastatic tissue only) if 
collected no more than 2 monthsprior to registration. Otherwise fresh biopsy of 
metastatic lesion is mandatory at baseline and should be performed no more 
than 2 months prior to registration . The requirement for biopsy (fresh) may be 
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omitted per treating physician’s discretion, if the biopsy
would cause undue morbidity to the patient and  if enough tissue from a prior 
metastaic lesion (archival biopsy) is not available.
QualTek developed and validated a PD-L1 IHC assay using
Merck's proprietary 22C3 antibody, and will be used for this study11-12.
The study site’s pathology core will be used to store, process, and ship samples 
to QualTek.
For patient samples, positively charged ProbeOn Plus slides (Fisher ProbeOn 
Plus Catalog Number 22-230-900) must be used for tissue sections. Slide 
measurements should strictly be 75mm x 25mm x 1mm. Other standard-sized 
positively-charged slides (75mm x 25 mm x 1mm) are acceptable as a last resort, 
however QualTek must be notified as there is a risk that outside slides cannot be 
stained. The slides must be sized as described above or the sample cannot be 
tested and will be returned.
Tumor tissue for biomarker analysis must be provided as five (5) freshly cut, 
serially sectioned, unstained slides cut at 4 microns per patient for PD-L1 
testing.
Storage and Shipping: Samples may be held as blocks indefinitely at the site and 
then cut in batches. Slides must be shipped to QualTek immediately after 
sectioning to comply with the protocol’s testing requirements. Patient slides must 
be shipped within seven (7) days of sectioning. Slides must be shipped cold (2-
8°C) and in the dark.
See QualTek MISP Sample Handling Manual (available as stand-alone 
document) for detailed information regarding the processing, labelling and 
shipping of tissue samples prior to shipment.
Samples are to be shipped to: 
QualTek Molecular Laboratories 
MISP Receiving
300 Pheasant Run
Newtown, PA USA 18940
Phone: 215.504.7402
Email: MISPsamples@qmlabs.com
10.0
STATISTICAL CONSIDERATIONS
For PFS, assumptions are that the addition of pembrolizumab will increase PFS to 5 
months compared to historical control of 3 months. Assuming exponential survival, with
27 evaluable patients, there is 80% power to detect this difference using a one- 
tailed z test at p<0.05.
Recruitment of 30 participants to accrue 27 evaluable will last approximately 30 months 
(2.5 years) and participants will be followed for a maximum of 2 years from enrollment of 
the last patient. The primary outcomes chosen is PFS based on mechanism of action..
PFS will be analyzed using a Kaplan-Meier curve. A confidence interval for the median 
PFS will be calculated (Brookmeyer, R. and Crowley, J. (1982), “A Confidence Interval for 
the Median Survival Time,” Biometrics, 38, 29–41.), and if the confidence interval is
totally above 3 months, then it may be concluded that the PFS exceeds 3 months.
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Objective response rate will be summarized using a proportion and an exact 95% 
binomial confidence interval. Anti-tumor activity will be reported as a percentage change 
in the sum of the dimensions of all measurable lesions as defined by RECIST 1.1 criteria. 
The baseline imaging before treatment will be compared to each subsequent imaging 
assessment. The maximum anti-tumor activity will be reported using the assessment
with the smallest sum of dimensions (maximum response).
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by 
Janssen Scientific Affairs. Amendments will be distributed by the lead institution 
(Northwestern) to all affiliate sites upon approval by the Northwestern University IRB.
11.3
Registration Procedures
Patients may not begin protocol treatment prior to registration. All patient registrations will 
be registered centrally through the Clinical Research Office at Northwestern University 
before enrollment to study.
Registering a Patient to a Phase II Study
BEFORE a patient can be treated on study, please complete and submit the 
following items to confirm eligibility and receive a subject identification number:
• Eligibility eCRF (complete in NOTIS)
• Eligibility checklist (signed and dated by the treating physician – upload 
in NOTIS)
• Signed and dated informed consent document (upload in NOTIS)
• Pathology Report (upload in NOTIS)
The QAM will review the registration, register the patient, assign an identification 
number, and send a confirmation of registration to involved personnel. 
Registration will then be complete and the patient may begin study treatment. 
The QAM can be contacted at croqualityassurance@northwestern.edu.
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11.4
Data Submission
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate document). 
Generally, for all phase II patients, data are due at the end of every cycle.
11.5
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to Appendices for additional information). The level of risk attributed to this study 
requires high level monitoring, as outlined in the DSMP. The assigned QAM, with 
oversight from the Data Monitoring Committee, will monitor this study in accordance with 
the study phase and risk level. Please refer to the Appendices for additional data 
submission instructions.
11.6
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.
11.6.1  Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change.
11.6.2  Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM
using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved protocol 
that:
 
Is generally noted or recognized after it occurs.
 
Has no substantive effect on the risks to research participants.
 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected
 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).
A protocol deviation may be considered an instance of Reportable New 
Information (RNI) if it: Has harmed or increased the risk of harm to one or more 
research participants.
 
Has damaged the scientific integrity of the data collected for the study.
 
Results from willful or knowing misconduct on the part of the investigator(s).
 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
Any deviation that would constitute an instance of Reportable New 
Information must be reported to the Northwestern IRB within 5 business days 
of knowledge or notification.
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11.7
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI
regulations and guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP.
11.8
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
policies and processes set forth in the Lurie Cancer Center DSMP. The assigned QAM 
will prepare a preliminary data summary (to be approved by the DMC) no later than 3 
months after the study reaches its primary completion date (the date that the final subject 
is examined or receives an intervention for the purposes of final data collection for the 
primary endpoint). If the investigator’s wish to obtain DMC-approved data prior to this 
point (or prior to the point dictated by study design), the PI must send a written request
for data to the QAM which includes justification. If the request is approved, data will be 
provided no later than 4 weeks after this request approval. The data will be presented to 
the DMC at their next available meeting, and a final, DMC-approved dataset will be 
released along with any DMC decisions regarding publication. The investigators are 
expected to use only DMC-approved data in future publications. The investigators should 
submit a copy of the manuscript to the biostatistician to confirm that the DMC-approved 
data are used appropriately.  Once the biostatistician gives final approval, the manuscript 
may be submitted to external publishers.
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12.0
REFERENCES
1.
Kaplan, H.G. & Malmgren, J.A. Impact of triple negative phenotype on breast cancer prognosis.
Breast J 14, 456-63 (2008).
2.
Pogoda, K., Niwinska, A., Murawska, M. & Pienkowski, T. Analysis of pattern, time and risk 
factors influencing recurrence in triple-negative breast cancer patients. Med Oncol 30, 388 
(2013).
3.
Carrick, S. et al. Single agent versus combination chemotherapy for metastatic breast cancer.
Cochrane Database Syst Rev, Cd003372 (2005).
4.
Miwa, M. et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates
5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue.
Eur J Cancer 34, 1274-81 (1998).
5.
Blum, J.L. et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic 
breast cancer. J Clin Oncol 17, 485-93 (1999).
6.
Fumoleau, P. et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients 
with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 40, 536-42 
(2004).
7.
Muller, V. et al. Quality of life under capecitabine (Xeloda(R)) in patients with metastatic breast 
cancer: data from a german non-interventional surveillance study. Oncol Res Treat 37, 748-55 
(2014).
8.
Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of 
immune evasion. Nat Med 8, 793-800 (2002).
9.
Sabatier, R. et al. Prognostic and predictive value of PDL1 expression in breast cancer.
Oncotarget 6, 5449-64 (2015).
10.
Muenst, S. et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor 
prognosis in human breast cancer. Breast Cancer Res Treat 146, 15-24 (2014).
11.
Garon, Edward B. Naiyer A. Rizvi. “Pembrolizumab for the Treatment of Non–Small-Cell Lung
Cancer.” nejm.org. The New England Journal of Medicine. April 19, 2015
12.
Dolled-Filhart, Marisa, et al. (including QualTek supporting authors) “Development of an 
Immunohistochemistry Assay to Measure Programmed Death Receptor Ligand 1 Expression in 
Tumor Tissue.” Submitted for publication.
13.
Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer 
patients
Katarzyna Pogoda, Anna Niwińska, Magdalena Murawska, Tadeusz Pieńkowski
Med Oncol. 2013 March; 30(1): 388. Published online 2013 January 5. doi: 10.1007/s12032-012-
0388-4 PMCID: PMC3586394
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13.0
APPENDICES
 
Appendix 1: ECOG Performance Status 
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but
ambulatory and able to carry out work of a light or sedentary nature (e.g., light
housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable
to carry out any work activities. Up and about more than 50% of waking hours
3
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours.
4
100%  bedridden.  Completely  disabled.  Cannot  carry  on  any  self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis,
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative
Oncology Group, Robert Comis M.D., Group Chair.
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Appendix 2: CONTRACEPTION (specifications for Pembrolizumab)
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) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.);
OR
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
OR
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug 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
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if 
it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for subjects participating at sites in this 
country/region.
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study subjects of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy. If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study.
IRB #: STU00203215 Approved by NU IRB for use on or after 9/16/2019 through 9/15/2020.

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Other Study Number: TBD
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Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT
or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. 
Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
In addition, volumetric analysis will be explored by central review for response assessment.

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Appendix 4: AE Assessment Guidelines for Reporting to Merck
V4.0 CTCAE Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This 
does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of 
stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat 
a pre-existing condition that has not worsened is not a serious adverse event. A pre-existing condition is a clinical condition that is diagnosed 
prior to the use of a Merck product and is documented in the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and 
to Merck within 2 working days to meet certain local requirements); or
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must 
be reported within 24 hours to the Sponsor and to Merck within 2 working days..
Seriousness
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a 
serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken
Did the adverse event cause Merck product to be discontinued?
Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that 
supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document 
must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test drug and the adverse event based upon the available information.
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation
with the components and their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of Merck product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal 
product)?
Relationship to
Merck Product
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other 
host or environmental factors

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Other Study Number: TBD
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The following components are to be used to assess the relationship between the test drug and the AE: (continued)
Dechallenge
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) 
Sponsor’s product(s) is/are only used one time.)
Relationship
to Merck Product
(continued)
Rechallenge
Was the subject re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a 
single-dose drug trial); or (3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY 
HAVE BEEN CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency with 
Trial Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or 
drug class pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck 
product relationship).
Yes, there is a reasonable possibility of
Merck product relationship.
There is evidence of exposure to Merck product. The temporal sequence of the AE onset relative to the 
administration of Merck product is reasonable. The AE is more likely explained by Merck product than by another 
cause.
No, there is not a reasonable possibility of
Merck product relationship
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck 
product is not reasonable OR the AE is more likely explained by another cause than the Merck product. (Also 
entered for a subject with overdose without an associated AE.)

NU Study Number: NU 16B08
Other Study Number: TBD
14.0
HISTORY OF PROTOCOL AMENDMENTS
Version: Amnedment 7   9.13.18                                                                                                                             59
Amendment 1–October 24th, 2016
Sections(s) 
Affected
Prior Version
Amendment 1
Changes
Rationale
Protocol cover page
IND number:
exempt
Updated to: Pre- 
IND Number 
is132860
Study deemed non- 
exempt by sponsor 
and will be 
submitted to FDA.
Section 7.3.3.3
Reporting to FDA
N/A
New section added to state 
details about FDA reporting
Study deemed non- 
exempt by sponsor 
and will be 
submitted to FDA
Section 11.5
Data Management 
and 
monitoring/Auditing
The level of risk 
attributed to this study 
requires [high], as 
outlined in the DSMP
Modified to :
The level of risk attributed to 
this study requires high level 
monitoring, as outlined in the 
DSMP
For clarity
Amendment 2–January 30th , 2017
Sections(s) 
Affected
Prior Version
Amendment 2 Changes
Rationale
Title page
Pre-IND number 
listed
Converted to IND number
IND application 
accepted by FDA 
and IND number 
granted.
Study summary and 
section 3.1.5 and
3.2.5(eligibility criteria)
Criteria regarding 
patients with CNS 
involvement was 
listed as an 
exclusion criteria
This criteria has been moved to 
the inclusion criteria
The language used 
to describe it 
makes it more 
applicable as an 
inclusion criteria
Section 2.1
Primary objective
Primary objective 
stated
Added language to indicate that 
the RECIST 1.1 criteria will be 
used to assess the primary 
objective.
For clarity
Section 3.1.1
Inclusion criteria
Statement that 
patients must 
have hormone 
refractory breasts 
cancer
Added: Her2-negative to the 
statement .Also, added “ on one 
or more endocrine therapies” .
For clarity and to 
denote that the 
patient does NOT 
have to have 
received all 3 
hormone agents 
before calling them 
hormone
refractory. They 
should have 
received at least 1 
of the agents, and 
determined to be 
hormone refractory 
per treating 
physician (based
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on clinical 
judgement)
Section 3.1.6. 
Inclusion criteria
Baseline
laboratory  tests to 
be done within 4 
weeks(28 days)
modified to: baseline lab tests to 
be done within 2 weeks(14
days)
For safety and 
convenience
Section 3.1.7
Inclusion criteria
Pregnancy test 
within 7 days prior 
to registration
AND must be at 
least within 3 days 
prior to first dose
of study drug.
Modified to state only: “within 7 
days prior to registration”
For convenience
Section 3.2.2
Exclusion criteria
A caveat stating 
that patients 
receiving PD-1, 
PD-L1 or2 agents 
are eligible even 
though prior anti- 
cancer therapy is
not permitted (with 
some exceptions).
Language added to clarify that a 
wash-out period of 2 weeks
prior to registration is required 
for these agents.
For safety and 
clarity
Section 3.2.4
Exclusion criteria
Criteria about 
patients treated 
with radiotherapy 
not being eligible 
for the study(with 
some exception)
Note added to state that “any 
lesions treated with radiation 
therapy cannot be used in 
disease assessment.”
For clarity
Section 3.2.6
Exclusion criteria
Statement that 
patients receiving 
any other 
investigational 
agent will not be 
eligible for the 
study.
Language added to clarify that a 
wash-out period of 2 weeks
prior to registration is required 
for such patients to be eligible.
For safety and 
clarity
Section 3.2.8
Exclusion criteria
Criteria stating 
that patients with 
known 
hypersensitivity to 
capecitabine is
not eligible. But 
patients with prior 
treatment with 
capecitabine is 
eligible.
Language inserted to clarify that 
a wash-out period of 2 weeks is 
required for any patient with 
history of prior treatment with 
capecitabine to be eligible for 
this study.
For safety and 
clarity
Section 3.2.9
Exclusion criteria
Criteria stating 
exclusion of 
autoimmune 
disease patients 
with some caveats 
for exceptions.
One more caveat added stating 
that
“Patients with auto immune 
disease  that does not recur 
unless patient is exposed to an 
external trigger (i.e. gluten and
For flexibility and 
clarity
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Version: Amnedment 7   9.13.18                                                                                                                             61
celiac disease) may also be 
eligible”.
Section 3.2.11
Exclusion criteria
List of uncontrolled 
intercurrent illness 
that made patient 
ineligible, included 
ECG abnormality
ECG abnormality removed from 
this list
For flexibility
Section 4.2.3 
sub-section of 
treatment 
administration
N/A
New sub-section added to state 
details about
“Continuation of Investigational 
Therapy after Radiographic 
Progression 
(Pseudoprogression)”
For safety and 
clarity to state that 
treatment can be 
continued in the 
setting of 
pseudoprogression
Section 4.3.1
Dose modifications
Details about 
dose 
modifications for 
pembrolizumab 
and capecitabine
Added language:
1.   Dose reductions for 
pembrolizumab are not 
permitted.
2.   Capeciatbine should be 
withheld/dose reduced 
for drug –related 
toxicities.
3.   Capecitabine dose 
reduction table inserted.
4.   Subjects should be 
placed back on study 
therapy within 3 weeks 
of the scheduled 
interruption of 
capecitabine and 12 
weeks of interruption of 
pembrolizumab, unless 
otherwise discussed 
with the Principal 
Investigator and QAM.
5.If pembrolizumab is held 
for toxicity, participants 
are permitted to 
continue on protocol 
therapy with 
capecitabine alone. If 
capecitabine is held for 
toxicity, participants are
permitted to continue on 
therapy with 
pembrolizumab alone.
6.   If one drug is 
permanently withdrawn 
for toxicity (i.e. the
For safety and 
clarity
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patient cannot dose 
reduce any further on 
capecitabine), then the 
patient should come off 
study completely.
Section 4.4 subsection 
Concomitant 
medications/treatments 
to be taken with 
precaution
Previous details
Language added regarding 
medication and non-medication 
risk factors for Stevens-Johnson 
Syndrome, Toxic Epidermal 
Necrolysis and Immune- 
mediated myocarditis.
Based on 
pembrolizumab 
action letter 
received from 
Merck, dated
2.10.17
Section 4.9
Supportive Care 
guidelines and Toxicity 
Management
Previous details
Language added to state that 
toxicity will be attributed to 
either or both drugs per 
physician’s clinical judgement, 
and dose modifications/delays 
will be made accordingly.
In addition, two new subsections
4.9.8 and 4.9.9 have been 
added to state the management 
of Stevens-Johnson Syndrome, 
Toxic Epidermal Necrolysis and 
Immune-mediated myocarditis
For clarity
Based on 
pembrolizumab 
action letter 
received from 
Merck, dated
2.10.17
Section 5.0
Study procedures
Study procedures 
table with 
footnotes
Modifications made:
1.   Added -28 days to 
screening column to 
clarify duration
2.   Column stating “every 3 
cycles” renamed as 
“After every 3 cycles”
3.   Footnote 1 modified to 
state that a ‘full physical 
exam ‘will be done
every time. Also, 
respiration has been 
removed from vitals.
4.   In footnote 2 and 13 the 
language has been 
modified for clarity. 
Thyroid test have been 
elaborated. Time points 
for measurement clearly 
stated.
5.   Tumor measurement 
during follow-up has 
been removed from the 
table.
6.   Footnote 12 has been 
modified to clearly state 
the time points for 
concomitant medication
For clarity and 
consistency
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monitoring. The ‘x’ for 
con-meds in the ’after 3 
cycles’ column has
been removed’ from the 
table.
7.   New footnote 15 added 
to describe toxicity 
assessment. The ‘X’ in 
the follow-up column for 
this has been removed.
Section 6.1.1
Endpoint assessment 
description of 
measurable disease
Description of 
measurable 
disease was taken 
from outdated 
RECIST version
Description of measurable 
disease updated to RECIST 1.1
Correction of error 
and for consistency 
with rest of the 
protocol
Section 6.1.2
Endpoint assessment 
description of Non- 
Measurable Disease
Description of non- 
measurable 
disease was taken 
from outdated 
RECIST version
Description of non-measurable 
disease updated to RECIST 1.1
Table inserted for
“Evaluation of Overall Timepoint 
Response for Patients without 
Measurable disease at 
baseline”.
Correction of error , 
consistency with 
rest of the protocol 
and increased 
clarity
Section 6.1.3
Endpoint assessment 
description of Target 
lesions
Description of 
target lesions was 
taken from 
outdated RECIST 
version
Description of target lesion 
updated to RECIST 1.1
Correction of error 
and for consistency 
with rest of the 
protocol
Section 6.2.1
Endpoint 
assessment 
description of Clinical 
lesions
Description of 
clinical lesion was 
taken from 
outdated RECIST 
version
Description of clinical lesion 
updated to RECIST 1.1
Correction of error 
and for consistency 
with rest of the 
protocol
Section 6.2.2
Endpoint assessment 
description of 
Cytology, Histology
Language 
describing 
cytology and 
histology in 
relation to PR and 
CR
This section removed
This section is not 
applicable to this 
protocol
Section 6.3.1
Primary endpoint
Description of 
primary endpoint.
Language added:
1.   RECIST 1.1 will be 
used to assess primary 
endpoint.
2.   Description of 
CR,PR,PD and SD 
inserted
3.   Note inserted stating 
that the first set of 
scans is required to 
establish that patient is
For clarity
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evaluable for primary 
endpoint.
Section 6.3.2
Secondary endpoint
Description of 
secondary 
endpoint
Note inserted stating that the 
first set of scans is required to 
establish that patient is 
evaluable for secondary 
endpoint.
For clarity
Section 8.1.10
Side effects of 
pembrolizumab 
listed
Stevens-Johnson Syndrome, 
Toxic Epidermal Necrolysis and 
Immune-mediated myocarditis 
added to the category of ‘rare 
but serious life-threatening side- 
effects of pembrolizumab.
Based on 
pembrolizumab 
action letter 
received from 
Merck, dated
2.10.17
Section 8.2.9
Capecitabine 
availability and supply
Statement that 
patients will be 
given 14 days’ 
supply of tablets 
at the start of 
study treatment.
Language added to state that
from their respective 
pharmacies.
For clarity
Amendment 2–March 15,  2017
(additional changes made after initial SRC approval of amendment 2 dated
1.30.17)
Sections(s) 
Affected
Prior Version
Amendment 2 Changes
Rationale
Section 1.4 
background: 
exploratory studies
Language 
describing the 
evaluation of ct- 
DNA( circulating 
tumor DNA)
Removed all language referring 
to ct-DNA as exploratory studies
Removal of ct-DNA 
evaluation as 
exploratory 
objective due to 
issues with 
Guardant 360 
commercial 
processing 
laboratory.
Section 2.3 and
Section 6.3.3
Exploratory Objectives 
and Endpoints
One of the 
exploratory 
objectives was the 
assessment of ct- 
DNA in peripheral 
blood samples at 
baseline and at 
time of 
progression, using 
kits provided by 
Guardant 360 and 
processed  at 
Guardant.
Removed all language referring 
to Guardant 360 and ct-DNA 
assessment as exploratory 
objective.
Removal of ct-DNA 
evaluation as 
exploratory 
objective due to 
issues with 
Guardant 360 
commercial 
processing 
laboratory.
patients will collect the tablets
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Section 3.2.15
Patients with a 
history of another 
malignancy that 
progressed or 
required treatment 
within  5 years 
prior to
registration are 
not eligible for 
participation. 
Note: the 
exceptions to this 
include non- 
melanoma skin 
cancer or excised 
carcinoma in situ 
of the cervix.
Updated the window for past 
malignancy from 5 years to 1 
year.
.
To increase 
flexibility for 
enrollment
Section 5.0
Study procedures table
Footnote 14 and 
the corresponding 
row in the table 
stated the 
research blood 
sample 
collection(ct-DNA
with Guardant 360 
kits) at screening 
and end of 
treatment.
Removed the footnote 14 that 
detailed ct-DNA collection with 
Guardant kits and also removed 
the corresponding row in the 
table.
Replaced footnote 14 with 
details about optional baseline 
biopsy for PD-L1 assessment 
and tagged it to the appropriate 
row in the table for clarity
Removal of ct-DNA 
evaluation as 
exploratory 
objective due to 
issues with 
Guardant 360 
commercial 
processing 
laboratory.
For added clarity
Section 9.2
Correlatives/Special 
studies
Details about ct- 
DNA assessment 
as an exploratory 
study
Removed all language related to 
ct-DNA and Guardant 360.
Removal of ct-DNA 
evaluation as 
exploratory 
objective due to 
issues with 
Guardant 360 
commercial 
processing 
laboratory.
Amendment 3–June 1st , 2017
SRC-approved June 26, 2017
Sections(s) 
Affected
Prior Version
Amendment 3 Changes
Rationale
Title page
and Section 3.0
PI: Sarika Jain, 
MD
Changed PI to: William Gradishar, 
MD. All contact information 
inserted.
Dr.Jain leaving 
NU and handing 
over study to 
Dr.Gradishar
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Section 2.3 –Exploratory
Objectives 
and
Section 6.3.3
Exploratory Endpoint
and Section 9.1
PD-L1 testing (correlative 
studies)
Baseline tissue 
biopsy of 
metastatic site for 
PD-L1 
assessment, was 
optional and if 
patient did not 
consent, then 
archived tissue 
may be used 
subject to patient 
consent.
Modified to state:
“A baseline tissue biopsy of a 
metastatic site will be 
obtained for PD-L1 
immunohistochemical (IHC)
assessment, from all patients. 
An archived specimen may
be used (metastatic tissue 
only) if collected within 2 
months of registration. 
Otherwise fresh biopsy of 
metastatic lesion is 
mandatory at baseline and 
should be performed within
28 days prior to Day 1.”
For increased 
convenience
Section 3.0
Eligibility criteria 
introduction
and Section 10.0 
statistics
A total of 33-39 
subjects will be 
needed for this 
trial
A total of 30 subjects will be 
needed to obtain 27 evaluable 
patients this trial.
Similar updates made in 
statistics section to state this 
clearly.
Correction of error.
For clarity
Section 3.1.6
Inclusion criteria
Baseline laboratory 
tests were to be 
done at least 2 
weeks prior to 
registration.
Coagulation 
parameters 
required to be 
tested for all 
patients as an 
eligibility criteria
Modified to state that baseline 
laboratory tests are to be done 
within 14 days prior to 
registration.
Note inserted to state that 
coagulation parameters are 
required only for patients 
needing biopsy.
Correction of error
For safety and 
flexibility
Section 3.1.9
Inclusion criteria
Details about 
male 
contraception 
requirements for 
eligibility
“Added note:
“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).”
For increased clarity
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Section 3.2.3
and
Section 3.2.9
Section 3.2.9
stated that prior 
capecitabine was 
permitted and no 
wash-out period 
was required for 
enrollment.
New eligibility criteria 3.2.3
added stating:
“Patients who have received 
prior capecitabine are not 
eligible.”
Section 3.2.9 modified to 
remove the ‘capecitabine 
permitted without wash-out’ 
language. Now, it only contains 
language regarding ineligibility 
due to hypersensitivity to 
capecitabine, fluorouracil or its 
components.
In order to
streamline 
enrollment.
Section 4.3.1
Dose modification
and Section 4.2.2
Capecitabine treatment 
administration
Language regarding
dose modification of
Capecitabine
Added language:
“If capecitabine doses are 
missed, and it is < 7  doses, 
they may be made up within 
the same cycle.”
For increased
clarity and safety
Section 5.0 Study
Procedures
Footnote 2:
Tumor 
measurements by 
CT c/a/p bone 
scan(per treating 
physician’s 
discretion).
Footnote6: 
PT/PTT/INR was 
optional. To be 
done only if 
patient consented 
for optional 
biopsy.
Footnote2: Updated to:
“CT c/a/p AND bone scan. In 
place of bone scan, a PET/CT 
may be used. If CT is 
contraindicated, MRI may be 
used. Any additional imaging 
such as MRI can be completed 
at the physician's discretion.”
Footnote 6 updated to state that
PT/PTT/INR is to be done if 
the patient is required to 
have a biopsy (in order to 
test for bleeding parameters 
before biopsy). It is to be 
performed and resulted 
before the biopsy.
Correction of error.
And to increase 
flexibility regarding 
permitted imaging 
modalities.
To align with 
updates made to 
biopsy 
requirements as 
stated in footnote
14 and sections 2.3,
3.1.6, 6.3.3 and 9.1
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Footnote 14
Baseline tissue 
biopsy of 
metastatic site for 
PD-L1 
assessment, was 
optional and if 
patient did not 
consent, then 
archived tissue 
may be used 
subject to patient 
consent.
Footnote 14 modified to state :
“A baseline tissue biopsy of a 
metastatic site will be obtained 
for PD-L1 immunohistochemical 
(IHC) assessment, from all 
patients. An archived specimen 
may be used (metastatic tissue 
only) if collected within 2 months 
of registration. Otherwise fresh 
biopsy of metastatic lesion is 
mandatory at baseline and 
should be performed within 28 
days prior to Day 1.”
To align with
updates made to 
biopsy 
requirements as 
stated in sections
2.3, 6.3.3 and 9.1
Amendment 4– August 22nd , 2017
SRC-Approved August 23, 2017 and October 4, 2017
Sections(s) 
Affected
Prior Version
Amendment 4 Changes
Rationale
Title page
Cesar Santa- 
Maria, MD as 
Sub- 
Investigator
Removed Dr. Santa-Maria as Sub- 
Investigator
Dr.Santa-Maria 
has left 
Northwestern 
University
Section 1.4 and 2.3
Exploratory 
studies/objectives;
Section 6.3.3 exploratory 
endpoint
for
PD-L1 assessment
A fresh baseline 
tissue biopsy of a 
metastatic site was 
mandatory and was 
to be performed 
within 28 days prior 
to day 1 . An 
archived specimen 
of metastatic tissue 
could be used if 
collected within 2 
months of 
registration.
Language modified to state that:
The fresh biopsy should be 
obtained no more than 2 
months prior to registration. 
An archival tissue of a 
metastatic lesion can be used 
if collected  no more than 2 
months prior to registration. 
Otherwise fresh biopsy of 
metastatic lesion is
mandatory at baseline and 
should be performed no more 
than 2 months prior to 
registration.
A note has been added by which 
this requirement can be omitted: 
“The requirement for biopsy
(fresh) may be omitted per treating 
physician’s discretion, if the
biopsy would cause undue 
morbidity to the patient and  if 
enough tissue from a prior 
metastatic lesion (archival biopsy) 
is not available.”
For increased 
flexibility, which 
will  facilitate 
enrollment.
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Section 5.0
Study procedures table
Footnote 3 and
14
contained 
previous 
specifications 
regarding biopsy
Footnote 14 moved to footnote 
3
and reworded to state 
that The fresh biopsy 
should be obtained no 
more than 2
months prior to registration.
An archival tissue of a 
metastatic lesion can be 
used if collected  no more 
than 2 months prior to 
registration. Otherwise 
fresh biopsy of metastatic 
lesion is
mandatory at baseline and 
should be performed no 
more than 2 months prior 
to registration.
A note has been added by 
which this requirement can be 
omitted: “The requirement for 
biopsy
(fresh) may be omitted per 
treating physician’s discretion, if 
the
biopsy would cause undue 
morbidity to the patient and  if 
enough tissue from a prior 
metastatic lesion (archival 
biopsy) is not available.”
Other footnotes renumbered 
as needed.
For increased 
flexibility, which 
will  facilitate 
enrollment.
Section 4.2.2 and
Section 8.2.5
Capecitabine drug 
administration
Tablets are to be 
taken morning 
and evening but 
at least 8 hours 
apart.
Language modified to state: “ 
Capecitabine is to be taken 
preferably 12 hours apart (with 
minimum 8 hours between 
doses)
For increased 
clarity
Section 4.3.1
Dose modification for
Capecitabine
If capecitabine 
doses are missed 
and it is
<7 days of 
doses, they may 
be made up 
within the same 
cycle.
Corrected  “< 7 days of doses”
to “< 7 doses.”
Correction of 
error. To be 
consistent with 
the rest of the 
protocol.
Section 8.1.10
Side Effects
N/A
Added risks of sarcoidosis 
and encephalitis with 
pembrolizumab
Requested by the
IRB during CR001
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Amendment 5 , November 8th ,2017
Sections(s) Affected
Prior Version
Amendment 5 Changes
Rationale
Section 4.2.2
Capecitabine dose 
reduction table
The dose reduction 
level (-2) is stated as 
600mg/m2
The dose reduction level (-2)   
modified to  640mg/m2
Correction of error.
The dose reductions 
are a 20% reduction, 
which makes the 
second reduction 
640mg/m2,It was earlier 
stated as 600mg/m2 in 
error.
Section 4.3
 capecitabine dose 
modifications 
Table 2:Hematologic 
toxicities
For ANC <1500mm3
and/or Platelets< 
100,000/mm3 
Hold until 
ANC>=1500/mm3 and 
PLt >=100,000 3 
resume at 20% dose 
reduction
For ANC >=1500/mm3
and platelets
>=100,000/mm3=no 
dose modifications
Modified to :
For ANC <1000mm3
and/or Platelets< 
100,000/mm3 
Hold until ANC>=1000/mm3 
and   PLt >=100,000 3
 resume at 20% dose 
reduction
Modified to: 
For ANC >=1000/mm3
and platelets
>=100,000/mm3=no dose 
modification
For convenience and 
flexibility
Section 4.9.10
Management of Infusion 
reactions
 Language: “ Error! 
Reference source not 
found” 
Replaced by: “ Table 5” 
(referring to table 5 below)
Correction of error
Amendment 6 , February 14th  2018
Sections(s) Affected
Prior Version
Amendment 6 Changes
Rationale
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Section 3.1.6
Eligibility criteria 
Baseline laboratory test 
acceptable values 
included
AST and ALT ≤2.5XULN 
OR 
≤5XULN for subjects 
with liver metastasis
 The  language pertaining 
to liver metastasis 
“≤5XULN for subjects with 
liver metastasis”  has been 
removed.
 For safety. All patients 
are now required to 
have AST and ALT 
≤2.5XULN to be 
enrolled into the study.
(refer to related update 
in section 5.0, footnote 
5)
Section 4.3.1
Table 1
Pembrolizumab Dose 
modifications
Previous table (as sent 
by Merck) 
Replaced by new table sent 
by Merck titled
“Dose Modification and 
Toxicity Management 
Guidelines for Immune-
related AEs Associated 
with Pembrolizumab”.
Per Merck (sponsor of 
pembrolizumab) 
Section 4.3
Table 4
Capecitabine dose 
modification (Palmar-
plantar erythrodynesia 
syndrome
For Grade >=3, 
direction was to hold 
until symptoms resolve
Added language “ Hold 
until symptoms resolve to 
Grade 1 or lower. Resume 
with dose reduction of 1 
level (20% dose reduction).
For increased clarity
Section 4.4 
Concomitant medications
The prohibited 
medications section 
contained direction that 
“The use of physiologic 
doses of corticosteroids 
may be approved after 
consultation with the 
Sponsor” 
The requirement of 
consulting with sponsor 
(PI) has been removed.
This requirement is no 
longer needed, since 
the new pembrolizumab 
dose modification table 
clearly states that 
“For severe and life-
threatening irAEs, IV 
corticosteroid should 
be initiated first 
followed by oral 
steroid.”
IRB #: STU00203215 Approved by NU IRB for use on or after 9/16/2019 through 9/15/2020.

NU Study Number: NU 16B08
Version: Amnedment 7   9.13.18                                                                                                                             72
Section 5.0 
Study procedures table 
Footnote 2(containing 
details regarding CT and 
bone scan) 
Details about CT/MRI 
and bone scan.
Added language
 “For patients who are 
unable to obtain scans at 
the designated time points, 
a window of 7-10 days is 
allowed. This exception is 
not applicable to the 
screening period. Bone 
scans are to be repeated at 
each time point ONLY if the 
patient has bone metastasis 
or if it is clinically indicated. 
If the original bone scan 
during screening is 
negative, then bone scans 
are not required in 
subsequent visits. “
 
To increase flexibility of 
protocol and putting 
bone scans in line with 
standard of care 
practices while 
minimizing exposure
Section 5.0 
Study procedures table 
Footnote 5
(details about serum 
chemistry)
Description of tests 
included in serum 
chemistry panel.
Serum chemistry is to be 
performed within 14 
days of Day 1
Added language 
“Patients with liver 
metastatic will have 
additional liver function 
testing done on C1D7 and 
C1D14, which can be done 
locally and sent to NU for 
review.” 
Updated to “ Serum 
chemistry to be performed 
within 14 days prior to 
registration”
For safety. 
Correction of error. To 
maintain consistency 
with rest of the 
protocol.
Section 6.3.3
and section 2.3
Exploratory endpoint:
PFS and ORR 
assessment (using 
irRECIST)
Endpoint stated as: 
“ORR will be assessed 
every 3 cycles (every 9 
weeks) with imaging 
(CT 
chest/abdomen/pelvis 
and bone scan.”
Updated to : “ORR will be 
assessed every 3 cycles 
(every 9 weeks) with 
imaging (CT 
chest/abdomen/pelvis and 
bone scan [if indicated]).”
Added “if indicated” 
provision for bone 
scan, in order to 
minimize exposure and 
discomfort of patients, 
if a test is not 
required.”
(Refer to related update 
in section 5.0, footnote 
2)
IRB #: STU00203215 Approved by NU IRB for use on or after 9/16/2019 through 9/15/2020.

NU Study Number: NU 16B08
Version: Amnedment 7   9.13.18                                                                                                                             73
Amendment 7 , September 13th  2018
Sections(s) Affected
  Prior Version
Amendment 7 Changes
Rationale
Section 4.3 
Capecitabine Dose 
Modifications
(Table 4: Palmar-Plantar 
Erythrodysesia 
syndrome)
 Dose modifications for 
Grade 2 stated:
“Hold until symptoms 
resolve to grade 0 or 1.
  Resume a 20% dose 
reduction.”
 The 20% dose reduction is 
now per treating 
physician’s discretion. 
Language has been added 
to state this clearly. 
For safety, flexibility 
and to align better with 
current clinical 
practices
Section 4.4 
Concomitant 
Medications/Treatments
 Radiation therapy was 
included as a prohibited 
treatment with a caveat 
that “radiation therapy to 
a symptomatic solitary 
lesion or to the brain 
may be allowed at the 
investigator’s discretion” 
 The caveat has been 
modified to state that 
radiation therapy to 
symptomatic lesions (more 
than one lesion) or to the 
brain may be allowed at the 
investigator’s discretion. 
For increased flexibility
and to align better with 
current clinical 
practices
IRB #: STU00203215 Approved by NU IRB for use on or after 9/16/2019 through 9/15/2020.