A Randomized Phase II Study of Pembrolizumab, an Anti-Programmed Cell Death (PD)-1 Antibody, in Combination With Carboplatin Compared to Carboplatin Alone in Breast Cancer Patients With Chest Wall Disease
Phase: PHASE2
Conditions: Breast Cancer, Chest Wall Disease
Sponsor: Laura Huppert, MD, BA

Proprietary and Confidential
The information in this document is considered privileged and confidential and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal 
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A Randomized Phase II Study of Pembrolizumab, an anti-PD (programmed cell death)-1 
Antibody, in Combination with Carboplatin Compared to Carboplatin Alone in Breast 
Cancer Patients with Chest Wall Disease
IND NUMBER: 132879
UCSF Protocol number: CC #157521
Version number:  9.0
Version Date: March 31, 2025
TBCRC Protocol number:  044
Study Drug: Pembrolizumab
Coordinating Center: University of California San Francisco (UCSF)
Study Chair (Principal Investigator/Sponsor-Investigator):
Laura Huppert, MD
University of California, San Francisco (UCSF)
Helen Diller Family Comprehensive Cancer Center
Co-PI:
Neelima Vidula, MD (Massachusetts General Hospital)
UCSF Co-Investigators:
Andrei Goga, MD
Jo Chien, MD
Michelle Melisko, MD
Mark Moasser, MD
Pamela Munster, MD
John Park, MD
Sarah Donahue, NP
Gretchen Santos, NP
Sally Fang-Tu, NP
Translational Breast Cancer Research Consortium (TBCRC) Collaborators:
Minetta Lu, MD (Mayo Clinic Cancer Center)
Tina Hieken, MD (Mayo Clinic Cancer Center)
Ben Ho Park, MD (Vanderbilt-Ingram Cancer Center )
Johns Hopkins University acting on behalf of the TBCRC
NCT0309535

UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03/31/2025
Protocol CC#: 157521
Phase II – Pembrolizumab
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Statistician:
Jimmy Hwang, PhD
UCSF Helen Diller Family Comprehensive Cancer Center
Lead Clinical Research Coordinator:
Amy DeLuca
Central Trial Management* by:
Hoosier Cancer Research Network (HCRN)
* Note: The HCRN discontinued providing central trial management services for this study, 
effective March 31, 2025.
Revision History
Version 9.0     03/31/25
Version 8.0 
06/21/22
Version 7.0    03/27/21
Version 6.0
10/22/20
Version 5.0     03/27/19
Version 4.0
09/20/18
Version 3.0
01/24/18
Version 2.0 
09/14/17
Version 1.4 
10/03/16
Version 1.3
08/10/16
Version 1.2 
07/08/16
Version 1.1 
02/05/16
Version 1.0 
12/07/15

UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03/31/2025
Protocol CC#: 157521
Phase II – Pembrolizumab
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PROTOCOL SIGNATURE PAGE
Protocol No.: 157521
Version Date: 03/31/2025
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Committee on Human Research (CHR), and Data Safety Monitoring Committee (DSMC). 
2.
I will conduct the study in accordance with applicable CHR requirements, Federal regulations, and 
state and local laws to maintain the protection of the rights and welfare of study participants. 
3.
I certify that I, and the study staff, have received the requisite training to conduct this research 
protocol. 
4.
I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in accordance 
with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the Statement of 
Investigator (Form FDA 1572), and with local regulatory requirements. In accordance with the 
FDA Modernization Act, I will ensure the registration of the trial on the www.clinicaltrials.gov 
website. 
5.
I agree to maintain adequate and accurate records in accordance with CHR policies, Federal, state 
and local laws and regulations.
Keep a copy for your files.
Principal Investigator          
Printed Name
Signature
Date

UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03/31/2025
Protocol CC#: 157521
Phase II – Pembrolizumab
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UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03/31/2025
Protocol CC#: 157521
Phase II – Pembrolizumab
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PROTOCOL SIGNATURE PAGE – PARTICIPATING SITES 
Protocol No.: 157521
Version Date: 03/31/2025
Participating Site(s)
Principal Investigator Name: 
 
Institution Name:
Address:  
Telephone: 
 
E-mail:  
Principal Investigator Name: 
 
Institution Name:
Address:  
Telephone:  
E-mail:  
I have read this protocol and agree to conduct the protocol in accordance with Good Clinical 
Practices (ICH-GCP) and the applicable IRB, ethical, federal, state, and local regulatory 
requirements.  
Principal Investigator
Site
Printed Name
Institution Name
Signature
Date

UCSF Helen Diller Family Comprehensive Cancer Center
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Protocol CC#: 157521
Phase II – Pembrolizumab
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TRIAL SCHEMA
 
Pembrolizumab 
(+/- Carboplatin)
Patients with chest wall disease (triple negative breast cancer, 
hormone resistant, or HER2 positive) and any or no distant sites 
of involvement
Exam, Imaging, Blood, Stool & Tumor Biopsy Testing          
for Correlative Studies 
2:1 Randomization
Arm A: Pembrolizumab & 
Carboplatin for at least 6 
cycles 
Arm B: Carboplatin
Primary Endpoint: 
Disease Control Rate 
Pembrolizumab
(+/- Carboplatin)
Arm Bx: Cross 
Over on 
Progression 
Exam (3, 6, 9, 12, 18 wks)                                
Imaging (q 6wks until 18 weeks, then q 9 wks thereafter)       
Blood and Tumor Biopsy Correlative Studies (Baseline, 
C3D1)                         
Registration

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TABLE OF CONTENTS 
Protocol Signature Page..........................................................................................................3
Protocol Signature Page – Participating Sites.......................................................................4
TRIAL SCHEMA ....................................................................................................................5
1.0
TRIAL SUMMARY TABLE....................................................................................13
2.0
TRIAL DESIGN ........................................................................................................14
2.1
Trial Summary.......................................................................................................14
3.0
BACKGROUND & RATIONALE ..........................................................................14
3.1
Background ............................................................................................................14
3.1.1
Pharmaceutical and Therapeutic Background .....................................................15
3.1.2
Microbiome Studies Background ........................................................................16
3.1.3
Preclinical and Clinical Trial Data.......................................................................17
3.1.4
Rationale for the Trial and Selected Subject Population .....................................24
3.1.5
Rationale for Dose Selection ...............................................................................27
3.1.6
Rationale for Endpoints .......................................................................................29
3.1.6.1
Efficacy Endpoints........................................................................................29
3.1.6.2
Biomarker Research......................................................................................29
4.0
OBJECTIVES............................................................................................................30
4.1
Primary Objective .................................................................................................30
4.2
Secondary Objectives ............................................................................................30
5.0
METHODOLOGY ....................................................................................................30
5.1
Entry Criteria ........................................................................................................30
5.1.1
Diagnosis/Condition for Entry into the Trial.......................................................31
5.1.2
Subject Inclusion Criteria ....................................................................................31
5.1.3
Subject Exclusion Criteria ...................................................................................33
5.2
Trial Treatments....................................................................................................35
5.2.1
Dose Selection/Modification ...............................................................................36
5.2.1.1
Dose Selection ..............................................................................................36
5.2.1.2
Dose Modification and Toxicity Management for Immune-Related AEs 
Associated with Pembrolizumab and Combination Therapy .......................36
5.2.2
Carboplatin Dose .................................................................................................42

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5.2.3
Carboplatin Administration .................................................................................42
5.2.4
Dose Modification of Carboplatin and Management of Toxicity........................42
5.2.5
Dose Interruptions................................................................................................46
5.2.6
Pembrolizumab Dose Administration..................................................................47
5.2.7
Trial Blinding/Masking........................................................................................47
5.3
Randomization or Treatment Allocation ............................................................47
5.4
Stratification...........................................................................................................47
5.5
Concomitant Medications/Vaccinations (allowed & prohibited)......................47
5.5.1
Acceptable Concomitant Medications.................................................................47
5.5.2
Prohibited Concomitant Medications ..................................................................48
5.6
Rescue Medications & Supportive Care..............................................................49
5.6.1
Supportive Care Guidelines.................................................................................49
5.7
Diet/Activity/Other Considerations .....................................................................52
5.7.1
Diet.......................................................................................................................52
5.7.2
Contraception.......................................................................................................52
5.7.3
Use in Pregnancy .................................................................................................53
5.7.4
Use in Nursing Women........................................................................................54
5.8
Subject Withdrawal/Discontinuation Criteria....................................................54
5.9
Subject Replacement Strategy..............................................................................55
5.10
Clinical Criteria for Early Trial Termination ....................................................55
6.0
TRIAL FLOW CHART............................................................................................56
6.1
Screening and Treatment Periods: ......................................................................56
6.1.1
Arm A: Pembrolizumab plus Carboplatin, Arm Ax: Pembrolizumab Only........56
6.1.2
Arm B: Carboplatin ONLY .................................................................................59
6.1.3
Arm Bx: Pembrolizumab (+/- Carboplatin).........................................................61
6.2
End of Treatment...................................................................................................63
7.0
TRIAL PROCEDURES ............................................................................................65
7.1
Trial Procedures ....................................................................................................65
7.1.1
Administrative Procedures...................................................................................65
7.1.1.1
Informed Consent .........................................................................................65
7.1.1.2
Inclusion/Exclusion Criteria .........................................................................66
7.1.1.3
Medical History ............................................................................................66
7.1.1.4
Prior and Concomitant Medications Review................................................66

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7.1.1.5
Disease Details and Treatments....................................................................66
7.1.1.6
Assignment of Screening Number................................................................67
7.1.1.7
Registration and Assignment of Randomization Number............................67
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)....................................68
7.1.2
Clinical Procedures/Assessments ........................................................................68
7.1.2.1
Adverse Event (AE) Monitoring ..................................................................68
7.1.2.2
Full Physical Exam.......................................................................................68
7.1.2.3
Directed Physical Exam................................................................................68
7.1.2.4
Vital Signs ....................................................................................................68
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ............69
7.1.2.6
Tumor Imaging and Assessment of Disease.................................................69
7.1.2.7
Assessments for Arm B patients prior to crossing over to pembrolizumab 
only (Arm Bx) ..............................................................................................69
7.1.2.8
Tumor Tissue Collection and Correlative Studies Blood Sampling.............70
7.1.2.9
Stool Collection for Microbiome Studies.....................................................71
7.1.3
Laboratory Procedures/Assessments ...................................................................71
7.1.3.1
Withdrawal/Discontinuation.........................................................................73
7.1.3.2
Blinding/Unblinding.....................................................................................73
7.1.4
Visit Requirements ..............................................................................................73
7.1.4.1
Screening ......................................................................................................73
7.1.4.2
Treatment Period ..........................................................................................74
7.1.4.3
Post-Treatment Visits ...................................................................................75
7.1.4.4
Safety Follow-Up Visit.................................................................................75
7.1.4.5
Follow-up Visits ...........................................................................................75
7.2
Assessing and Recording Adverse Events ...........................................................75
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Study Chair and to Merck....................................................................................76
7.2.2
Reporting of Pregnancy and Lactation to the Study Chair and to Merck............77

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7.2.3
Immediate Reporting of Adverse Events to the Study Chair and to Merck ........77
7.2.3.1
Serious Adverse Events ................................................................................77
7.2.4
Evaluating Adverse Events..................................................................................78
7.2.5
Study Chair Responsibility for Reporting Adverse Events .................................82
7.2.6
Events of Clinical Interest....................................................................................82
8.0
STATISTICAL ANALYSIS PLAN .........................................................................82
8.1
Statistical Analysis Plan Summary ......................................................................82
8.2
Statistical Analysis Plan ........................................................................................84
8.2.1.1
Primary Efficacy Analysis............................................................................84
8.2.1.2
Futility analysis for carboplatin arm.............................................................84
8.2.1.3
Safety/toxicity analysis for pembrolizumab/carboplatin arm.......................85
8.2.1.4
Futility analysis for pembrolizumab/carboplatin arm...................................85
8.2.2
Secondary Efficacy Analyses ..............................................................................85
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ..................................................................................................................85
9.1
Investigational Product .........................................................................................85
9.2
Packaging and Labeling Information..................................................................86
9.3
Clinical Supplies Disclosure..................................................................................86
9.4
Storage and Handling Requirements...................................................................86
9.5
Returns and Reconciliation...................................................................................86
10.0
ADMINISTRATIVE AND REGULATORY DETAILS .......................................86
10.1
Confidentiality .......................................................................................................86
10.2
Compliance with Financial Disclosure Requirements .......................................87
10.3
Compliance with Law, Audit and Debarment ....................................................87
10.4
Compliance with Trial Registration and Results Posting Requirements.........87
10.5
Data Management..................................................................................................87
10.6
Protocol Review and Amendments ......................................................................88
11.0
MULTI-CENTER GUIDELINES............................................................................88
12.0
ETHICS AND GOOD CLINICAL PRACTICE Ethics and Good Clinical 
Practice .......................................................................................................................89

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13.0
REFERENCES ..........................................................................................................90
APPENDIX 1 ECOG.............................................................................................................97
a.
ECOG Performance Status...................................................................................97
b.
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ...............97
APPENDIX 2 Response evaluation......................................................................................98
13.1
Response evaluation ..............................................................................................98
13.2
Chest wall disease assessment...............................................................................98
APPENDIX 3 - Data and Safety Monitoring Plan for Multicenter Institutional Study 
(Phase 2 or 3)..............................................................................................................99
Appendix 4 TBCRC (Translational Breast Cancer Research Consortium) ..................104
APPENDIX 5 TBCRC Stool Collection Kit ......................................................................106

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Phase II – Pembrolizumab
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LIST OF ABBREVIATIONS 
AE adverse event 
Alk phos alkaline phosphatase
ALT alanine transaminase 
ANC absolute neutrophil count 
ASCO American Society for Clinical Oncology 
AST aspartate transaminase 
AUC area under the curve 
BSA body surface area 
BUN blood urea nitrogen
CHR Committee on Human Research (UCSF IRB) 
CR complete response 
CRA Clinical Research Associate 
CRC Clinical Research Coordinator 
CRF case report form 
CT computerized tomography 
CTC Common Terminology Criteria
CTCs circulating tumor cells 
CXR chest x-ray 
Dbil direct bilirubin
DFS disease-free survival 
DLT dose limiting toxicity 
ECI event of clinical interest
ECOG Eastern Cooperative Group
ER/PR Estrogen Receptor/Progesterone Receptor
FDA Food and Drug Administration 
GRF Glomerular Filtration Rate
HER2 Human epidermal growth factor receptor 2
HGB hemoglobin 
IND investigational new drug application 
IEC Independent Ethics Committee 
IRB Institutional Review Board 
IV   Intravenous
LDH lactate dehydrogenase 
MDR multi-drug resistance 
MK-3475 pembrolizumab
MRI Magnetic Resonance Imaging 
MTD maximum tolerated dose 
MYC oncogene often over expressed in triple negative and hormone resistant breast cancer
NCI National Cancer Institute 
OS Overall Survival
PI Principal Investigator 
PD progressive disease
PD-1 Programmed cell death 1
PD-L1 Programmed Death Ligand 1
PD-L2 Programmed Death Ligand 2

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Phase II – Pembrolizumab
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PFS Progression Free Survival
PR partial response 
PRC UCSF Protocol Review Committee 
RBC red blood cell 
RR response rate
SAE serious adverse event 
SD stable disease
Tbil total bilirubin
TIM-3 immune checkpoint receptor
TNBC triple negative breast cancer
ULN upper limit of normal 
WBC white blood cell

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Phase II – Pembrolizumab
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1.0 TRIAL SUMMARY TABLE
Abbreviated Title
Pembrolizumab and Carboplatin vs. Carboplatin Alone in 
Breast Cancer Patients with Chest Wall Disease
Trial Phase
Multi-center phase II consortium 
Clinical Indication
Breast Cancer with Chest Wall Disease
Trial Type
Randomized Phase II; 2:1 randomization
Type of Control
Carboplatin (Arm B)
Cross-over allowed to pembrolizumab alone on progression 
(Arm Bx)
Route of Administration
IV administration of Pembrolizumab and/or Carboplatin
Trial Blinding
No blinding
Treatment Groups 
Arm A: Pembrolizumab and carboplatin for at least 6 cycles 
followed by pembrolizumab maintenance treatment (Arm 
Ax) in patients with stable or responding disease 
Arm B: Carboplatin alone until documented disease 
progression followed by cross-over to pembrolizumab alone 
(Arm Bx) (+/- carboplatin)
Number of trial subjects
84 (56 in Arm A, 28 in Arm B)
An additional 9 patients (6 in the pembrolizumab/carboplatin 
arm and 3 in the carboplatin alone arm) may be accrued for 
subject replacement to offset an approximate drop out rate of 
10%.
Estimated Enrollment 
Period
18 months
Estimated Duration of 
Trial
24 months
Duration of Participation
36 months

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2.0 TRIAL DESIGN
2.1
Trial Summary
This is a phase II multicenter study including breast cancer patients with chest wall disease that 
is hormone resistant (ER positive/PR positive/HER2 negative breast cancer with progressive 
disease on 2 prior lines of hormonal therapy) or triple negative (ER negative/PR negative/HER2 
negative, TNBC). We will also allow accrual of patients with HER2+ disease whose chest wall 
disease has progressed on all approved/feasible HER2 targeted therapies.  Patients with HER2+ 
disease may continue trastuzumab during study therapy. Eighty-four patients will be enrolled at 
Translational Breast Cancer Research Consortium (TBCRC) sites and will be randomized 2:1 to 
receive treatment with pembrolizumab and carboplatin (n=56, Arm A) or carboplatin alone 
(n=28, Arm B) until documented disease progression. Patients randomized to Arm B may cross-
over following progression to pembrolizumab with or without carboplatin at investigator’s 
discretion (Arm Bx). Patients may have received any number of prior lines of chemotherapy. 
Patients in Arm A will be treated with pembrolizumab 200 mg IV and carboplatin AUC 5 IV 
every 3 weeks for at least 6 cycles followed by maintenance pembrolizumab 200 mg IV every 3 
weeks if stable or responding disease (Arm Ax). Patients in Arm B will be treated with 
carboplatin AUC 5 IV every 3 weeks until progression, whereupon they may cross-over to 
pembrolizumab 200 mg IV every 3 weeks with or without carboplatin at investigator’s discretion 
(Arm Bx). Patients with prior thrombocytopenia or carboplatin exposure will be treated with 
carboplatin AUC 4 IV every 3 weeks on both Arm A and B. An interim analysis for futility will 
be performed after 18 patients are enrolled into Arm B to allow early stopping of that trial arm 
for lack of efficacy. The primary endpoint is to compare disease control rates at 18 weeks of 
treatment. This study is powered to detect a 20% difference in disease control rates between arms 
with a hazard ratio of 0.52 (2 sided logrank test,  = 0.10 and  = 0.20). Secondary endpoints 
include disease control rates by irRECIST, progression free survival, toxicity, and overall 
response rate. Exploratory endpoints (to be explored in a companion translational study) include 
changes in tumor PD-L1 (programmed death ligand 1) gene expression, tumor and peripheral 
blood immune composition and cytokine expression, plasma tumor DNA, circulating tumor 
cells, and tumor MYC oncogene expression using tumor biopsy and peripheral blood testing 
before and after treatment; correlations with these markers and disease control rate will be 
assessed. Altogether, this study promises to improve our understanding of pembrolizumab for the 
treatment of breast cancer with chest wall disease.
3.0 BACKGROUND & RATIONALE
3.1
Background
The programmed cell death 1 (PD-1) pathway represents a major immune control switch which 
may be engaged by tumor cells to overcome active T-cell immune surveillance. Pembrolizumab, 
MK-3475, is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate 
tumor regression and ultimately immune rejection (1).

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Merck is studying pembrolizumab for various oncology indications. Pembrolizumab was 
recently approved for the treatment of metastatic melanoma in September, 2014. In this study, 
we will evaluate the combination of pembrolizumab and carboplatin vs. carboplatin alone 
followed by pembrolizumab alone on disease progression for the treatment of breast cancer 
patients with chest wall disease.
3.1.1
Pharmaceutical and Therapeutic Background
The importance of intact functions of immune surveillance in controlling outgrowth of neoplastic 
transformations has been known for decades (2). 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 (T regs) correlates with improved prognosis and long-term 
survival in solid malignancies such as ovarian, colorectal, and pancreatic cancer, hepatocellular 
carcinoma, malignant melanoma, and renal cell carcinoma. Tumor-infiltrating lymphocytes can 
be expanded ex vivo and re-infused, inducing durable objective tumor responses in cancers such 
as melanoma (3, 4).
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) (5, 6). The structure of murine 
PD-1 has been resolved (7). PD-1 and family members are type I transmembrane glycoproteins 
containing an Ig Variable-type (IgV-type) domain responsible for ligand binding and a 
cytoplasmic tail responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 
contains two tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif 
and an immunoreceptor tyrosine-based switch motif. 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 (6, 8-10). The mechanism by which PD-1 down 
modulates T cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins (11, 12). 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 (13, 14). Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells, as well as subsets of macrophages and 
dendritic cells (15). The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can 
be induced in a variety of cell types including nonhematopoietic tissues most notably on vascular 
endothelium; whereas PD-L2 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 (12). Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor. High expression of 
PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to correlate with poor 

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Phase II – Pembrolizumab
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prognosis and survival in various cancer types, including renal cell carcinoma (16), pancreatic 
carcinoma (17), hepatocellular carcinoma (18), and ovarian carcinoma (19). Furthermore, PD-1 
has been suggested to regulate tumor-specific T cell expansion in subjects with melanoma (20). 
The observed correlation of clinical prognosis with PD-L1 expression in multiple cancers 
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.
Therapeutic studies in mouse models show that administration of antibodies blocking PD-1/PD-
L1 interaction enhances infiltration of tumor-specific CD8+ T cells and leads ultimately to tumor 
rejection, either as a monotherapy or in combination with other treatment modalities. Anti-mouse 
PD-1 and anti-mouse PD-L1 have demonstrated antitumor responses as a monotherapy in models 
of squamous cell carcinoma, pancreatic carcinoma, melanoma, and colorectal carcinoma. 
Blockade of the PD-1 pathway effectively promoted CD8+ T-cell infiltration into the tumor and 
the presence of IFN-γ, granzyme B, and perforin, indicating that the mechanism of action 
involved local infiltration and activation of effector T cell function in vivo (17, 21-25). In 
addition, the combination of gemcitabine and anti-PD-L1 mAb demonstrated synergy in the 
rejection of pancreatic mouse tumors (17). In-house experiments have confirmed the in vivo 
efficacy of PD-1 blockade as a monotherapy as well as in combination with chemotherapy in 
syngeneic mouse tumor models.
Immuno-modulatory agents recently showed promising efficacy in multiple cancer types. Two 
recent Phase III studies of Ipilimumab (IPI), an anti-CTL4 mAb, showed significant prolongation 
of overall survival in subjects with melanoma (26, 27). Recent data with anti-PD-1 antibodies 
have validated PD-1 as an attractive target for clinical intervention (28-30). Importantly, 
responses have been of long duration as pembrolizumab is generally well tolerated. Based on 
these data and considerations, the anti-PD-1 antibody, MK-3475, appears to be an attractive 
candidate for continued clinical development in cancer.
3.1.2
Microbiome Studies Background
Recent data show the host gut microbiome influences response 
to 
immune checkpoint inhibition (84-86). Preclinical data support 
manipulation of the microbiome via fecal microbial transplant 
(FMT) or oral supplementation with beneficent organisms to 
enhance immunotherapy response and abrogate tumor growth 
as 
well as modulate toxicity. While the specific taxa reported to 
date vary across studies, a convergent mechanism is postulated 
to 
underpin these observations (and may be separately targetable) 
(87).
Phase I clinical studies testing these hypotheses in human 
cancers are underway. However, these microbial differences 
are 
relatively modest and little is known about the microbiome in 
association with breast cancer treatment. The TBCRC 
infrastructure, focus on correlative science and collaborative 
nature makes it uniquely suitable for synchronization of 

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V er si o n d at e: 0 3/ 3 1/ 2 0 2 5
Pr ot o c ol C C #: 1 5 7 5 2 1
P h a s e II – P e m br oli z u m a b
 P a g e 1 8 of 1 0 9
micr o bi o me c orrelati ves acr oss i m m u n o- o nc ol o g y breast ca ncer st u dies. A sta n dar dize d a p pr oac h 
s pa n ni n g m ulti ple st u dies o pti mizes scie ntific disc o ver y p ote ntial b y mi ni mizi n g variati o n d ue t o 
met h o d ol o gic differe nces i n sa m ple c ollecti o n, st ora ge, pre parati o n a n d a nal ysis, a n d ma xi mizi n g 
c o h ort size, statistical p o wer, p ote ntial s y ner g y wit h ot her o mics, f u ncti o nal st u dies, bl o o d a n d 
hist o pat h ol o g y a nal yses. Ha vi n g a si n gle la b orat or y perf or m D N A e xtracti o n, li brar y pre p a n d 
se q ue nci n g wit h batc he d sa m ples mi ni mizes varia bilit y a n d batc h effects. Wit h t his a p pr oac h, 
se veral c urre nt c halle n ges i n micr o bi o me researc h i ncl u di n g s mall sa m ple size a n d lac k of 
sta n dar dizati o n acr oss all p hases of i n vesti gati o n i ncl u di n g sa m ple c ollecti o n a n d st ora ge, a n d 
sa m ple pre parati o n ca n be 
mi ni mize d, w hile e x pl orati o n of o pti mal a nal ytic platf or ms is 
ma xi mize d.
3. 1. 3
Precli nic al a n d Cli nic al Tri al D at a
Precli nical a n d cli nical data fr o m Merc k is as f oll o ws ( 1).
Precli nical Data
Pe m br oliz u ma b bi n ds t o h u ma n a n d C y n o m ol g us m o n ke y P D- 1 wit h c o m para ble affi nit y a n d 
bl oc ks t he bi n di n g of h u ma n a n d C y n o m ol g us m o n ke y P D- 1 t o P D- L 1 a n d P D- L 2 wit h 
c o m para ble p ote nc y. Pe m br oliz u ma b d oes n ot cr oss-react wit h d o g, rat, or m o use P D- 1. 
Pe m br oliz u ma b d oes n ot bi n d i m m u n o gl o b uli n s u perfa mil y me m bers cl uster of differe ntiati o n 
2 8 ( C D 2 8), c yt ot o xic T-l y m p h oc yte-ass ociate d pr otei n 4 ( C T L A- 4), or i n d uci ble T-cell 
c osti m ulat or (I C O S).
Pe m br oliz u ma b str o n gl y e n ha nces T-l y m p h oc yte i m m u ne res p o nses i n c ult ure d bl o o d cells fr o m 
healt h y h u ma n d o n ors, ca ncer patie nts, a n d pri mates. I n T-cell acti vati o n assa ys usi n g h u ma n 
d o n or bl o o d cells, t he half- ma xi mal effecti ve c o nce ntrati o n ( E C 5 0) has bee n a p pr o xi matel y 0. 1 t o 
0. 3 n M. I n a d diti o n t o i nterle u ki n- 2 (I L- 2), t u m or necr osis fact or al p ha ( T N F α), i nterfer o n 
ga m ma (I F N ), a n d le vels of ot her c yt o ki nes were f o u n d t o be m o d ulate d b y pe m br oliz u ma b. 
T he a nti b o d y p ote ntiates e xisti n g i m m u ne res p o nses o nl y i n t he prese nce of a nti ge n a n d d oes n ot 
n o ns pecificall y acti vate T-cells. I n t he i n vitr o peri p heral bl o o d m o n o n uclear cell ( P M B C) a n d 
w h ole bl o o d c yt o ki ne release assa ys, t he c yt o ki ne le vels i n d uce d b y pe m br oliz u ma b were l o w 
a n d c o m para ble t o t h ose i n d uce d b y trast uz u ma b. Pe m br oliz u ma b d oes n ot i n d uce a nti b o d y-
de pe n de nt cell- me diate d c yt ot o xicit y ( A D C C) or c o m ple me nt- de pe n de nt c yt ot o xicit y ( C D C).
Usi n g a nti m uri ne P D- 1 s urr o gate a nti b o dies, P D- 1 bl oc ka de has bee n s h o w n t o si g nifica ntl y 
i n hi bit t u m or gr o wt h i n a variet y of s y n ge neic m uri ne t u m or m o dels. I n t hese e x peri me nts i n 
mice, a nti- P D- 1 t hera p y is s y ner gistic wit h c he m ot hera pe utic a ge nts s uc h as ge mcita bi ne a n d 5-
fl u or o uracil ( 5- F U) a n d c o m bi nati o n t hera p y res ults i n i ncrease d c o m plete t u m or re gressi o n rates 
i n vi v o ( 1). St u dies als o re veale d t hat i m m u n os u p pressi ve d oses of de xa met has o ne i ncl u de d i n 
c o m bi nati o n wit h a ge nts use d i n sta n dar d- of-care treat me nt f or N S C L C d o n ot re d uce t he a nti-
t u m or efficac y of a n a nti- m uri ne P D- 1 s urr o gate a nti b o d y. 

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The pharmacokinetics (PK) of pembrolizumab were evaluated in a non-Good Laboratory Practices 
(GLP) single dose PK study and two GLP repeat-dose toxicokinetic (TK) studies (1 month and 6 
month) in Cynomolgus monkeys. Pembrolizumab stability as a modified IgG4 molecule was 
evaluated in vivo in mice. 
After single-dose IV administration at 0.3, 3, or 30 mg/kg in cynomolgus monkeys, decline of 
serum concentration followed multiphase kinetics. Anti-drug antibodies (ADAs) were detected 
in most of the treated animals. Clearance (CL) and terminal half-life (t1/2) appeared to be dose-
dependent in the dose range tested with t1/2 varying from 4 to 10 days. 
In the 1-month repeat-dose (once weekly) GLP toxicity study at 6, 40, or 200 mg/kg in
Cynomolgus monkeys, ADAs were detected in most of the low-dose (6 mg/kg) treated animals. 
The systemic exposure over the 7-day dosing interval (AUC0-7 days) was sex-independent and 
increased with increasing dose. The mean t½ values in individual animals ranged from 15.7 to 
22.3 days) across the doses (1).
In the 6-month repeat-dose (every other week) GLP toxicity study at 6, 40, or 200 mg/kg in 
Cynomolgus monkeys, ADAs were detected in most of the low-dose (6 mg/kg) treated animals. 
The systemic exposure to pembrolizumab was independent of sex and was approximately dose-
proportional across all doses. The mean t1/2 values in individual ADA-negative animals ranged 
from 21 to 22 days across doses.
IgG4 wild type molecule can undergo in vivo molecular rearrangement called Fab-arm (or half 
molecule) exchange by swapping their half molecule with other IgG4 half molecules, thereby 
generating bispecific or hybrid antibodies. Pembrolizumab is a hinge mutated IgG4 (S228P), 
which prevents in vivo half-molecule swap (formation of hybrid). An in vivo mice experiment 
has demonstrated that pembrolizumab did not form hybrid antibody with another wild type IgG4 
molecule.
The potential for systemic toxicity of pembrolizumab was assessed in a 1-month repeat-dose 
toxicity study with a 4-month recovery in cynomolgus monkeys and in a 6-month repeat dose 
toxicity study with a 4-month recovery period in cynomolgus monkeys. In the 1-month toxicity 
study, cynomolgus monkeys were administered an IV dose of 6, 40, or 200 mg/kg once weekly 
for a total of five doses. Four monkeys/sex/group were euthanized during Week 5. The 
remaining two monkeys/sex/group were euthanized during Week 23, after a four-month post-
dose period. In this study, pembrolizumab was well tolerated in monkeys with the systemic 
exposure (AUC) up to approximately 170,000 μg/day/mL over the course of the study. There 
was no test article-related mortality, and test article-related changes were limited to an increased 
incidence of inguinal swelling, and increased splenic weights in males receiving 200 mg/kg. 
Both of these findings were not considered adverse and there was no histopathologic correlation. 
Splenic weights were normal at the post-dose necropsy. Anti-pembrolizumab antibodies were 
detected in 7 out of 8 animals in the 6 mg/kg dose group and 1 animal out of 8 in the 40 mg/kg 
dose group, and were associated with an apparent increase in clearance of pembrolizumab. The 
presence of anti-drug antibodies (ADA) in monkeys in the low-dose group and in one monkey in 
the mid-dose group did not impact the pharmacodynamic response because sufficient target 
engagement was demonstrated for the duration of the study (with the exception of 1 low-dose 

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monkey). Additionally, anti-pembrolizumab antibodies were not detected in any monkeys in the 
high-dose group, suggesting that potential toxicity has been evaluated at the highest exposure 
levels in the study. Based on the lack of adverse test article-related findings in this study, no 
observed adverse effect level (NOAEL) was ≥200 mg/kg (1).
In the 6-month toxicity study, the potential for systemic toxicity was assessed in cynomolgus 
monkeys administered an IV dose of 6, 40, or 200 mg/kg once every other week for 
approximately 6 months (a total of 12 doses) followed by a 4-month treatment free period. Three 
animals/sex/group were designated for interim necropsy at the end of the 6-month dosing phase 
(3 days after receiving the last dose in Study Week 23); and the remaining monkeys were 
designated for final necropsy following the 4-month treatment-free period. Pembrolizumab was 
well tolerated at all dose levels. There were no test article-related antemortem findings, 
electrocardiographic or ophthalmic findings, changes at injection sites, gross observations or 
organ weight changes at the interim or final necropsy. Because there were no test article-related 
histomorphologic findings at interim necropsy, histomorphologic evaluation of tissues collected 
at final necropsy was not conducted. The presence of ADA was observed in 5 out of 10 animals 
at 6 mg/kg/dose during the dosing phase, which correlated with an apparent increased rate of 
elimination of pembrolizumab in these animals. No anti-pembrolizumab antibodies were 
detected at 40 or 200 mg/kg/dose during the dosing phase, and no pembrolizumab serum 
concentration profiles in these two groups suggested an effect of ADA on pembrolizumab 
elimination rate. During the treatment-free period, anti-MK-3475 antibodies were detected in 
two animals at 6 mg/kg/dose, which already had ADA present during the dosing phase, and in 
two additional animals (one at 6 mg/kg/dose and one at 200 mg/kg/dose), which were ADA 
negative during the dosing phase. The detection of anti-pembrolizumab antibodies had a minimal 
effect on the mean group systemic exposure to pembrolizumab during the study and did not 
impact the evaluation of potential toxicity of pembrolizumab for the duration of the 6-month 
study because there were no test article-related effects on any of the parameters examined and as 
no monkey in the mid- and high-dose groups developed ADA during the dosing phase. In 
conclusion, pembrolizumab administered once every other week over a 6-month duration to 
cynomolgus monkeys was well tolerated and the NOAEL was ≥200 mg/kg/dose (the highest 
dose tested).
In addition, tissue cross-reactivity studies using monkey and human specimens were conducted 
to evaluate the potential cross reactivity of pembrolizumab with cryosections of cynomolgus 
monkey tissues and normal human tissues. Results demonstrated the expected on-target staining 
of the membranes of mononuclear leukocytes in both species. The off-target staining 
(cytoplasmic and stromal) that occurred in many tissues of both species was considered spurious 
binding inherent to the experimental conditions of the in vitro tissue cross-reactivity studies with 
no in vivo toxicological significance (1).
Clinical Data
Eight ongoing, Merck-sponsored clinical trials: P001, P002, P011, P012, P013, P021, P023, and 
P028 are evaluating pembrolizumab (1). Subjects received 1 of 6 different pembrolizumab dose 
regimens, either as monotherapy (P001, P002, P011, P012, P013, P028) or as combination 

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therapy (P021, P023). P011 is a combination therapy trial in which pembrolizumab monotherapy 
was compared with pembrolizumab in combination with cisplatin/pemetrexed and 
carboplatin/paclitaxel.
P001 is an open-label, Phase I, first-in-human (FIH) study of IV pembrolizumab in subjects with 
progressive locally advanced or metastatic carcinomas, especially melanoma or NSCLC (non 
small cell lung cancer). Part A of the study involved dose escalation that used a traditional 3+3 
design. Cohorts of 3 to 6 subjects were enrolled sequentially at escalating doses of 1, 3, or 10 
mg/kg administered Q2W. Once the dose escalation was completed, additional subjects were 
enrolled into Parts A1 and A2 to further characterize the PK and pharmacodynamics of 
pembrolizumab.
In Parts B and D, subjects with metastatic melanoma were enrolled to assess the safety and 
antitumor activity of pembrolizumab. Additionally, Part B explored 3 different dose regimens in 
subjects with metastatic melanoma: 10 mg/kg Q2W, 10 mg/kg Q3W, and 2 mg/kg Q3W.
In Part C, subjects with NSCLC (with prior systemic therapy) were enrolled at 10 mg/kg Q3W to 
assess the tolerability, safety, and antitumor activity of pembrolizumab in NSCLC. In Part F, 
subjects with NSCLC in Cohort F-1 (without prior systemic therapy) and Cohort F-2 (with prior 
systemic therapy), whose tumors expressed PD-L1, were enrolled at 10 mg/kg Q2W and 10 
mg/kg Q3W to characterize the tolerability, safety, and antitumor activity of pembrolizumab. A 
small cohort of previously treated subjects with NSCLC and at least 2 lines of systemic therapy, 
whose tumors did not express PD-L1, were enrolled and treated at a dose of 10 mg/kg Q2W in 
Cohort F-2. In Cohort F-3, previously treated subjects with NSCLC whose tumors express PD-
L1 were enrolled at 2 mg/kg Q3W to better characterize the efficacy, safety, and antitumor 
activity of pembrolizumab.
Each of the 2 disease specific cohorts (melanoma and NSCLC) were enrolled to confirm 
tolerability and evaluate tumor response to pembrolizumab. P002 is a partially blinded, 
randomized, Phase II study designed to evaluate 2 doses of pembrolizumab versus a 
chemotherapy control arm in subjects with IPI-refractory metastatic melanoma. Subjects were 
randomized in a 1:1:1 ratio to receive pembrolizumab 2 mg/kg Q3W or pembrolizumab 10 
mg/kg Q3W, or chemotherapy (according to current clinical practice) for the treatment of 
melanoma. Subjects assigned to the control chemotherapy arm could cross over to the 
experimental pembrolizumab arm once progression was confirmed (approximately ≥ Week 12).
P006 is a multicenter, worldwide, randomized, controlled, open-label, 3-arm pivotal Phase III 
study of 2 dosing regimens of IV pembrolizumab versus IV ipilimumab in subjects with 
unresectable or metastatic melanoma who had not received prior ipilimumab treatment. Subjects 
were randomized in a 1:1:1 ratio to receive pembrolizumab at 10 mg/kg Q2W, 10 mg/kg Q3W, 
or ipilimumab at 3 mg/kg Q3W for a total of 4 doses.
P010 is a multicenter, worldwide, randomized, adaptively designed Phase II/III trial of IV 
pembrolizumab at 2 dosing schedules versus docetaxel in subjects with NSCLC with PD-L1 
positive tumors, who have experienced disease progression after platinum-containing systemic 

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therapy. Subjects were randomized in a 1:1:1 ratio to receive pembrolizumab 10 mg/kg Q3W, 2 
mg/kg Q3W, or docetaxel 75 mg/m2 Q3W.
P011 is an open-label, nonrandomized, multicenter Phase I study of pembrolizumab 
monotherapy in Japanese subjects with advanced solid tumors and in combination with 
cisplatin/pemetrexed and carboplatin/paclitaxel in subjects with advanced NSCLC in Japan. In 
Part A (monotherapy, 3+3 design), subjects with advanced solid tumors received escalating 
doses of pembrolizumab 2 mg/kg Q2W (dose level 1) or 10 mg/kg Q2W (dose level 2). In Part B 
(combination, 3+6 design), subjects with advanced NSCLC receive pembrolizumab 10 mg/kg 
Q3W in combination with either cisplatin/pemetrexed (Cohort 1) or carboplatin/paclitaxel 
(Cohort 2) are to be enrolled.
P012 is a multicenter, nonrandomized, multi-cohort Phase Ib trial of pembrolizumab in subjects 
with PD-L1 positive advanced solid tumors. All subjects receive pembrolizumab 10 mg/kg 
Q2W. Cohort A enrolled subjects with TNBC; Cohorts B and B2 enrolled subjects with 
squamous cell carcinoma of the head and neck; Cohort C enrolled subjects with urothelial tract 
cancer of the renal pelvis, ureter, bladder, or urethra; and Cohort D enrolled subjects with 
adenocarcinoma of the stomach or gastroesophageal junction.
P013 is an open-label, multicenter trial of pembrolizumab in subjects with hematologic 
malignancies. All subjects receive pembrolizumab at 10 mg/kg Q2W. Cohort 1 is enrolling 
subjects with intermediate-1, intermediate-2, or high-risk myelodysplastic syndrome who have 
failed at least 4 cycles of hypomethylating agent treatment. Cohort 2 is enrolling subjects with 
relapsed/refractory multiple myeloma. Cohort 3 is enrolling subjects with relapsed/refractory 
Hodgkin lymphoma who are ineligible for or refused a stem cell transplant and whose disease 
has relapsed after treatment with or failed to respond to brentuximab vedotin. Cohort 4a is 
enrolling subjects with relapsed/refractory mediastinal large B cell lymphoma who are ineligible 
for or refused a stem cell transplant, and Cohort 4b is enrolling subjects with any other positive 
PD-L1 positive relapsed/refractory non-Hodgkin lymphoma who are ineligible for or refused a 
stem cell transplant.
P021 is a multicenter, open-label Phase I/II study of IV pembrolizumab at 2 dosing schedules in 
combination with chemotherapy or immunotherapy in subjects with locally advanced or 
metastatic NSCLC. The study is composed of 2 parts.
The objective of Part 1 is to determine the recommended Phase II dose (RP2D) for 
pembrolizumab in combination with different chemotherapy and/or immunotherapy regimens:
• Cohort A – 1:1 randomization to carboplatin and paclitaxel plus either pembrolizumab
2 mg/kg or pembrolizumab 10 mg/kg
• Cohort B – 1:1 randomization to carboplatin, paclitaxel, and bevacizumab plus either
pembrolizumab 2 mg/kg or pembrolizumab 10 mg/kg
• Cohort C – 1:1 randomization to carboplatin and pemetrexed plus either pembrolizumab
2 mg/kg or pembrolizumab 10 mg/kg
• Cohort D – ipilimumab plus pembrolizumab
• Cohort E – erlotinib plus pembrolizumab

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• Cohort F – gefitinib plus pembrolizumab
The objective of Part 2 is to evaluate the antitumor activity of pembrolizumab in combination 
with chemotherapy or immunotherapy. Part 2 includes a randomized comparison of 
chemotherapy ± pembrolizumab based on the doses defined in Part 1, as well as a cohort 
expanding the ipilimumab cohort from Part 1:
• Cohort G – 1:1 randomization to carboplatin and pemetrexed with or without
pembrolizumab 200 mg
• Cohort H – ipilimumab (RP2D from Part 1 Cohort D) plus pembrolizumab, followed by
pembrolizumab monotherapy
P022 is a multicenter, worldwide, Phase I/II 3-part trial of IV pembrolizumab in combination 
with oral dabrafenib and/or trametinib in subjects with advanced or metastatic melanoma. Part 1 
is a non-randomized, multi-site, open-label portion of the study using a traditional 3+3 design to 
evaluate safety, tolerability, and dosing of pembrolizumab (MK) in combination with dabrafenib 
(D) and trametinib (T) in BRAF mutation-positive (V600 E or K) melanoma subjects. 
Additionally in Part 1, dosing of pembrolizumab in combination with trametinib only (MK+T) 
will be explored in BRAF mutation-negative (without V600 E or K) melanoma subjects, to 
evaluate safety, tolerability, and efficacy of MK+T in Part 2 in this population. Part 2 is a non-
randomized, multisite, open-label portion of the study using an expansion cohort to further 
evaluate safety and confirm dose of MK+D+T. Also in Part 2, an expansion cohort will be used 
to further evaluate safety and preliminary efficacy in the MK+T combination. Part 3 is a 
randomized (1:1), active-controlled, multi-site, 2-arm study of the confirmed dose of the triplet 
combination (MK+D+T) versus placebo (PBO) in combination with D+T (PBO+D+T).
P023 is an open-label, Phase I, multicenter, trial of pembrolizumab in combination with 
lenalidomide (Len) and dexamethasone (Dex) or pembrolizumab and Len in subjects with 
relapsed/refractory multiple myeloma who have failed at least 2 lines of prior therapy, including 
a proteasome inhibitor (e.g., bortezomib or carfilzomib) and an immunomodulary derivative 
(thalidomide, pomalidomide, lenalidomide). The trial uses a modified 3+3 design for dose 
determination, followed by dose confirmation and expansion, a further evaluation of safety, and 
a preliminary assessment of efficacy. During dose determination, cohorts of approximately 3 to 6 
subjects are enrolled and receive pembrolizumab 2 mg/kg or 1 mg/kg IV Q2W in each 28-day 
cycle, in combination with Dex 40 mg QW and/or Len 25 mg or 10 mg on Days 1 to 21. After a 
preliminary MTD/maximum administered dose (MAD) is identified, additional subjects are 
enrolled at a fixed dose of pembrolizumab 200 mg or 100 mg in combination with Len/Dex to 
confirm the MTD/MAD.
P024 is a multicenter, international, randomized, open-label trial of IV pembrolizumab 
monotherapy vs. the choice of multiple, standard-of-care, platinum-based chemotherapies in 
subjects previously untreated for their Stage IV, PD-L1 strong, NSCLC. All subjects are 
randomized in a 1:1 ratio to receive pembrolizumab at 200 mg IV Q3W or 1 of the 5 following 
platinum doublets:
• pemetrexed at 500 mg/m2 Q3W and carboplatin AUC 5-6 day 1 Q3W for 4 to 6 cycles
followed by optional pemetrexed 500 mg/m2 Q3W

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• pemetrexed 500 mg/m2 Q3W and cisplatin 75 mg/m2 day 1 Q3W for 4 to 6 cycles
followed by optional pemetrexed 500 mg/m2 Q3W
• gemcitabine 1250 mg/m2 days 1 and 8 and cisplatin 75 mg/m2 day 1 Q3W for 4 to
6 cycles
• gemcitabine 1250 mg/m2 days 1 and 8 and carboplatin AUC 5-6 day 1 Q3W for 4 to
6 cycles
• paclitaxel 200 mg/m2 Q3W and carboplatin AUC 5-6 day 1 Q3W for 4 to 6 cycles
followed by optional pemetrexed maintenance
P025 is an open-label, non-randomized, multicenter Phase Ib study of pembrolizumab in 
Japanese subjects with positive PD-L1 advanced NSCLC in Japan. All subjects received 
pembrolizumab at 10 mg/kg Q3W.
P028 is an open-label, non-randomized, multicenter, multicohort Phase Ib trial of 
pembrolizumab in subjects with PD-L1 positive advanced solid tumors. Subjects are enrolled 
into 1 of the following 20 solid tumor cohorts: A1 Colon or Rectal Adenocarcinoma; A2 Anal 
Canal Squamous Cell Carcinoma; A3 Pancreas Adenocarcinoma; A4 Esophageal Squamous Cell 
Carcinoma or Adenocarcinoma (Including GE Junction); A5 Biliary Tract Adenocarcinoma 
(Gallbladder and Biliary Tree but excluding Ampulla of Vater Cancers); A6 Carcinoid Tumors; 
A7 Neuroendocrine Carcinomas (well or moderately differentiated Pancreatic Neuroendocrine 
Tumor); B1 ER Positive HER2 Negative Breast Cancer; B2 Ovarian Epithelial, Fallopian Tube 
or Primary Peritoneal Carcinoma; B3 Endometrial Carcinoma; B4 Cervical Squamous Cell 
Cancer; B5 Vulvar Squamous Cell Carcinoma; C1 Small Cell Lung Cancer; C2 Mesothelioma 
(Malignant Pleural Carcinoma; D3 Nasopharyngeal Carcinoma; E1 Glioblastoma Multiforme E2 
Leiomyosarcoma; or E3 Prostate Adenocarcinoma. All subjects receive pembrolizumab P029 is 
a multicenter, open-label, 3-part Phase I/II trial of IV pembrolizumab in combination with 
subcutaneous Pegylated Interferon Alfa-2b (PEG-IFN) or IV ipilimumab in subjects with 
advanced or metastatic melanoma or renal cell carcinoma. Part 1A, the Phase I portion of the 
trial, will define the preliminary MTD or MAD of pembrolizumab + PEG-IFN (Group A) and 
pembrolizumab + ipilimumab (Group B), and confirm the tolerability of these treatment 
doublets.
Part 1B is a single-arm expansion cohort designed to better characterize the safety and 
tolerability, as well as to evaluate preliminary efficacy of the pembrolizumab + ipilimumab 
combination in melanoma subjects. Part 2, the randomized portion of the trial, will evaluate 
preliminary clinical efficacy in advanced melanoma at the RP2D for pembrolizumab + PEG-IFN 
and the Phase II Dose determined in Part 1A and 1B for pembrolizumab + ipilimumab. 
Evaluation of pembrolizumab monotherapy may also occur during Part 2.
P030 is a multisite, worldwide, expanded access program for subjects with metastatic melanoma 
who have limited or no treatment options. Subjects must have progressed after prior systemic 
therapy, including standard-of-care agents which include ipilimumab and a BRAF/MEK 
inhibitor when indicated. Subjects cannot be eligible for an available pembrolizumab clinical 
trial or have participated in a pembrolizumab clinical trial. Subjects are evaluated for safety at 
baseline and before each cycle of treatment with pembrolizumab 2 mg/kg/Q3W. Subjects are 
treated until progression of disease or until the subject has received up to 2 years of treatment.

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P041 is an open-label, nonrandomized, multicenter Phase Ib study to evaluate the safety, 
tolerability, and antitumor activity of treatment with pembrolizumab 2 mg/kg Q3W in subjects 
with advanced melanoma in Japan. Treatment with pembrolizumab will continue unless a subject 
meets the discontinuation criteria such as disease progression (evaluated by modified Response 
Evaluation Criteria In Solid Tumors [RECIST] 1.1), unacceptable toxicity, or completion of 24 
months of treatment with pembrolizumab.
P045 is a randomized, active-controlled, multisite, open-label, Phase III trial to evaluate the 
efficacy of treatment with pembrolizumab versus paclitaxel, docetaxel, or vinflunine in subjects 
with metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed 
following platinum-containing chemotherapy. Subjects are randomized in a 1:1 ratio to receive 
pembrolizumab 200 mg Q3W or the Investigators’ choice of paclitaxel 175 mg/m2 Q3W, 
docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. The study also evaluates the safety 
and tolerability profile of pembrolizumab in subjects with recurrent/progressive metastatic 
urothelial cancer.
P055 is a multicenter, unblinded, open-label, single-cohort, Phase II trial to determine the safety, 
tolerability, and antitumor activity of a 200 mg Q3W dose of pembrolizumab in subjects with 
recurrent and/or metastatic head and neck squamous cell carcinoma who have progressed on 
platinum and cetuximab therapy. Antitumor activity is also assessed in the subset of subjects for 
whom a biopsy sample is determined to be PD-L1 positive.
3.1.4
Rationale for the Trial and Selected Subject Population
Pembrolizumab, an anti-PD-1 antibody, has shown efficacy for the treatment of a number of 
different solid tumors resulting in the first FDA approval for the treatment of advanced 
melanoma in September 2014.  Recent Phase I data suggests single agent efficacy in TNBC 
expressing PD-L1 (31). The purpose of this study is to investigate the use of pembrolizumab in 
combination with carboplatin in breast cancer patients with chest wall disease, with associated 
immunologic and genomic correlative studies to determine mechanism of action.
Up to 30% of patients with breast cancer may experience chest wall recurrence (32). Patients 
who develop chest wall recurrence after mastectomy or following lumpectomy and radiation 
with hormone resistant or TN breast cancer have a poor prognosis (33), with almost all 
developing distant metastases. Even with combined modality treatment with surgery, radiation, 
and chemotherapy, patients with skin involvement from breast cancer  have a high risk of 
developing distant metastases (34). Chest wall disease has a high morbidity with possible 
complications including skin ulceration, pain, bleeding, and lymphedema (32). In addition, local 
disease recurrence is almost always associated with subsequent systemic relapse (35). Therefore, 
better therapies are needed for treating chest wall disease from breast cancer. 
Thus far, anti-PD-1 antibodies have not been specifically investigated for the treatment of chest 
wall disease in patients with breast cancer. We hypothesize that the anti-PD-1 antibody, 
pembrolizumab, may be effective in treating chest wall or inflammatory disease in patients who 
have TN or hormone resistant breast cancer. Extrapolating from the promising outcomes noted in 
melanoma with pembrolizumab (36), we hypothesize that chest wall and skin involvement with 
breast cancer will likewise respond to pembrolizumab, as breast cancer, like melanoma, often 

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involves the skin and subcutaneous tissues. High levels of PD-1 have been associated with a 
poorer prognosis in patients with breast cancer, so targeting this pathway may be beneficial in 
improving outcomes (37, 38). In vitro, basal type breast cancer cells were noted to have high PD-
L1 expression (39) and preliminary data suggest single agent efficacy in TNBC expressing PD-
L1 and in some cases of hormone resistant disease (personal communication 8/14, Merck). The 
basal breast cancer subtype has been found to be associated clinically with higher rates of loco-
regional recurrence (40), hence targeting the PD-1 pathway may be beneficial in treating chest 
wall recurrence in patients with breast cancer. In addition, recent pre-clinical data has shown that 
nearly 50% of breast cancer tumor specimens may have mutations in PD-1 with a high 
predominance in TNBC (41, 42). Additionally, lymphovascular invasion with breast cancer is 
associated with a higher risk of recurrent chest wall disease (43), and PD-1 has been associated 
with the presence of intense lymphocytic infiltration (44) so a heightened immune response 
triggered by the anti-PD-1 antibody may be beneficial in treating chest wall disease. A recent 
study also showed that topical imiquimod, a Toll like receptor agonist, may be beneficial in 
treating recurrent skin metastases in patients with breast cancer (45), lending further support to 
the possible benefit of immunotherapy, such as the anti-PD-1 antibody, in the setting of skin and 
chest wall involvement of breast cancer. 
Two recent phase I trials have suggested the efficacy of anti-PD-1/PD-L1 antibodies in TNBC. 
In a phase Ib study, Nanda et al evaluated pembrolizumab in patients with advanced heavily 
pretreated triple negative breast cancer whose tumors expressed PD-L1 (31). Of 27 patients 
enrolled, 1 patient had a complete response, 4 patients had a partial response, and 7 patients had 
stable disease, for a clinical benefit rate of 44%. The median time to response was 18 weeks. A 
second phase I study evaluated MPDL3280A (atezolizumab), an anti-PD-L1 monoclonal 
antibody, in patients with pre-treated metastatic TNBC (46-48). Fifty-four patients with 
metastatic TNBC that had progressed on several lines of prior chemotherapy were treated with 
atezolizumab in a phase Ib expansion. Approximately 69% of patients had at least 5% of tumor 
cells positive for PD-L1 by IHC staining. Twenty-one patients with PD-L1 positive disease were 
evaluable for efficacy; 2 complete and 2 partial responses were observed.  At the time of 
presentation at the recent American Association of Cancer Research Meeting in April 2015, 3 of 
4 responses were ongoing, and the median time to progression had not yet been reached (range 
18-56 weeks). For the PD-L1 positive population, the 24 week progression free survival rate was 
27%, with a median duration of survival of 40 weeks (range 2-85 weeks).
Carboplatin was selected as a chemotherapy partner with pembrolizumab in this trial based on 
data demonstrating efficacy in both the first and later line settings in the treatment of metastatic 
breast cancer (49).  Response rates range from 10 to 27%, and PFS has been noted to be around 4 
months with platinum monotherapy (54-56,57). Platinum agents are also effective in 
subpopulations of metastatic or recurrent breast cancer with impaired DNA repair mechanisms, 
including but not limited to those with germline or acquired mutations in BRCA 1 or 2 (50). 
In this study, chemotherapy (carboplatin) will be combined with immunotherapy 
(pembrolizumab). Chemotherapy may facilitate anti-tumor immunity (51) by inducing 
immunologic cell death leading to adaptive tumor specific immune responses, modulating tumor 
antigens and immune checkpoint molecules, and facilitating antigen processing (52). Platinum 
agents may help mediate an immune response through a variety of mechanisms including the 

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upregulation of mannose-6-phosphate receptors and an increase in perforin-independent 
permeability to granzyme-B released  by cytotoxic T-lymphocytes (53), induction of autophagy 
allowing for an infiltration of dendritic cells and T cells in a tumor (54), and the induction of 
immunogenic cell death via calreticulin expression (55). Platinum agents may also decrease 
regulatory T-cells and decrease myeloid-derived suppressor cells (52). Wu et al studied the 
immunogenicity of apoptotic ovarian cancer cells obtained from patients with ovarian cancer 
undergoing treatment with paclitaxel and carboplatin (56). The authors found that apoptotic 
ovarian cancer cells unleash a strong cytotoxic T cell response with anti-tumor activity in vitro. 
With chemotherapy treatment, changes occurred in patient peripheral blood specimens; the 
percentage of regulatory T cells decreased and the proportions of natural killer cells, helper T 
cells, cytotoxic T lymphocytes, and interferon gamma secreting CD8+ T cells increased, 
suggesting an anti-tumor immune response from chemotherapy. 
Chemotherapy has been combined with immunotherapy in pre-clinical studies. An animal tumor 
model combined an anti-PD-1 antibody with low dose cyclophosphamide, and a tumor vaccine, 
and noted antigen-specific immune responses, tumor immune cell infiltration, and regression of 
tumors in animals (57). Pre-clinical studies in ovarian cancer cells have shown that immune 
activation may trigger platinum induced apoptosis and restore sensitivity to platinum agents. El-
Gazzar et al studied AD5-10, a monoclonal antibody to tumor necrosis factor-related apoptosis-
inducing ligand (TRAIL), and found that this agent re-sensitizes ovarian cancer cells to 
apoptosis, and that this effect is augmented by carboplatin, due to carboplatin induced triggering 
of TRAIL receptor expression on ovarian cancer cells (58).  In vivo, AD5-10 restored ovarian 
cancer sensitivity to carboplatin.
Clinical studies have combined chemotherapy and immunotherapy. In patients with advanced 
ovarian cancer, oregovomab, a monoclonal antibody to CA125, was combined with 
chemotherapy with carboplatin and paclitaxel in 2 dosing schedules (simultaneous combined 
therapy or delayed oregovomab therapy)(59). Simultaneous combination therapy with 
oregovomab and chemotherapy induced more rapid and strong humoral immunity.
Immune checkpoint blockade has also been investigated with chemotherapy. The combination of 
ipilimumab, a monoclonal antibody to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), 
an immune checkpoint molecule, with dacarbazine significantly improved survival in patients 
with metastatic melanoma compared with dacarbazine alone (OS 11.2 months in 
ipilimumab/dacarbazine cohort vs. 9.1 months for dacarbazine cohort) (60).  Recent studies have 
suggested that the combination of anti-PD-1 immunotherapy and chemotherapy with a platinum 
agent may be more effective than platinum based chemotherapy alone. Antonio et al studied the 
combination of nivolumab, an IgG4 PD-1 inhibitor, in combination with platinum doublet 
chemotherapy in patients with advanced non small cell lung cancer. One year overall survival 
rates were 59-87%, an improvement from typical one year overall survival rates of 
approximately 54% with platinum doublet chemotherapy alone (61). The KEYNOTE-021 trial is 
an ongoing trial evaluating pembrolizumab in combination with carboplatin and paclitaxel or 
carboplatin and pemetrexed, in patients with advanced non-small cell lung cancer (62). The 
initial results from this study were presented at the ASCO 2015 meeting. Forty-four patients 
were treated, with preliminary overall response rates ranging from 30-58%. One patient 
experienced a grade 3 rash, which was a dose limiting toxicity. Twenty-seven percent of patients 

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experienced grade 3-4 adverse events which included reversible transaminitis, anemia, rash, and 
colitis. Overall, the combination of pembrolizumab with chemotherapy including carboplatin 
was found to be both safe and effective (63). The patients enrolled in this study will have chest 
wall disease that is triple negative or hormone resistant, supporting the use of carboplatin in the 
control arm, as well as in combination with pembrolizumab (64, 65).
This study seeks to determine whether pembrolizumab in combination with carboplatin vs. 
carboplatin alone is effective in breast cancer patients with hormone resistant or triple negative 
disease who have chest wall disease. In a companion translational study, we will determine the 
immunologic and genomic basis underlying the mechanism of action. In Arm A, pembrolizumab 
will be combined with carboplatin, while Arm B will receive carboplatin alone, with cross-over 
to pembrolizumab on progression (Arm Bx). We hypothesize that the combination of 
pembrolizumab and carboplatin will have heightened activity in treating chest wall disease 
compared with carboplatin alone.  As patients with systemic sites of disease are eligible, we will 
also have the opportunity to evaluate the effectiveness of this therapy on distant sites of disease. 
Based on these compelling data, we propose to evaluate the combination of pembrolizumab and 
carboplatin in this study.
3.1.5
Rationale for Dose Selection 
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type. 
As outlined below, this dose is justified by:
Clinical data from 8 randomized studies in melanoma and NSCLC indications demonstrating flat 
dose and exposure efficacy relationships from  2 mg/kg Q3W to 10 mg/kg (Q2W), representing 
an approximate 5 to 7.5 fold exposure range. 
KEYNOTE-001 was an open-label phase I study designed to evaluate safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics, and anti-tumor activity of single-agent 
pembrolizumab. The dose escalation portion of this study evaluated 3 dose levels, 1 mg/kg, 3 
mg/kg, and 10 mg/kg, administered every 2 weeks. The dose expansion cohorts evaluated 2 
mg/kg every 3 weeks and 10 mg/kg every 3 weeks in subjects with advanced solid tumors. All 
dose levels were well tolerated and no dose-limiting toxicities were observed. This first-in-
human study of pembrolizumab showed evidence of target engagement and objective evidence 
of tumor size reduction at all dose levels. No maximum tolerated dose (MTD) has been 
identified. In addition, 2 randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg vs. 10 mg/kg every 3 weeks have been completed, and 1 
randomized cohort evaluating 10 mg/kg every 3 weeks vs. 10 mg/kg every 2 weeks has also been 
completed. The clinical efficacy and safety data demonstrate a lack of important differences in 
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 Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of exposures, 
supporting suitability of 200 mg Q3W. 
An integrated body of evidence suggests that 200 mg every 3 weeks should provide similar 
efficacy to 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks. 
In translating to other tumor indications, similar flat exposure-response relationships for efficacy 
and safety in subjects with melanoma can be expected, as the anti-tumor effect of 
pembrolizumab is driven through immune system activation rather than through a direct 
interaction with tumor cells, rendering it independent of the specific tumor type. In addition, 
available PK results in subjects with melanoma, NSCLC, and other tumor types support a lack of 
meaningful difference in PK exposures obtained at tested doses among tumor types. Thus, the 
200 mg every 3 week fixed-dose regimen is considered an appropriate fixed dose for other tumor 
indications as well.
A fixed-dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. The existing data suggests that 200 mg 
every 3 weeks is the appropriate dose and schedule for pembrolizumab.
Pembrolizumab and Carboplatin
Patients will be randomized in a 2:1 ratio to receive either carboplatin AUC 5 IV and 
pembrolizumab 200 mg IV every 3 weeks for at least 6 cycles (Arm A) followed by 
pembrolizumab 200 mg IV every 3 weeks if stable or responding disease (Arm Ax) or 
carboplatin AUC 5 IV every 3 weeks alone (Arm B) until disease progression, at which time 
they may cross-over (Arm Bx) to pembrolizumab 200 mg IV every 3 weeks with or without 
carboplatin at the investigator’s discretion. Patients with prior thrombocytopenia or prior 
carboplatin exposure will receive carboplatin AUC 4 IV on Arm A and Arm B. Please see 
section 3.1.3 for rationale for using carboplatin in this study. In prior studies, carboplatin has 
demonstrated efficacy when dosed as monotherapy at AUC 6 or in combination at an AUC of 4 
or 5 every 3 weeks with efficacy (66, 67). Carboplatin has been dosed at AUC 5 or 6 every 3 
weeks in combination with pembrolizumab, (63). For this study, we selected the carboplatin dose 
of AUC 5 and AUC 4 IV every 3 weeks, in order to minimize potential toxicity in combination 
with pembrolizumab. If patients are randomized to Arm A and continue on to pembrolizumab 
only (Arm Ax), carboplatin may be added back into the treatment regimen at the investigator’s 
discretion and with approval from the Study Chair. 
Carboplatin Monotherapy
Carboplatin has been used as monotherapy for the treatment of metastatic breast cancer. 
Response rates range from 10 to 27%, and PFS has been noted to be around 4 months with 
platinum monotherapy (54-56,57). In this study, carboplatin will be dosed at AUC 5 IV every 3 
weeks. Patients with prior thrombocytopenia or prior carboplatin exposure will be dosed at 
carboplatin AUC 4 IV every 3 weeks. Although carboplatin AUC 6 IV every 3 weeks is standard 
of care for metastatic breast cancer per the NCCN guidelines, this is often complicated by 

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toxicity warranting dose reduction and/or delays or discontinuation of treatment. To minimize 
toxicity to patients in Arm B who may have been pre-treated with prior lines of chemotherapy, 
and to provide similar carboplatin dosing to the combination arm, carboplatin will be dosed at 
AUC 4 or 5 IV every 3 weeks in this study. 
3.1.6
Rationale for Endpoints
3.1.6.1
Efficacy Endpoints
In this study, we will determine the disease control rate in patients with chest wall disease at 18 
weeks of treatment with pembrolizumab and carboplatin vs. carboplatin alone (primary 
objective), including both chest wall and distant sites of disease as applicable. 18 weeks was 
selected to assess the primary endpoint as this was the median time to response in a recent phase 
I trial of pembrolizumab in triple negative breast cancer (31). Additionally, we will determine 
disease control rates using irRECIST, progression free survival, objective response rate, and 
toxicity (secondary objectives) after treatment with pembrolizumab and carboplatin vs. 
carboplatin alone. We will also determine disease control rate based on PD-L1 expression. 
Disease control has been evaluated as a viable response endpoint in prior studies on patients with 
unresectable locally advanced breast cancer, given the  short period of control of this disease (68, 
69). 
3.1.6.2
Biomarker Research
Biomarker research will be performed in a companion translational study. Using tissue biopsies 
and blood collected at baseline and at cycle 3 day 1 of treatment (or at progression if sooner), we 
will perform immunologic correlative studies to look specifically for changes in PD-L1 
expression (75)  with treatment. Cytokine expression of interleukin-2 (IL-2), tumor necrosis 
factor alpha (TNF-alpha), and interferon-gamma will be evaluated before and after treatment in 
blood (at baseline, at cycle 3 day 1 of treatment) (40, 76, 77). We will also evaluate peripheral T 
cells for PD-1 expression at baseline and cycle 3 day 1 of treatment (78, 79) to see if these 
markers correlate with disease control rate. 
In addition, we will evaluate serial plasma tumor DNA (80, 81) to assess possible markers of 
response and resistance, and circulating tumor cells at baseline and cycle 3 day 1 of treatment 
(82, 83).  We will determine whether MYC, an oncogene often over-expressed in triple negative 
and hormone resistant breast cancer, is associated with high levels of PD-1 and TIM-3 (immune 
checkpoint receptor) on immune cells in tumor biopsies (84-86). Preliminary data from Andrei 
Goga’s lab has shown that tumor associated T cells demonstrate up-regulation of the PD-1 
checkpoint molecule and TIM-3 in response to MYC as a driver oncogene. We will also 
determine whether these correlative markers correlate with disease control rate. 
Altogether, this unique study promises to improve our understanding of pembrolizumab in chest 
wall disease from the clinical, immunologic, and genomic perspectives. 

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4.0 OBJECTIVES
4.1
Primary Objective 
To determine the disease control rate (including CR, PR and stable disease as defined by 
RECIST 1.1 at 18 weeks of treatment in breast cancer patients with chest wall disease 
treated with pembrolizumab and carboplatin or carboplatin alone.
4.2
Secondary Objectives 
1. To determine the disease control rate (including CR, PR and stable disease as defined by 
irRECIST at 18 weeks of treatment in breast cancer patients with chest wall disease 
treated with pembrolizumab and carboplatin or carboplatin alone.
2. To determine progression free survival in patients treated with pembrolizumab and 
carboplatin vs. carboplatin alone.
3. To determine the toxicity of pembrolizumab and carboplatin vs. carboplatin alone.
4. To determine 18 week disease control rate based on tumor PD-L1 expression via 
immunohistochemistry.
5. To determine the overall response rate of patients treated with pembrolizumab and 
carboplatin vs. carboplatin alone.
6. Support standardized gut microbiome sample collection, storage, preparation and analysis 
to optimize scientific discovery potential by minimizing variation due to methodologic 
differences in sample collection, storage, preparation and analysis, as well as permitting 
cross-study comparisons and testing of multiple analytics platforms to explore gut 
microbiome associations with the clinical response to immunotherapy.
5.0 METHODOLOGY
5.1
Entry Criteria
This proposed pilot study seeks to investigate the combination of pembrolizumab and carboplatin 
versus carboplatin alone in patients with breast cancer with chest wall disease. Patients with 
hormone resistant, triple negative, or HER2+ breast cancer with chest wall disease are eligible 
regardless of sites of distant metastases. Patients enrolled may have undergone prior surgery and 
chemotherapy. Prior platinum based chemotherapy is allowed only in patients without evidence 
of progressive disease while receiving carboplatin; prior radiation therapy is allowed but not 
required for study entry. Patients with hormone receptor positive disease must have 
demonstrated progressive disease on at least 2 prior lines of hormone therapy. Patients with brain 
metastases will be eligible if their intracranial disease has been controlled for at least 1 month. 
Enrollment will not be contingent on PD-L1 expression although this will be analyzed. 

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5.1.1
Diagnosis/Condition for Entry into the Trial
Patients must have chest wall disease secondary to breast cancer to be considered for entry into 
the trial as noted above.
5.1.2
Subject Inclusion Criteria
1. Advanced breast cancer with locally recurrent chest wall disease not amenable to surgical 
excision with curative intent.
a.
Distant sites of disease are allowed
b. Prior radiation to the chest wall is not required
2. The following disease subtypes are eligible:
a.
Triple negative disease (defined as ER < 10%, PR < 10%, HER2 negative)
b. Hormone receptor positive, HER2 negative disease with evidence of progression 
on at least two prior lines of hormone therapy, unless, per treating investigator’s 
judgement, is not considered a candidate for further endocrine therapy.
c.
 HER2 positive disease with evidence of disease progression on trastuzumab, 
pertuzumab, T-DM1 and oral tyrosine kinase inhibitor unless contraindicated with 
no other HER2 targeted therapy options available. Patients in this category will be 
classified by ER status.
i. Histologically confirmed HER2+ breast carcinoma, with HER2+ defined 
by in situ hybridization (ISH) or fluorescence in situ hybridization (FISH) 
or immunohistochemistry (IHC) methodology using standard criteria.
ii. Cardiac function must be determined within 4 weeks of study entry to be > 
50% using ECHO or MUGA.
3. Any number of prior lines of therapy are allowed 
a.
Prior platinum based therapy is allowed in the following settings:
i. Treatment in the neoadjuvant and/or adjuvant setting without clear 
progression of disease
ii. Treatment in the metastatic setting without clear progression of disease.
b. Neo/adjuvant treatment with a checkpoint inhibitor is allowed if the last treatment 
was at least 12 months from the diagnosis of metastatic disease.

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4. At least two weeks from last systemic chemotherapy for breast cancer, with recovery of 
all treatment related toxicity to grade 1 or less. Subjects with ≤ Grade 2 neuropathy are an 
exception to this criterion. No specific window is required for hormone therapy.
5. At least two weeks from last radiation therapy, with recovery of all treatment related 
toxicity to grade 1 or less (excluding alopecia).
6. Prior CNS disease is allowed if stable for at least one month since whole brain radiation 
therapy, and 2 weeks since stereotactic radiotherapy, and not requiring steroids. Patients 
whose CNS disease was surgically treated may be enrolled if stable for at least one 
month, and not requiring steroids.
7. Able to provide tissue from a newly obtained core or excisional biopsy of a chest wall 
tumor lesion.  Newly-obtained is defined as a specimen any time after the last systemic or 
local therapy utilized to treat the disease.  Subjects for whom newly-obtained samples 
cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived 
specimen only upon agreement from the Study Chair.
8. Willing and able to provide written informed consent.
9.  18 years of age on day of signing informed consent.
10. ECOG performance status of less than or equal to 2
Adequate organ function as defined in Table 1 within 10 business days of treatment initiation. 
Table 1  Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count 
(ANC)
≥1,000 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment)
Renal
Serum creatinine OR
Measured or calculateda 
creatinine clearance
(GFR can also be used in place 
of creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 
1.5 X institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN  OR

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≤ 5 X ULN for subjects with liver metastases
Albumin
>2.5 g/dL
Coagulation
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT)
Activated Partial 
Thromboplastin Time (aPTT)
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
11. Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.  
12. Female subjects of childbearing potential should be willing to use an acceptable form of 
birth control or be surgically sterile, or abstain from heterosexual activity for the course 
of the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. 
13. Male subjects should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.
5.1.3
Subject Exclusion Criteria
1. Treatment with an investigational agent within 4 weeks of the first dose of treatment.
2. A diagnosis of immunodeficiency or is currently receiving systemic steroid therapy at 
any dose or is receiving any other form of immunosuppressive therapy. Steroid therapy is 
not allowed within 7 days prior to the first dose of trial treatment.  However, topical and 
intranasal corticosteroids are allowed, and not an exclusion for participation.
3. Known active TB (Bacillus Tuberculosis). Patients with a distant history of tuberculosis 
that was appropriately treated and have no evidence of active infection are eligible to 
participate. Patients with a history of latent tuberculosis that was appropriately treated are 
also eligible to participate. 
4. Hypersensitivity to pembrolizumab or any of its excipients.
5. Hypersensitivity to carboplatin or cisplatin

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6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to a previously administered agent.
-
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion.
-
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.  
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.    
9. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
10. Has a history of (non-infectious)  pneumonitis/interstitial lung disease that required  
steroids or has current pneumonitis/  interstitial lung disease.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.  
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, screening visit through 120 days after the last dose of trial 
treatment.
15. Prior checkpoint inhibitor therapy in the metastatic setting. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).

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18. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first 
dose of  study drug. Administration of killed vaccines is allowed.
5.2
Trial Treatments
The treatment to be used in this trial is outlined below in Table 2.
Treatment will be continued until clear progression is documented using RECIST, or until 
unacceptable toxicity or withdrawal of consent.  Patients who are believed to have 
pseudoprogression based on irRECIST may continue on study therapy after consultation with the 
study PI. Patients on Arm A may stop carboplatin after a minimum of 6 cycles to minimize 
toxicity if they have stable or responding disease per physician discretion and will continue 
maintenance pembrolizumab 200 mg IV every 3 weeks. If patients on Arm A discontinue 
carboplatin before 6 cycles due to reasons other than progressive disease, the possibility of 
continuing pembrolizumab 200 mg IV every 3 weeks should be discussed with the Study Chair.
Table 2Arm A: Carboplatin AUC 5 IV every 3 weeks and pembrolizumab 200 mg IV every 3 
weeks for at least 6 cycles followed by maintenance pembrolizumab 200 mg IV every 3 weeks 
until progression (Arm Ax). Carboplatin will be dosed at AUC 4 IV every 3 weeks for patients 
with prior thrombocytopenia or carboplatin exposure. (For HER2+ patients, this arm will also 
include trastuzumab administered every 3 weeks using standard dosing). 
Arm B: Carboplatin AUC 5 IV every 3 weeks alone until progression. Cross over (Arm Bx) to 
single agent pembrolizumab 200 mg IV every 3 weeks alone is allowed following documented 
progression. Carboplatin may be continued or added back into the treatment regimen at the 
investigator’s discretion. Carboplatin will be dosed at AUC 4 IV every 3 weeks for patients with 
prior thrombocytopenia or carboplatin exposure. (For HER2+ patients this will include 
trastuzumab administered every 3 weeks using standard dosing). 
Table 2  Trial Treatment
Drug
Dose/
Potency
Dose
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each
3 week cycle
Arm A and 
Arm Bx
*Carboplatin
AUC 
5 
or 
AUC 4
Q3W
IV infusion
Day 1 of each 
3 week cycle
Arm A and 
Arm B
**Trastuzumab
If needed, 8 
mg/kg 
loading dose 
followed by 6 
Q3W (any 
dosing 
schedule 
allowed)
IV infusion
Coordinate with 
pembrolizumab if 
possible, but this 
is not required.
Arm A and 
Arm B

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Drug
Dose/
Potency
Dose
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
mg/kg every 
3W
*The schedule of carboplatin may be modified to weekly dosing given on a 2 week on, 
one week off schedule as needed to manage hematologic or gastrointestinal toxicity.  
Patients must start at the study dose and schedule.  Any changes to the dosing schedule 
should be approved by the Study Chair.
**Trastuzumab will only be given to patients with HER2+ disease.
Randomization should occur a maximum of 3 business days prior to C1D1 of trial treatment. 
Patients receiving combination therapy will receive carboplatin first followed by 
pembrolizumab.
5.2.1
Dose Selection/Modification
5.2.1.1
Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section 3.1.4.  
Dose adjustments are to be made according to the organ system showing the greatest degree of 
toxicity.
5.2.1.2
Dose Modification and Toxicity Management for Immune-Related AEs 
Associated with Pembrolizumab and Combination Therapy
Adverse events (both non-serious and serious) associated with pembrolizumab exposure, 
including coadministration with additional compounds, may represent an immunologic etiology.  
These immune-related AEs (irAEs) may occur shortly after the first dose or several months after 
the last dose of pembrolizumab/combination treatment and may affect more than one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Based on existing clinical study data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab/combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Dose modification and toxicity 
management guidelines for irAEs associated with pembrolizumab/combination treatment are 
provided in Table 3 below. See Section 5.6.1 for supportive care guidelines, including use of 
corticosteroids.
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to a 
single component is likely to be difficult. Therefore, while the investigator may attribute a 

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toxicity event to the combination, to carboplatin alone or to pembrolizumab alone, for adverse 
event listed in Table 3, both interventions must be held according to the criteria in Table 3 Dose 
Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
Associated with Pembrolizumab.
Holding Study Interventions:
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications.
Restarting Study Interventions:
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 3.

If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions.

If the toxicities do resolve and conditions are aligned with what is defined in Table 3, the 
combination of carboplatin and pembrolizumab may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the combination or to 
carboplatin alone, re-initiation of pembrolizumab as a monotherapy may be considered at 
the principal investigator’s discretion.

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Table 3: Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with Pembrolizumab 
Monotherapy and IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.
Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last 
study intervention treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other Therapies
Monitoring and Follow-up
Grade 2
Withhold 
Pneumonitis 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Add prophylactic antibiotics for 
opportunistic infections
  Monitor participants for signs and symptoms of 
pneumonitis
  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Grade 2 or 3
Withhold
Diarrhea/Colitis 
Recurrent 
Grade 
3 
or 
Grade 4
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus 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 
f
i
d
l
li i

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Grade 2 a
Withhold
  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or 
equivalent) followed by taper
AST 
or 
ALT 
Elevation 
or 
Increased 
Bilirubin
Grade 3 b or 4 c
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 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)
T1DM 
or 
Hyperglycemia
New 
onset 
T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence 
of 
-cell failure
Withhold d
  Initiate insulin replacement therapy for 
participants with T1DM
  Administer antihyperglycemic in 
participants with hyperglycemia
  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold 
or 
permanently 
discontinue d
  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold 
or 
permanently 
discontinue d
  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
  Monitor for signs and symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
  Monitor for signs and symptoms of thyroid 
disorders

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Grade 2
Withhold
Nephritis:
grading 
according 
to 
increased 
creatinine 
or 
acute 
kidney 
injury
Grade 3 or 4
Permanently 
discontinue
  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper
  Monitor changes of renal function
Grade 2
Withhold
Neurological 
Toxicities
Grade 3 or 4
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 1
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Suspected SJS, 
TEN, or DRESS
Withhold
Exfoliative 
Dermatologic 
Conditions
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
Persistent Grade
2
Withhold
Grade 3
Withhold 
or 
discontinue based 
on the event e 
All Other irAEs
Recurrent 
Grade 3 
or 
Grade 4 
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.

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a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if 
baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs.

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5.2.2
Carboplatin Dose
Carboplatin will be dosed every 3 weeks according to the treatment schedule previously 
described. 
Carboplatin dose in mg = (desired AUC)(GFR + 25)
GFR (estimated) = (140 – age in years) (weight in kg)(for females x 0.85) 
(SCr in mg/dL) (72)
NOTE: Creatinine clearance is capped at 125 ml/min.
5.2.3
Carboplatin Administration
Carboplatin will be prepared and administered as per standard guidelines. Please refer to the 
package insert for details on carboplatin preparation and administration. 
Patients should receive appropriate premedications before each dose of carboplatin including 
standard antiemetics.  Steroid premedication should be avoided or minimized if possible. 
5.2.4
Dose Modification of Carboplatin and Management of Toxicity
Every effort should be made to administer study treatment on the planned dose and schedule. 
Suggested dose reduction criteria are described below for carboplatin administered in this study. 
These criteria are provided as guidance only. Decisions on dose reduction and resumption of 
treatment will be determined according to the judgment of the Investigator and per standard 
guidelines.  
Modifying Carboplatin Dosing Schedule
As noted in section 5.2 Table 2 footnote, the schedule of carboplatin may be changed to the 2 
week on, one week off schedule as needed to manage toxicity and maintain dosing.  Changes to 
the schedule must be approved by the study Study Chair. The initial Day 1 and Day 8 dose 
should be at an AUC of 2, but may be modified thereafter for toxicity at the treating 
investigator’s discretion. Re-escalation of carboplatin dose may be discussed with the Study 
Chair. 
Table 4. Carboplatin Dose Modification and Toxicity Management
Event
Carboplatin Dose Modification 
Neutropenia
≥ 1000/mm3 

No change to carboplatin 

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Event
Carboplatin Dose Modification 
< 1000/mm3 

Hold carboplatin until ANC >1000/ mm3

Dose-reduce carboplatin by 1 dose level (-1 AUC) at the next cycle 
for all subsequent doses
GCSF may be used between days 2–6 according to patient need, at physician 
discretion, and to avoid dose reduction. 
Neutropenic Fever
ANC ≤ 1000/mm3, fever ≥ 
38.5°C

Hold carboplatin until resolved (ANC > 1000/mm3, fever < 
38.5°C). 

Resume carboplatin with a dose reduction of 1 dose level (–1 AUC) 
at the next cycle for all subsequent cycles
GCSF may be used between days 2–6 according to patient need, at physician 
discretion, and to avoid dose reduction. 
Thrombocytopenia
≥ 75,000/mm3

No change to carboplatin.
50–<75,000/mm3

Hold carboplatin until recovery to 75,000/ mm3

Dose-reduce carboplatin with a 1 dose level reduction (-1 AUC) at 
the next cycle for all subsequent cycles.
< 50,000/mm3 

Hold carboplatin until recovery to ≥75,000/ mm3

First episode: Hold carboplatin until platelets are ≥75,000/mm3. 
Dose-reduce carboplatin with a 1 dose level reduction (-1 AUC) at 
the next cycle for all subsequent cycles.

Second episode: Hold carboplatin until platelets are ≥ 75,000/mm3. 
Dose-reduce carboplatin with one additional level reduction (-2 
AUC from baseline) at the next cycle for all subsequent cycles.

Third episode: Stop carboplatin. 
Anemia
All grades
For all anemia events related to carboplatin regardless of grade, iron studies 
should be checked and iron should be replaced as indicated.

Red blood cell transfusions can be given at the investigators’ 
discretion as needed for symptom control.
Hepatic
Grade 0 or 1
No change. 
Grade 2
Grade 2 bilirubin:

Hold carboplatin until bilirubin resolves to ≤ grade 1. Resume 
carboplatin at their previous dose(s).

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Event
Carboplatin Dose Modification 
A rise in indirect bilirubin with a normal direct bilirubin believed to be 
attributable to Gilbert’s disease does not require change in dose or a drug hold. 
A note to file should be created.
Grade 2 AST or ALT: 

Hold carboplatin until AST/ALT resolve to ≤ grade 1.

If AST/ALT resolves to ≤ grade 1, resume carboplatin at previous 
dose
Grade 3
Grade ≥ 3 bilirubin (not due to Gilbert’s disease): 

Stop carboplatin. 
Grade 3 AST or ALT: 

Hold carboplatin until AST/ALT resolve to ≤ grade 1.

Resume carboplatin at one dose level reduction (–1 AUC) at the next 
combined cycle for all subsequent cycles.
Grade 4
Grade 4 AST or ALT: 

Stop carboplatin. 
Nausea/Vomiting/Anorexia
Grade 0–2
No change to carboplatin.

Nausea and/or vomiting should be controlled with adequate anti-
emetic therapy. Prophylactic anti-emetic therapy (e.g., aprepitant, 
ondansetron, palonosetron, etc.) should be administered to all 
patients; specific agents are at the discretion of the treating 
physician. 

Patients are encouraged to take plenty of oral fluids. 
If symptoms persist despite maximal anti-emetic therapy:

No change carboplatin.
≥ Grade 3

Hold carboplatin until resolved to ≤ grade 1.

Resume carboplatin at previous dose with modification of 
premedications. 
For persistent toxicity ≥ grade 3 despite maximal supportive care, 

Dose reduce carboplatin by one dose level (–1 AUC) at the next 
chemotherapy cycle for all subsequent cycles.
Mucositis/Stomatitis
Grade 0–2
No change.
≥ Grade 3
Hold carboplatin until symptoms have resolved to ≤ grade 1.

Resume carboplatin at the previous dose with modification of 
premedications. 

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Event
Carboplatin Dose Modification 
For persistent toxicity ≥ grade 3 despite maximal supportive care:

Dose reduce carboplatin by one dose level for all subsequent doses. 
Neurotoxicity
Grade 0–2
No change. 
Grade 3
Hold carboplatin until neuropathy improves to ≤ grade 2. Resume carboplatin 
based on the number of episodes:

First episode: No change to carboplatin.

Second episode: No change to carboplatin.

Third episode: Stop carboplatin. 
Grade 4
Stop carboplatin. 
Anaphylaxis/Hypersensitivity
Mild (e.g., mild flushing, rash, 
pruritis)
Mild symptoms (grade 1: e.g., transient flushing, rash or fever):

Complete carboplatin infusion.

No treatment required, but observe patient at least until symptoms 
have resolved. 
Moderate (e.g., moderate 
flushing, rash, mild dyspnea, 
chest discomfort)
Moderate symptoms (grade 2: e.g., rash, flushing, urticaria, dyspnea, chest 
discomfort): 

Hold carboplatin infusion. 

Give intravenous diphenhydramine 25-50 mg and intravenous 
dexamethasone 10 mg. 

Resume carboplatin infusion after recovery of symptoms at half the 
previous rate for 15 minutes. If no recurrence of symptoms, the 
planned rate may be resumed. 

If symptoms recur after re-challenge, stop carboplatin infusion. 
Patient should proceed with additional chemotherapy at the 
discretion of the treating physician. 
Any moderate hypersensitivity reaction should be discussed with the protocol 
chair if drug is to be continued. 
Severe (e.g., hypotension 
requiring pressers, 
angioedema, respiratory 
distress requiring 
bronchodilators)
Severe or life-threatening symptoms (grade 3 or 4: e.g., hypotension, 
angioedema, respiratory distress or anaphylaxis): 

Stop carboplatin infusion. 

Administer diphenhydramine 25-50 mg and dexamethasone 10 mg 
IV. Add epinephrine or bronchodilators as needed per institutional 
guidelines.

Stop carboplatin. Patient should proceed with additional 
chemotherapy at the discretion of the treating physician. 

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Event
Carboplatin Dose Modification 
Other Clinically Significant Toxicity Excluding Fatigue, Alopecia, and Leukopenia at Physician 
Discretion
Grade 0 or 1
No change.
Grade 2
Hold carboplatin until resolved to ≤ grade 1.

Resume carboplatin with no change in dose.
 ≥ Grade 3
Stop carboplatin and contact the protocol chair for further instructions.
Abbreviations: ANC: absolute neutrophil count; IV: intravenous injection
Grades refer to CTCAE version 4
*All dose reductions will be based on blood counts obtained prior to planned cycle of 
chemotherapy per study protocol. Nadir counts will not be measured routinely. 
The following dose levels will be utilized for the purpose of dose modifications for toxicity:
Table 5. Dose Adjustments for Carboplatin (AUC)
Dose 
Adjustment
Carboplatin 
Dose
Carboplatin 
Dose
Starting dose
AUC = 5
AUC = 4
–1a
AUC = 4
AUC = 3
–2a
AUC = 3
AUC = 2
aDose to be given only if a dose reduction is required.
5.2.5
 Dose Interruptions 
Dose interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Study Chair. The reason for interruption should 
be documented in the patient's study record.
*If carboplatin is held due to toxicity for more than one week, pembrolizumab should be given 
on schedule.
*In general, missed carboplatin doses should be made-up.
*If carboplatin is held for 3 weeks, cycles will be numbered based on carboplatin and 
pembrolizumab separately. 

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5.2.6
Pembrolizumab Dose Administration
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. The +/- 3 day window is based on day 1 of the previous cycle. If carboplatin dosing is 
changed to two weeks on, one week off, there is a      -1/+2 day window for dosing on Day 8.
All trial treatments will be administered on an outpatient basis.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
Details on the preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual provided with the study drug by Merck.
5.2.7
Trial Blinding/Masking
This is an open-label trial; therefore, the Study Chair, investigator and subject will know the 
treatment administered.
5.3
Randomization or Treatment Allocation
84 breast cancer patients with chest wall disease that is hormone resistant or triple negative will 
be randomized 2:1 to treatment with pembrolizumab and carboplatin (n=56) vs. carboplatin 
alone (n=28). An additional 9 patients may be accrued (6 Arm A and 3 Arm B) for subject 
replacement to offset an approximate drop-out rate of 10%. 
5.4
Stratification
This study will not be stratified.
5.5
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the Merck Clinical team.  The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician. 
5.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 

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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.
Myeloid growth factors may be used at physician discretion to allow on time and safe 
administration of chemotherapy. 
Palliative radiation is permitted on study with PI approval. Carboplatin will be held during 
radiation therapy and must be restarted within 3 weeks (no greater than 3 weeks) post-radiation. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs.
5.5.2
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:

Investigational agents other than pembrolizumab

Chemotherapy other than carboplatin

Hormone therapy of any kind 

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.  

Live vaccines 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 
adverse event of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Study Chair.
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive 
other medications that the investigator deems to be medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.

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5.6
Rescue Medications & Supportive Care
5.6.1
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below. Where appropriate, oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents can be considered if 
symptoms do not improve with administration of corticosteroids.   Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
For each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related to 
pembrolizumab. It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event. 

Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.

Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA)
o
For Type 1 Diabetes Mellitus or Grade 3-4 Hyperglycemia

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
Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 

Hypophysitis (inflammation of pituitary gland):
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 

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
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 6 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475).
Table 6 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 p.o. (or equivalent 
dose of antihistamine).
Acetaminophen 500-
1000 mg p.o. (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:
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 
No subsequent dosing

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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Life-threatening; pressor or 
ventilatory support indicated
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued 
from further trial treatment 
administration.
5.7
Diet/Activity/Other Considerations
5.7.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting.
5.7.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
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; 

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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 
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)  
• male condom or female condom (cannot be used together)
†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 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.
5.7.3
Use in Pregnancy
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 Hoosier Cancer Research Network (HCRN) within 
1 business day. HCRN will report this information within 1 business day to the Study Chair and 
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).  

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The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Study Chair.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Study Chair and to Merck and followed as described above and in 
Section 7.2.2.
5.7.4
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment.
5.8
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Study Chair if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  
A subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

Confirmed disease progression 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, using irRECIST. 

Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Sections 7.1.4.3-7.1.4.5. After the end of treatment, each subject will be followed for 
30 days for adverse event monitoring (serious adverse events will be collected for 90 days after 
the end of treatment as described in Section 7.2.3.1).  Subjects who discontinue for reasons other 

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Phase II – Pembrolizumab
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than progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to 
follow-up.  
5.9
Subject Replacement Strategy
Up to 9 subjects (6 in the pembrolizumab/carboplatin arm and 3 in the carboplatin alone arm) 
may be replaced if patients drop out of the study for reasons other than disease progression or 
toxicity, to ensure an adequate sample size to determine the primary endpoint. This replacement 
strategy accounts for an approximately 10% drop out rate.
5.10 Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be provided so that 
appropriate adjustments to subject treatment can be made.

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Phase II – Pembrolizumab
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6.0 TRIAL FLOW CHART
6.1
Screening and Treatment Periods: 
6.1.1
Arm A: Pembrolizumab plus Carboplatin, Arm Ax: Pembrolizumab Only
Study Period
Screening period
Treatment Period (3-week, 21-day cycles)
Treatment Cycle/Title
Screening
1i
2
3
4 and 
Beyondii
Post-completion 6 cycles Carboplatin 
(maintenance Pembrolizumab, Arm Ax)iii
Scheduled Day
-28 to 1 (pre-dose)
1
1
1
1
N/A
Scheduling Window (Days)iv
N/A
N/A
±3
±3
±3
N/A
Administrative Procedures
Informed consent
X
Informed consent for correlative studies
X
Inclusion/Exclusion criteria
X
Demographics and Medical History
X
Prior and Concomitant Medication Reviewv
X
X
X
X
X
X
Clinical Procedures/Assessments
Full physical examinationvi
X
X
X
X
X
X
Vital signs and weightvii
X
X
X
X
X
X
Carboplatin administrationviii
X
X
X
X
Pembrolizumab administrationix
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Adverse Events Monitoring
X
X
X
X
X
X
Child-bearing potentialx
X
ECHO/MUGAxi
X
X
Laboratory Procedures/Assessments: Analysis performed by local laboratories
CBC with Differentialxii
X
X
X
X
X
X
Chemistryxiii
X
X
X
X
X
X
Urinalysisxiv
X
PT/INR and aPTTxv
X
X
TSHxvi
X
X
X
X
Pregnancy Test Urine/Serum HCGxvii
X
Correlative Procedures/Assessments: Analysis performed by central laboratory
Blood, correlative samplesxviii
X
X

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Study Period
Screening period
Treatment Period (3-week, 21-day cycles)
Treatment Cycle/Title
Screening
1i
2
3
4 and 
Beyondii
Post-completion 6 cycles Carboplatin 
(maintenance Pembrolizumab, Arm Ax)iii
Scheduled Day
-28 to 1 (pre-dose)
1
1
1
1
N/A
Scheduling Window (Days)iv
N/A
N/A
±3
±3
±3
N/A
Tumor biopsy samplexix
X
X
Microbiome Sample Collectionxx
X
Tumor Imaging
CT Chest/Abdomen/Pelvisxxi
X
X
X
Bone Scanxxii
X
X
X
i Cycle 1, Day 1 may be on same day as randomization or at most 3 business days post randomization
ii Starting with Cycle 4, the pattern of study treatment administration and assessments and procedures performed in Cycles 1 through 3 will be repeated, unless 
stated otherwise, or unless treatment administration schedule is changed for toxicity. 
iii Upon completing 6 cycles of carboplatin, maintenance pembrolizumab may be given at 200 mg IV every 3 weeks if stable or responding disease (Arm Ax).
iv Windows for Day 1 of each cycle are based on Day 1 of the previous cycle. Day 8 windows are based on Day 1 of the same cycle.
v Record all medications taken within 30 days prior to randomization and all medications taken during treatment period of the study. 
vi Full physical examination includes photographs of chest wall disease with measurements within picture. Stick-on rulers should be utilized, and lesions should 
be named on rulers based on location. The same lesions should be tracked throughout the study. 
vii Vital sign measurements include temperature, pulse, blood pressure, respiratory rate, and weight (height at screening only).  
viii For Arm A, Carboplatin AUC 5 IV every 3 weeks in combination with pembrolizumab for at least 6 cycles followed by pembrolizumab maintenance 
treatment. For patients with prior thrombocytopenia or prior carboplatin exposure: Carboplatin AUC 4 IV every 3 weeks in combination with pembrolizumab for 
at least 6 cycles followed by pembrolizumab maintenance treatment. In the event of toxicities, at the discretion of the investigator, the carboplatin schedule may 
be changed to an alternate dosing schedule of two weeks on, 1 week off following the first cycle. If this alternate dosing schedule is used, CBCs and blood 
chemistries will be repeated on day 8 prior to carboplatin administration. The day 8 dose of carboplatin and the lab tests have a window of -1/+2 days.
ix Patients in Arm A will be treated with pembrolizumab 200 mg IV and carboplatin AUC 5 IV every 3 weeks for at least 6 cycles followed by maintenance 
pembrolizumab 200 mg IV every 3 weeks if stable or responding disease (Arm Ax). Patients with prior thrombocytopenia or prior carboplatin exposure will be 
treated with pembrolizumab 200 mg IV and carboplatin AUC 4 IV every 3 weeks for at least 6 cycles followed by maintenance pembrolizumab 200 mg IV every 
3 weeks if stable or responding disease (Arm Ax).
x See section 5.7.2 
xi For patients with HER2+ disease only: Cardiac function must be determined within 4 weeks of study entry to be > 50% using echocardiogram or MUGA. 
Frequency of ECHO/MUGA is determined by SOC guidelines. 
xii Screening laboratory tests must be performed within 10 business days prior to the first dose of study. Labs do not need to be repeated on C1D1 if done within 3 
days of first dose.
xiii Chemistry includes albumin, sodium, potassium, calcium, chloride, bicarbonate, BUN, creatinine, glucose, LDH, AST, ALT, alkaline phosphatase, total 
protein, total bilirubin, and direct bilirubin (if total bilirubin is elevated above the upper limit of normal).
xiv Screening laboratory tests must be performed within 10 business days prior to the first dose of study treatment. Labs do not need to be repeated on C1D1 if 
done within 3 days of first dose.
xv PT/INR and aPTT are required for screening (prior to the biopsy) and required prior to the cycle 3 biopsy or the biopsy at cross-over.  

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xvi TSH will be drawn every even cycle of pembrolizumab. If abnormal, TSH will be drawn every cycle.  
xvii As clinically indicated
xviii Blood samples for the correlative study will be collected at screening and at cycle 3 (or earlier, upon progression).  
xix Tumor biopsy samples for the correlative study will be collected at screening and at cycle 3 (or upon progression).
xx Study coordinator will assist patient in completing brief patient survey and provide home stool collection kit as detailed in Section 7.1.2.9  
xxi A diagnostic CT Chest/Abdomen/Pelvis with contrast to be completed at baseline and then every 6 weeks (+/-7 days) prior to the initiation of a new cycle, for 
6 cycles (i.e., weeks 6, 12, 18. After week 18, repeat imaging to be completed every 9 weeks (+/- 7 days). If treatment is held, imaging may be delayed per 
investigator discretion. 
xxii A bone scan is to be completed at baseline in all patients. If bone metastases are present on the baseline bone scan, patients will undergo bone scans as 
clinically indicated. Bone scans in patients with bone metastases may be obtained sooner for staging if a patient is symptomatic from their bone metastases. In 
patients without baseline bone metastases on bone scan, additional bone scans will not be obtained as part of surveillance unless clinically warranted.

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6.1.2
Arm B: Carboplatin ONLY
Study Period
Screening period
Treatment Period (3-week, 21-day cycles)
Treatment Cycle/Title
Screening
1i
2
3
4 and Beyondii
Upon progression, prior 
to Arm Bx cross-over
Scheduled Day
-28 to 1 (pre-dose)
1
1
1
1
Scheduling window (days)ii
N/A
N/A
±3
±3
±3
N/A
Administrative Procedures
Informed consent
X
Informed consent for correlative studies
X
Inclusion/Exclusion criteria
X
Demographics and Medical History
X
Prior and Concomitant Medication Reviewiv
X
X
X
X
X
X
Clinical Procedures/Assessments
Full physical examinationv
X
X
X
X
X
X
Vital signs and weightvi
X
X
X
X
X
X
Carboplatin administrationvii
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Adverse Events Monitoring
X
X
X
X
X
X
Child-bearing potential/Menopausal statusviii
X
ECHO/MUGAix
X
X
Laboratory Procedures/Assessments: Analysis performed by local laboratories
CBC with Differentialx
X
X
X
X
X
X
Chemistryxi
X
X
X
X
X
X
Urinalysisxii
X
X
PT/INR and aPTTxiii
X
X
X
TSHxiv
X
X
Pregnancy Test-Urine or Serum-HCGxv
X
X
Correlative Procedures/Assessments: Analysis performed by central laboratory
Blood correlative samplesxvi
X
X
X
Tumor biopsy samplexvii
X
X
X
Microbiome Sample Collectionxviii
X
Tumor Imaging
CT Chest/Abdomen/Pelvisxix
X
X
X
Bone Scanxx
X
X
X
i Cycle 1, Day 1, may be on same day as randomization or at most 3 business days post randomization
ii Starting with Cycle 4, the pattern of study treatment administration and assessments and procedures performed in Cycles 1 through 3 will be repeated, unless 
stated otherwise, or unless treatment administration schedule is changed for toxicity. 

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iii Windows for Day 1 of each cycle are based on Day 1 of the previous cycle. Day 8 windows are based on Day 1 of the same cycle. 
iv Record all medications taken within 30 days prior to randomization and all medications taken during treatment period of the study. 
v Full physical examination includes photographs of chest wall disease with measurements within picture. Stick-on rulers should be utilized, and lesions should 
be named on rulers based on location. The same lesions should be tracked throughout the study. 
vi Vital sign measurements include temperature, pulse, blood pressure, respiratory rate, and weight (height at screening only).  
vii For Arm B, Carboplatin AUC 5 IV every 3 weeks alone until progression. Carboplatin AUC 4 IV every 3 week alone for patients with prior thrombocytopenia 
or prior carboplatin exposure. Cross over to pembrolizumab 200 mg IV every 3 weeks with or without carboplatin (Arm Bx) is allowed following documented 
progression (see section 5.2). In the event of toxicities, at the discretion of the investigator, the carboplatin schedule may be changed to an alternate dosing 
schedule of two weeks on, 1 week off following the first cycle. If this alternate dosing schedule is used, CBCs and blood chemistries will be repeated on day 8 
prior to carboplatin administration. The day 8 dose of carboplatin and the lab tests have a window of -1/+2 days.
viii See section 5.7.2
ix For patients with HER2+ disease only: Cardiac function must be determined within 4 weeks of study entry to be > 50% using echocardiogram or MUGA. 
Frequency of ECHO/MUGA is determined by SOC guidelines. 
x Screening laboratory tests must be performed within 10 business days prior to the first dose of study treatment. Labs do not need to be repeated on C1D1 if 
done within 3 days of first dose.
Pregnancy tests as clinically indicated. TSH on Arm B will only be measured at baseline and prior to crossing over to pembrolizumab only (Arm Bx). 
xi Chemistry includes albumin, sodium, potassium, calcium, chloride, bicarbonate, BUN, creatinine, glucose, LDH, AST, ALT, alkaline phosphatase, total 
protein, total bilirubin, and direct bilirubin (if total bilirubin is elevated above the upper limit of normal)
xii Screening laboratory tests must be performed within 10 business days prior to the first dose of study treatment
xiii PT/INR and aPTT are required for screening (prior to the biopsy) and required prior to the cycle 3 biopsy or the biopsy at cross-over.  
xiv For patients on carboplatin only, TSH is only required at screening. Before crossing over to Arm Bx (pembrolizumab only), patients must have a new baseline 
TSH drawn. 
xv As clinically indicated
xvi Blood samples for the correlative study will be collected at screening and at cycle 3 (or upon progression, prior to Arm Bx cross-over). 
xvii Tumor biopsy samples for the correlative study will be collected at screening and at cycle 3 (or upon progression, prior to Arm Bx cross-over).
xviii Study coordinator will assist patient in completing brief patient survey and provide home stool collection kit as detailed in Section 7.1.2.9   
xix A diagnostic CT Chest/Abdomen/Pelvis with contrast is to be completed at baseline and then every 6 weeks (+/- 7 days) prior to the initiation of a new cycle, 
for 6 cycles (i.e., weeks 6, 12, 18). After week 18, repeat imaging to be completed every 9 weeks (+/- 7 days). If treatment is held, imaging can be delayed per 
investigator discretion. At Arm Bx cross-over, a new set of baseline scans must be obtained prior to pembrolizumab dosing.
xx A bone scan is to be completed at baseline in all patients. If bone metastases are present on the baseline bone scan, patients will undergo bone scans as 
clinically indicated. Bone scans in patients with bone metastases may be obtained sooner for staging if a patient is symptomatic from their bone metastases. In 
patients without baseline bone metastases on bone scan, additional bone scans will not be obtained as part of surveillance unless clinically warranted, and no 
bone scan is needed for these patients at Arm Bx cross-over. 

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6.1.3
Arm Bx: Pembrolizumab (+/- Carboplatin)
Study Period
Pre-crossoveri
Treatment Period (3-week, 21-day cycles)
Treatment Cycle/Title
1
2
3
4 and Beyondiii
Scheduled Day
1
1
1
1
Scheduling Window (Days)iv
N/A
N/A
±3
±3
±3
Administrative Procedures
Informed consent
Informed consent for correlative studies
Inclusion/Exclusion criteria
Demographics and Medical History
Prior and Concomitant Medication Reviewv
X
X
X
X
Clinical Procedures/Assessments
Full physical examinationvi
X
X
X
X
Vital signs and weightvii
X
X
X
X
Pembrolizumab administrationviii
X
X
X
X
Carboplatin administrationix
(X)
(X)
(X)
(X)
ECOG Performance Status
X
X
X
X
Adverse Events Monitoring
X
X
X
X
Child-bearing potential/Menopausal statusx
ECHO/MUGAxi
X
X
Laboratory Procedures/Assessments: Analysis performed by local laboratories
CBC with Differentialxii
X
X
X
X
Chemistryxiii
X
X
X
X
Urinalysisxiv
PT/INR and aPTTxv
X
TSHxvi
X
X
X
Pregnancy Test-Urine or Serum-HCGxvii
X
Correlative Procedures/Assessments: Analysis performed by central laboratory
Blood for correlative lab samplesxviii
X
Tumor biopsy samplexix
X
Microbiome Sample Collectionxx
X
Tumor Imaging
CT Chest/Abdomen/Pelvisxxi
X
X
X
Bone Scanxxii
X
X
X

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Phase II – Pembrolizumab
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i Arm Bx: Pembrolizumab only dosing must begin within 6 weeks of determined progression. All pre-crossover labs must be done within 10 business days of 
C1D1 of pembrolizumab. Tumor imaging must be done within 4 weeks of first dose of pembrolizumab (C1D1).
ii Cycle 1, Day 1, may be on same day as randomization or at most 3 business days post randomization.
iii Starting with Cycle 4, the pattern of study treatment administration and assessments and procedures performed in Cycles 1 through 3 will be repeated, unless 
stated otherwise. 
iv Windows for Day 1 of each cycle are based on Day 1 of the previous cycle. 
v Record all medications taken within taken during treatment period of the study. 
vi Full physical examination includes photographs of chest wall disease with measurements within picture. Stick-on rulers should be utilized, and lesions should 
be named on rulers based on location. The same lesions should be tracked throughout the study. 
vii Vital sign measurements include temperature, pulse, blood pressure, respiratory rate, and weight (height at screening only).  
viii For Arm Bx, pembrolizumab 200 mg IV every 3 weeks with or without carboplatin is allowed following documented progression (see section 5.2).
ix All carboplatin dosing and dose modification guidelines apply.
 See section 5.7.2
xi Frequency of ECHO/MUGA is determined by SOC guidelines. 
xii Screening laboratory tests must be performed within 10 business days prior to the first dose of study treatment. Labs do not need to be repeated on C1D1 if 
done within 3 days of first dose.
xiii Chemistry includes albumin, sodium, potassium, calcium, chloride, bicarbonate, BUN, creatinine, glucose, LDH, AST, ALT, alkaline phosphatase, total 
protein, total bilirubin, and direct bilirubin (if total bilirubin is elevated above the upper limit of normal)
xiv Urinalysis only to be repeated pre-crossover if clinically indicated.
xv PT/INR and aPTT are required prior to Arm Bx cross-over if progression occurs prior to cycle 3. 
xvi Prior to Arm Bx cross-over, patients must have a new baseline TSH drawn. TSH will be drawn at every even pembrolizumab cycle, or at every cycle if 
abnormal. 
xviiAs clinically indicated.
xviii Blood samples for the correlative study will be collected prior to Arm Bx cross-over, if progression occurs prior to cycle 3 of Arm B.
xix Tumor biopsy samples for the correlative study will be collected prior to Arm Bx cross-over, if progression occurs prior to cycle 3 of Arm B.
xx Study coordinator will assist patient in completing brief patient survey and provide home stool collection kit as detailed in Section 7.1.2.9   
xxi A diagnostic CT Chest/Abdomen/Pelvis with contrast is to be completed at baseline (within 4 weeks of C1D1 of pembrolizumab) and then every 6 weeks (+/- 
7 days) prior to the initiation of a new cycle, for 6 cycles (i.e., weeks 6, 12, 18). After week 18, repeat imaging to be completed every 9 weeks (+/- 7 days). If 
treatment is held, imaging can be delayed per investigator discretion.
xxii A bone scan is to be completed at baseline in all patients. If bone metastases are present on the baseline bone scan, patients will undergo bone scans as 
clinically indicated. Bone scans in patients with bone metastases may be obtained sooner for staging if a patient is symptomatic from their bone metastases. In 
patients without baseline bone metastases on bone scan, additional bone scans will not be obtained as part of surveillance unless clinically warranted, and no 
bone scan is needed for these patients prior to crossing over to Arm Bx.

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6.2
End of Treatment
End of Treatment
Treatment Cycle/Title
At time of Treatment Discontinuation
Safety Follow-up
Scheduled Day
N/A
30 days post last dosei
Scheduling Window (Days)
N/A
±3
Administrative Procedures
Prior and Concomitant Medication 
Reviewii
X
X
Subsequent anti-cancer therapy
X
Survival status
X
X
Review Adverse Eventsiii
X
X
i 30 days post last dose of study treatment or prior to initiation of new anti-cancer regimen (must be prior to new regimen, no scheduling window).
ii Record all medications taken at time of and after treatment discontinuation.
iii Record all AEs occurring within 30 days post treatment end. Report all SAEs occurring up to 90 days post treatment end or until subject initiates new anti-cancer therapy.

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Clinical Procedures
Full physical examinationiv
X
X
Vital signs and weightv
X
X
ECOG Performance Status
X
X
ECHO/MUGAvi
Laboratory Procedures/Assessments: Analysis performed by local laboratories
CBC with Differential
X
X
Chemistryvii
X
X
TSHviii
X
Tumor Imaging
CT Chest/Abdomen/Pelvisix
X
Bone Scanx
X
iv Full physical examination includes photographs of chest wall disease with measurements within picture. Stick-on rulers should be utilized, and lesions should be named on rulers 
based on location. The same lesions should be tracked throughout the study.
v Vital sign measurements include temperature, pulse, blood pressure, respiratory rate, and weight (height at screening only).
vi For patients with HER2+ disease only: Cardiac function must be determined within 4 weeks of study entry to be > 50% using echocardiogram or MUGA. Frequency of 
ECHO/MUGA is determined by SOC guidelines.
vii Chemistry includes albumin, sodium, potassium, calcium, chloride, bicarbonate, BUN, creatinine, glucose, LDH, AST, ALT, alkaline phosphatase, total protein, total bilirubin, 
and direct bilirubin (if total bilirubin is elevated above the upper limit of normal)
viii For patients most recently on pembrolizumab only.
ix Study discontinuation scans must be completed. If progression is noted in chest wall, scans must be completed to document systemic treatment response. If patients progress on 
imaging prior to their EOT visit, scans do not need to be repeated.
x Bone scan to be completed as clinically indicated.

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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the Study Chair and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
7.1.1
Administrative Procedures
7.1.1.1
Informed Consent
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Study Chair requirements.

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7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial. 
7.1.1.3
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.  
7.1.1.4
Prior and Concomitant Medications Review
7.1.1.4.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting the trial.  Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication. 
7.1.1.4.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial.  All medications related to reportable SAEs should be recorded as defined in Section 
7.2.
7.1.1.5
Disease Details and Treatments
7.1.1.5.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
7.1.1.5.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries.
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first 
dose of the new therapy. 

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7.1.1.6
Assignment of Screening Number
Patients will be screened by the medical oncologists in the oncology practice clinics at 
participating sites. Patients to be screened will include those currently followed in these 
practices, as well as those referred from outside providers. 
For each potential patient who signs informed consent to this study, demographic and consent 
process information will be entered into the Hoosier Cancer Research Network (HCRN) 
electronic data capture (EDC) system. Subjects will be automatically assigned a screening 
number (see study procedure manual (SPM) for details). The patient must have signed and dated 
the currently approved consent form before any study-related screening procedures are 
performed. 
7.1.1.7
Registration and Assignment of Randomization Number
The UCSF Coordinating Center for this study will be working with Hoosier Cancer Research 
Network (HCRN). As above, all patients who are consented will be entered into the electronic 
database capture system (EDC), which is password protected and meets HIPAA guidelines. All 
data will be collected and entered into the EDC system by Clinical Research Coordinators 
(CRCs) from UCSF and other participating centers.  
Registration and randomization of eligible patients may occur only after the pretreatment 
evaluation is complete and all eligibility criteria have been met. 
Prior to registration and randomization, the Study Chair at UCSF (or her designee) must review 
and approve each patient.  When a participating site determines that a patient meets eligibility 
criteria; the study site will send a completed eligibility checklist and de-identified supporting 
source documentation to the UCSF study team (see study procedures manual for details) for 
review; UCSF will check the forms for completeness and contact the site regarding any 
discrepancies. The approval of the Study Chair will be communicated back to the participating 
site prior to registration/randomization; documentation of this approval will be provided to 
HCRN at the time of registration/randomization.  
Eligible and approved patients for enrollment may then be registered through the Hoosier Cancer 
Research Network (HCRN) electronic data capture (EDC) system. Successful registration is 
when an “On Study” date is entered into the EDC system. HCRN’s EDC system will 
automatically assign a study-specific sequence number. All future study documentation related to 
the patient should include the assigned sequence number. Randomization will occur at the 
Hoosier Cancer Research Network after registration is complete. Subjects will be randomized 
2:1 to receive treatment with pembrolizumab and carboplatin (n=56, Arm A) or carboplatin alone 
(n=28, Arm B) until documented disease progression.
Any required local patient registration or tracking should occur per each participating site’s local 
requirements.  

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7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Patients will be assessed at each study visit for compliance to trial procedures including 
medications, diet, and activity. Activity and diet are as tolerated.
Subjects will be asked to provide a complete list of prescription and over-the-counter 
medications that have been taken within the previous 4 weeks prior to their screening visit. The 
investigator must be informed as soon as possible about any new medication taken from the time 
of screening until the end of the clinical phase of the study.  
7.1.2
Clinical Procedures/Assessments
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0 (see Section 13b).  Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. Grade 1 laboratory abnormalities and white blood cell differential abnormalities 
excluding neutrophils (i.e., lymphocytes, monocytes, basophils, etc.) do not need to be recorded 
as AEs. 
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is an event of a potentially 
immunologic etiology. 
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
7.1.2.2
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period including photographs of chest wall disease.  Clinically significant abnormal 
findings should be recorded as medical history.  A full physical exam should be performed 
during screening. 
7.1.2.3
Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.  
7.1.2.4
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in the 

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Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory rate, 
weight and blood pressure.  Height will be measured at screening only.
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 13a) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart.  
7.1.2.6
Tumor Imaging and Assessment of Disease
Patients will undergo tumor imaging and disease assessment with a diagnostic CT chest, 
abdomen, and pelvis with contrast at baseline, and every 6 weeks (+/- 7 days) prior to the 
initiation of a new cycle, for 6 cycles (i.e., weeks 6, 12, and 18- prior to cycles 3, 5, and 7). After 
week 18, patients will be scanned every 9 weeks (+/- 7 days) moving forward. Per the NCCN 
guidelines 3.2015 (section “Principles of monitoring metastatic disease”), imaging in patients 
with metastatic disease receiving chemotherapy (such as those enrolled in this study) may occur 
as frequently as every 2-4 cycles of treatment, so this is the standard of care. A PET/CT can be 
used if the CT is diagnostic. 
A bone scan will be completed at baseline in all patients. If bone metastases are present on the 
baseline bone scan, patients will undergo bone scans as clinically indicated.  Bone scans in 
patients with bone metastases may be obtained sooner for staging if a patient is symptomatic 
from their bone metastases. In patients without baseline bone metastases on bone scan, additional 
bone scans will not be obtained as part of surveillance unless clinically warranted. 
Study discontinuation scans must be completed to document systemic treatment response. 
If cycles are delayed, tumor assessments may be delayed per investigator discretion. 
Patients will undergo photography of their chest wall disease every 3 weeks (or more frequently, 
depending on clinic visits) prior to scheduled treatment. 
Arm B: Before crossing over to pembrolizumab only (Arm Bx), all patients will complete a 
diagnostic CT of chest, abdomen, and pelvis with contrast, and bone scan (if clinically indicated) 
to establish a new baseline and verify disease progression. 
7.1.2.7
Assessments for Arm B patients prior to crossing over to pembrolizumab 
only (Arm Bx)
Cross-over to pembrolizumab only (maintenance pembrolizumab, Arm Bx) is allowed for Arm B 
patients with documented disease progression. On Arm Bx, carboplatin may be continued or 
added back into the treatment regimen at the investigator’s discretion. Disease progression can 
be clinically verified with photos and measurements of chest wall disease, or increase in 
symptoms associated with evidence of progression on imaging, but does not need to meet 
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Tumor imaging must be completed prior to pembrolizumab dosing. All patients will complete a 
diagnostic CT of chest, abdomen, and pelvis with contrast, as well as a bone scan (if clinically 
indicated).
All patients will have a new baseline TSH drawn. Thereafter, TSH will be drawn every even 
cycle of pembrolizumab dosing. If abnormal, TSH will be drawn every cycle.
If progression occurs before cycle 3 (on Arm B), a biopsy and correlative blood samples should 
be obtained at end of study treatment (on Arm B) or at cross-over. 
At cross-over, the first dose of pembrolizumab will be considered Cycle 1 Day 1 of 
pembrolizumab. Prior to pembrolizumab dosing, all AEs must be recovered to Grade 1, except 
peripheral neuropathy and alopecia. Cycle 1 Day 1 of pembrolizumab dosing must occur within 
6 weeks of progression on carboplatin. 
7.1.2.8
Tumor Tissue Collection and Correlative Studies Blood Sampling
 1. Tumor Tissue-Fresh tumor tissue will be collected for correlative studies. All patients will 
undergo tumor biopsies (4 excisional biopsies of chest wall tumor lesion or 4 core biopsies) at 
baseline and at cycle 3 day 1 of treatment (or sooner, should progression occur). Tumor tissue 
from chest wall disease preferred. Correlative studies will be performed on tumor tissue in a 
companion trial.
Participants will be given information as part of the informed consent process that samples will 
be used for research tests that will include genetic studies and testing.  The intent is not to give 
participants (or his/her medical providers) the results of any testing done for research purposes; 
however, incidental germline (heritable) mutations may be identified of which a participant may 
or may not already be aware.  In the case that an incidental genetic finding is identified, the 
Protocol Chair of this project will be notified.  The possible decisions for handling incidental 
findings may include notification of the participant (and provider); recommendation for genetic 
counseling, which may or may not include genetic testing (e.g., if the finding was not done in a 
CLIA certified laboratory); or, neither.  In general, a member of the participant’s treating team 
will be given the information to help with notification.  In all cases, the current policy of the 
Johns Hopkins and local/participating site IRB, as applicable, will be followed and any 
additional approvals that may be required prior to participant notification will be secured in 
advance.
Any leftover study tissue or blood samples may be stored for future research studies. The 
subjects will consent to the future use of samples in the consent form for the study. The study PI 
and collaborators have approval by the TBCRC, which has custodial oversight of all
biospecimens collected as part of a TBCRC trial, to address the research questions described in 
the protocol document. All future use as part of residual or repository specimens collected in this 
trial for purposes not prospectively defined will require review and approval by the TBCRC 
according to its established policies, whether the specimens are stored in a central site or at a 
local institution or in a virtual repository.

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7.1.2.9
Stool Collection for Microbiome Studies
1. Patient Survey, Specimen Collection and Handling
Prior to initiation of protocol treatment, the study coordinator will complete with the patient a 
brief patient survey (Appendix 4) that addresses antibiotic use and diet and provide the patient 
with a stool collection kit and mailer and instructions for use (Appendix 5).  The Mawi kit 
iSWAB-Microbiome will be used to collect stool in one tube and may remain at room 
temperature for up to 40 days. Study patients will mail the sample directly to CosmosID 
 
 after collection. Study coordinators will return the completed patient 
survey after dispensing the stool collection kit to the Mayo Clinic Surgical Research Office via 
mail or email to:
Department of Surgery Research Office
 
Or 
Study Coordinator: 
 
 
Study Coordinator Supervisor:
 
2. Specimen Banking, Data Collection and Laboratory Analyses
Patient survey information linked to TBCRC patient study ID and demographic data will be 
maintained in a secure password-protected database in the Mayo Clinic Surgery Research Office. 
A study coordinator will be responsible for data collection including demographic and patient 
survey information, linking data with TBCRC trial identifiers and central coordination among 
sites and studies. 
Samples mailed directly to CosmosID will be stored at -70 and DNA extraction and V3-V4 16S 
sequencing will be performed on batched aggregated samples.  Raw samples and extracted 
samples will be maintained under appropriate conditions at CosmosID.  Raw sequencing output 
will be provided to investigators to link with clinical metadata and to perform analyses using 
various microbiome analysis pipelines.
Secondary use of bio-specimens for new endpoints must be submitted to the TBCRC Central 
Office for possible review by the TBCRC Correlative Science Review Committee.
7.1.3
Laboratory Procedures/Assessments
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.  

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Table 7  Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin†
Hemoglobin
Alkaline phosphatase
Glucose
  (β-hCG)†
Platelet count
Alanine aminotransferase (ALT)
Protein
PT 
WBC (total and differential)
Aspartate aminotransferase (AST)
Specific gravity 
aPTT 
Red Blood Cell Count
Lactate dehydrogenase (LDH)
Microscopic exam (If abnormal) 
Absolute Neutrophil Count
Carbon Dioxide ‡
results are noted
Absolute Lymphocyte Count
  (CO2 or bicarbonate)
Urine pregnancy test †
Thyroid stimulating hormone (TSH)
Creatinine
Calcium
Chloride
Glucose
 
 
Potassium  
 
Sodium
 
 
Total Bilirubin
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper limit of 
normal)
Total protein
Blood Urea Nitrogen
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required.  
‡ If considered standard of care in your region.

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Laboratory tests for screening should be performed within 10 business days prior to the first dose 
of treatment.  Pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing.  
Results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each dose of trial treatment. Grade 1 laboratory abnormalities and white blood cell 
differential abnormalities excluding neutrophils (i.e., lymphocytes, monocytes, basophils, etc.) 
do not need to be recorded as AEs.
7.1.3.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  After discontinuing treatment following assessment of CR, these subjects 
should return to the site for a Safety Follow-up Visit (described in Section 7.1.4.4) and then 
proceed to the Follow-Up Period of the study (described in Section 7.1.4.5).
7.1.3.2
Blinding/Unblinding
This study will not include blinding. 
7.1.4
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.4.1
Screening
Potentially eligible patients will sign a screening consent in order to be screened for the study.
7.1.4.1.1 Screening Period
Eligible patients will have the following procedures performed within 3 weeks prior to study 
drug dosing: 
1. Informed consent
2. Medical history and demographics
3. Record all medication(s) received within 30 days prior to the first dose of study treatment and 
note if the medication is ongoing.
4. Physical examination including photographs of chest wall disease. 
5. Vital signs including height and body weight.
6. ECOG Performance Status
7. Laboratory assessments including
a. Pregnancy test: urine hcg (serum hcg to be performed if urine hcg uninterpretable)
b. Complete blood count including hematocrit, hemoglobin, platelet count, white blood cell 
count and differential

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c. Comprehensive serum chemistry panel: albumin, sodium, potassium, calcium, chloride, 
bicarbonate, BUN, creatinine, glucose, LDH, AST, ALT, total bilirubin, total protein, direct 
bilirubin (if total bilirubin is elevated above the upper limit of normal), and alkaline phosphatase.
d. PT/aPTT
e. Thyroid function test: TSH
f. Urinalysis
8. Disease assessment: diagnostic CT chest, abdomen, pelvis with contrast and bone scan (all 
patients are required to have a bone scan at screening)
9. Tumor biopsy: Fresh tissue –see correlative lab manual requirements
10. Microbiome sample collection
7.1.4.2
Treatment Period
Every 3 weeks during treatment period
1. Prior and concomitant medication review
2. Adverse Event Assessment
3. Physical Examination including photographs of chest wall disease.
4. Vital signs 
5. ECOG Performance Status
6. Laboratory assessments including
a. Complete blood count including hematocrit, hemoglobin, platelet count, white blood cell count 
and differential
b. Comprehensive serum chemistry panel: albumin, sodium, potassium, calcium, chloride, 
bicarbonate, BUN, creatinine, glucose, LDH, AST, ALT, total bilirubin, total protein, direct 
bilirubin (if total bilirubin is elevated above the upper limit of normal), and alkaline phosphatase.
Every even cycle of pembrolizumab (2, 4, 6, etc.) 
Thyroid function test: TSH
Every 6 weeks until week 18 (weeks 6, 12, 18) and every 9 weeks thereafter
(At time of crossover, new baseline scans should be obtained. Scans should then be 
obtained at 6 week intervals following C1D1 of pembrolizumab.)
CT Chest/Abdomen/Pelvis 
Cycle 3, Day 1
Repeat tumor biopsy 
As Clinically Indicated
Bone scan 

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7.1.4.3
Post-Treatment Visits
1. Review adverse events
2. Physical Examination including photographs of chest wall disease
3. Vitals signs
4. ECOG Performance Status
5. Laboratory assessments (30 days post last treatment dose) including:
a. Complete blood count including hematocrit, hemoglobin, platelet count, white blood cell count 
and differential
b. Comprehensive serum chemistry panel: albumin, sodium, potassium, calcium, chloride, 
bicarbonate, BUN, creatinine, glucose, LDH, AST, ALT, total bilirubin, total protein, direct 
bilirubin (if total bilirubin is elevated above the upper limit of normal), and alkaline phosphatase.
6. Record all concomitant medications(s) added and/or changed. 
Patients will be followed for four weeks after removal from study or until death, whichever 
occurs first. Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.
7.1.4.4
Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with 
an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 90 
days of the end of treatment or before initiation of a new anti-cancer treatment should also be 
followed and recorded. 
7.1.4.5
Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should return for the 30 day safety follow-up as outlined above.   
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-

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specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’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, the 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 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation baseline period as 
a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator.
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. Grade 1 laboratory abnormalities and white blood cell differential 
abnormalities excluding neutrophils (i.e., lymphocytes, monocytes, basophils, etc.) do not need 
to be recorded as AEs.
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the Study 
Chair and 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.
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.

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If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported using the 
terminology “accidental or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 1 business 
day to HCRN who will then report this information within 1 business day to the Study Chair and 
Merck Global Safety. 
7.2.2
Reporting of Pregnancy and Lactation to the Study Chair 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), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 1 business day to HCRN who will then report this 
information within 1 business day to the Study Chair and Merck Global Safety. 
 
7.2.3
Immediate Reporting of Adverse Events to the Study Chair and to Merck
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is a new cancer (that is not a condition of the study);

Is associated with an overdose;

Is another important medical event 
Refer to Table 8 for additional details regarding each of the above criteria.
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time of 
start of study treatment through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 

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reported within 1 business day to HCRN 
 who will then report this 
information within 1 business day to the Study Chair and 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 to the attention of the investigator at any 
time outside of the time period specified in the previous paragraph also must be reported 
immediately to HCRN who will then report this information to the Study Chair and Merck 
 
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. 
 
at the time of submission to FDA. UCSF will 
coordinate all submissions to the FDA.
All subjects with serious adverse events must be followed up for outcome.
7.2.4
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.

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Table 8  Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not 
indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it 
occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); 
or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not worsened does 
not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious 
adverse event. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest 
and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization 
may be considered a serious adverse event when, based upon appropriate medical judgment, the event may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).

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Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and 
units
Action 
taken 
Did the adverse event cause the Merck product to be discontinued?
Relationship 
to test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused 
the adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing 
the likelihood of a relationship between the test drug and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between the Merck product and the AE; 
the greater the correlation with the components and their respective elements (in number and/or intensity), the more 
likely the Merck product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen?
Time 
Course
Did the AE follow in a reasonable temporal sequence from administration of the Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)?
Likely 
Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: 
(continued)
to Merck 
product
(continued) 
Dechallenge
Was the Merck product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the 
AE resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose 
drug trial); or (4) Merck product(s) is/are only used one time.)

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

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7.2.5
Study Chair Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
7.2.6
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 1 business day to HCRN 
. HCRN 
will then report this information within 1 business day to the Study Chair and Merck Global 
Safety. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI or follow up to an ECI must be reported within 1 business day 
to HCRN 
. HCRN will then report this information within 1 
business day to the Study Chair and 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 1 business day to HCRN. HCRN will then report this 
information within 1 business day to the Study Chair and 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 Study Chair and to Merck, that is not associated 
with clinical symptoms or abnormal laboratory results. 
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit 
of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. 
8.0 STATISTICAL ANALYSIS PLAN
8.1
Statistical Analysis Plan Summary 
The primary endpoint in this study is to determine the arm specific disease control rate 
(CR/PR/SD) at 18 weeks of therapy with pembrolizumab and carboplatin vs. carboplatin alone. 

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Patients will be randomized 2:1 to treatment with pembrolizumab and carboplatin vs. carboplatin 
alone.
Table 9 Statistical Analysis Summary
Carboplatin 
Carboplatin & 
Pembrolizumab 
Inter Group 
Differences
Cycle-6 disease 
control rate
0.10 
0.30 
Difference
0.20 
Median number of 
cycles with disease 
control
1.81 
3.45 
Difference
1.65 
Hazards
0.384 
0.201 
Hazards Ratio
 0.52 
Events needed
-- 
-- 
59 
Patients needed 
per arm
28
56
Total
84 
For n=28 
Carboplatin arm 
and n=56 
Pembrolizumab/
Carboplatin:  
Within-arm rate 
(95% CI) 
10.0%
(2.99%-20.80%)
30.0%
(20.39-40.11%)
We will accrue a total of 84 patients (56 in Arm A and 28 in Arm B) for efficacy assessments. 
Up to 9 subjects (6 in Arm A and 3 in Arm B) may be replaced (accounts for an approximately 
10% drop out rate) if patients drop out of the study for reasons other than disease progression or 
toxicity, to ensure an adequate sample size to determine the primary endpoint.
With this sample size, a 20% difference in disease control rate between arms with a hazard ratio 
difference of 0.52 can be detected. This calculation assumed a 2:1 allocation to the study arms as 
described above, and was determined using a 2-sided log rank test with  = 0.10 and  = 0.20 
(power = 80%). The within arm 18 week disease control rate estimates use  = 0.10, and are 
based on the Kaplan-Meier method, accounting for timing of assessments of new disease.
The rate of disease control with carboplatin alone was estimated as 10%, based on prior data 
with platinum agents in pre-treated metastatic breast cancer (65). The estimated rate of disease 

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control in the pembrolizumab/carboplatin arm was estimated at 30% based on 2 recent phase I 
studies with anti-PD-1/PD-L1 antibodies in breast cancer showing clinical benefit rates between 
27-44% in breast cancer (31, 46, 47). The response rate of patients with chest wall disease has 
been reported to be between 25-52% in prior studies (33). Based on this data, we selected use a 
cutoff of 30% for disease control in the pembrolizumab/carboplatin arm, so as not to exclude the 
potential efficacy of a novel agent in an aggressive, rapidly progressing disease. 18 weeks was 
selected as the time frame to determine the primary endpoint based on a recent phase I trial with 
pembrolizumab in breast cancer showing that the median time to response was 18 weeks (31), 
and also because prior studies have shown that the period of control of chest wall disease is 
relatively short (<3-4 months) (82).
Patients with early progressive disease in the control arm (carboplatin alone) before 18 weeks are 
unlikely to have disease control at 18 weeks, so this should not create much bias favoring the 
pembrolizumab/carboplatin arm. 
8.2
Statistical Analysis Plan
8.2.1.1
Primary Efficacy Analysis
The primary variable for assessment of the treatment is the disease control rate (CR/PR/SD) by 
RECIST 1.1 at week 18. A disease control rate of <10% would be considered undesirable at 
week 18 and >30% would be considered clinically meaningful. The study hypothesis is defined 
as: H0: π1  ≤ π0 (The disease control rate of the pembrolizumab/carboplatin arm is assumed to 
be smaller than the disease control rate of the carboplatin alone arm versus H1: π1 > π0 (The 
disease control rate of the pembrolizumab/carboplatin arm is assumed to be greater than the 
disease control rate of the carboplatin alone arm). Efficacy outcomes (rate of disease control, and 
progression free survival) will be evaluated at the end of each treatment cycle. The primary 
endpoint will be determined at 18 weeks of treatment. The 2 sided logrank test with   = 0.10 
and  = 0.20 (power = 80%) will be used to determine the statistical significance of arm specific 
efficacy. Supportive analyses will be done using estimates of progression free survival at week 
18 between treatment arms by the Kaplan-Meier method in order to account for any censoring 
patients.
8.2.1.2
Futility analysis for carboplatin arm
An interim analysis for futility will be performed after enrolling 18 patients in the carboplatin 
arm. Disease control is defined as evaluable patients who are observed with CR, PR and SD 
during the assessment period. Patients, who drop out, terminate the study early or crossover due 
to progression will be considered as non-responders. Because the efficacy endpoint is disease 
control, patients who are crossed-over in the study will be separately reported and also 
considered as non-responders or progressive-disease in the efficacy analyses (including 
progression free survival, in 8.2.2). If ≤ 2 patients are observed with disease control at week 18, 
then the null hypothesis may not be rejected, indicating that no further enrollment of carboplatin 
arm is warranted. If the disease control rate of carboplatin alone arm is indeed < 10%, the 
probability of terminating the carboplatin/control arm is 73.4%. 

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8.2.1.3
Safety/toxicity analysis for pembrolizumab/carboplatin arm
An interim analysis for safety and toxicity will be performed in the pembrolizumab/carboplatin 
arm. The study will be stopped for safety/toxicity if the number of patients experiencing 
treatment-related SAE or toxicities in pembrolizumab/carboplatin arm is excessive, and this 
toxicity is not thought to be related to carboplatin alone. A probability of treatment-related 
SAE/toxicity exceeding 0.33 will be considered prohibitively high. The table below (Table 10) 
shows the stopping rules of safety and toxicity based on a continuous Bayesian beta-binomial 
monitoring. 
Table 10: Stopping rule for toxicity: for given number of patients in the 
pembrolizumab/carboplatin arm, the study is suspended if the number of patients with treatment-
related SAE or toxicities is achieved
Number of patients in study
3-5
6-9
10-12
13-15
16-18
Number of treatment-related SAE/Toxicity
2
3
4
5
6
8.2.1.4
Futility analysis for pembrolizumab/carboplatin arm
An interim analysis for futility will not be done in the pembrolizumab/carboplatin arm as prior 
studies have shown efficacy of pembrolizumab in breast cancer (31).  
8.2.2
Secondary Efficacy Analyses
Secondary efficacy variables will include disease control rate by irRECIST, objective Response 
Rate (ORR) and progression free survival at week 18.
The disease control rate (CR/PR/SD) by irRECIST will be determined at week 18. ORR will be 
presented as the percentage of patients with CR/PR by RECIST for the primary endpoint as 
noted above, and by irRECIST for the secondary endpoint. Disease control of chest wall disease 
will be calculated it will be defined as the time from the baseline until the chest wall disease 
progression or death from any cause. Patients who have no chest wall disease at the time of the 
analysis will be censored at the time of last assessment demonstrating lack of progression. 
Disease control will also be based on PD-L1 expression via immunohistochemistry.
Time to event variables (Disease Control and ORR) and Progression Free Survival will be 
summarized by treatment arms using the Kaplan-Meier method, including graphical displays and 
incidence estimates at 4, 8 12, and 18 weeks. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
9.1
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations.

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Clinical Supplies will be provided by Merck as summarized in Table 11.
Table 11  Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Study Chair and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
9.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
9.5
Returns and Reconciliation
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 and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
Patient confidentiality will be maintained in accordance with standard HIPAA guidelines. In 
addition, all patients will be assigned a screening and randomization number as outlined in 
sections 7.1.1.6 and 7.1.1.7 above. 

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10.2 Compliance with Financial Disclosure Requirements
This trial will comply with financial disclosure requirements as outlined by the respective centers 
and states in which the trial occurs. 
10.3 Compliance with Law, Audit and Debarment
This trial will comply with all policies outlined by the respective centers and states in which the 
trial occurs.
10.4 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Study Chair of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.  UCSF will complete this requirement.   
10.5 Data Management
Each patient will be assigned a study identification number as outlined in sections 7.1.1.6 and 
7.1.1.7 above. All patients will then be entered into the EDC system, which is password 
protected and meets HIPAA guidelines. All data will be collected and entered into the EDC 
system by Clinical Research Coordinators (CRCs) from UCSF and other participating centers.  
Study meetings will occur at the coordinating center bimonthly, and updates will be provided to 
the TBCRC monthly. At these meetings, preliminary data will be reported. 
All serious adverse events, regardless of causality to study drug, will be reported to HCRN, the 
Site Investigator and/or the Study Coordinator at each institution, and also to the Study Chair.
All serious adverse events must be reported to HCRN 
 within 1 
business day after the investigator becomes aware of the event. Events should be reported using 
an HCRN SAE Submission Form. HCRN will then report this information to the Study Chair 
within 1 business day.
Follow-up information must also be reported to HCRN 
. within 1 
business day of receipt of the information by the investigator. HCRN will then report this 
information to the Study Chair within 1 business day of receipt of the information by the 
investigator.
HCRN will disseminate information regarding serious adverse events to the participating sites 
within 5 days of review of the information by the Study Chair (or her designee in the event of 
extended absence) only in the case that the event(s) is believed to be related (i.e., possibly, 

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probably, or definitely) to the study medication. UCSF will be responsible for reporting of events 
to the FDA and supporters, as appropriate (outlined below).
The UCSF DSMC will conduct remote data monitoring visits at the participating sites, as per 
DSMP and monitoring SOPs. Upon request, redacted source documents must be available for 
remote review. HCRN will perform remote data validation throughout the lifecycle of the study. 
If there are significant issues with the data identified at these sites, an onsite monitoring visit 
may be performed by HCRN (see appendix 3.0).The trial site may also be subject to quality 
assurance audit by Merck as well as inspection by appropriate regulatory agencies.
It is important for the site investigator and their relevant personnel to be available during the
monitoring visits and possible audits and for sufficient time to be devoted to the process.
10.6 Protocol Review and Amendments 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards of each participating center.
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB of each institution prior to implementation.  
The Protocol Chair (or designee) is responsible for the coordination and development of all 
protocol amendments, and will disseminate this information to the participating centers.
11.0 MULTI-CENTER GUIDELINES
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the Hoosier Cancer Research Network (HCRN). The required documents 
include, but are not limited to the following: local IRB approvals (i.e., protocol, consent form, 
amendments, patient brochures and recruitment material, etc.), IRB membership rosters, 
summary of unanticipated problems or protocol deviations, and documentation of expertise of 
the investigators. HCRN will provide each participating site with a comprehensive list of the 
necessary documents. It is the responsibility of the participating sites to maintain copies of all 
documentation submitted to HCRN.
The requirements for data management, submissions, and monitoring are outlined below.
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location. HCRN will inform the investigator at each site at such time 
that the records may be destroyed.
It is understood that any manuscript or releases resulting from the collaborative research must be 
approved by the Study Chair and will be circulated to applicable participating sites/investigators 
prior to submission for publication or presentation.

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Additionally, any publication of study data and results must conform to the publications policy 
as stated the Translational Breast Cancer Research Consortium’s (TBCRC) “Policies and 
Procedures”.
12.0 ETHICS AND GOOD CLINICAL PRACTICE ETHICS AND GOOD CLINICAL 
PRACTICE
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described in:
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996.
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations).
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996).
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to.

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13.0  REFERENCES 
1. Merck Sharp & Dohme Corp.  Pembrolizumab.  Investigator's Brochure.  Ed 9.  May 22, 
2015
2. Disis ML. Immune Regulation of Cancer. J Clin Oncol 2010;28:4531-8.
3. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al.Adoptive 
cell transfer therapy following non-myeloablative but lymphodepletingchemotherapy for the 
treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23(10):2346–
57.
4. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al.  Treatment of 
metastatic melanoma with autologous CD4+ T cells against NYESO-1. N Engl J Med 
2008;358:2698-703.
5. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48.
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 APPENDIX 1 ECOG
a. ECOG Performance Status
Table 12. 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.
b. Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).

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 APPENDIX 2 Response evaluation
13.1 Response evaluation
Both RECIST 1.1 and irRECIST will be used in this study. The irRECIST criteria are outlined 
by Bohnsack O, Ludaji K, and Hoos A.  (Adaptation of the immune-related response criteria: 
irRECIST.  2014. ESMO; Abstract 4958). 
The irRECIST criteria refer to RECIST 1.1: 
Eisenhauer EA et al.  New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47 (83).
13.2 Chest wall disease assessment
Clinical assessment of chest wall disease will occur by the treating provider and/or the study site 
coordinator. Chest wall disease assessment will occur in accordance with RECIST 1.1. These 
guidelines are also summarized here for ease of reference.
Measurable disease is defined as a superficial lesion with a minimum size of 10 mm by caliper 
measurements by clinical exam or at least 10 mm in longest diameter by CT scan. Clinical 
lesions will only be considered measurable when they are superficial and ≥ 10 mm diameter as 
assessed using calipers. Documentation by color photography including a ruler to estimate the 
size of the lesion will be done. When lesions can be evaluated by both clinical exam and 
imaging, the imaging evaluation will be used for target lesion assessment.
Non measurable lesions will not be selected as target lesions, but will be selected and followed 
as non-target lesions. These lesions will also be documented by color photography. 

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APPENDIX 3 - Data and Safety Monitoring Plan for Multicenter Institutional Study 
(Phase 2 or 3)
Data and Safety Monitoring Plan for a Multicenter Study Phase II or III Trial 
1.Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial includes:  

Semiannual auditing (depending on accrual). 

Review of serious adverse events. 

Minimum of a biennial regulatory auditing visit. 
Hoosier Cancer Research Network will work with the DSMC to provide requested reports at the 
intervals agreed upon by UCSF and HCRN.
2.Monitoring and Reporting Guidelines 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair; 
HCRN provides administration, data management, and organizational support for the 
participating sites in the conduct of a multicenter clinical trial. HCRN will work with the UCSF 
Coordinating Center to conduct quarterly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters. The Study Chair 
is responsible for the overall conduct of the trial and for auditing its safety and progress at all 
participating sites. The Study Chair will conduct continuous review of data and participant safety 
at monthly UCSF Site Committee meetings.  The discussions are documented in the UCSF Site 
Committee meeting minutes.   
All institutional Phase II or III therapeutic trials are designated with a moderate risk assessment. 
The data is audited by a DSMC Monitor/Auditor on a semiannual basis with a random selection 
of twenty percent of the participants (or at least three participants if the calculated value is less 
than three).   The DSMC Monitor/Auditor will audit a maximum of 5 cycles of treatment in the 
participants selected for review or until the selected participants discontinue study participation 
or the trial is closed with the IRB.  Additionally, the assigned DSMC Monitor/Auditor will 
review no more than 10 total participant charts during the course of auditing this trial.  DSMC 
Monitor/Auditors will send a follow-up report to the study team within 20 business days after the 
monitoring visit is complete for the PI and the study team to resolve all action items from this 
report within 20 business days.  An abbreviated regulatory review (i.e., reviewing protocol and 
consent versions, SAEs, PVs, DOA logs, 1572 forms, etc.) will occur at each participant 
monitoring review; however, a full regulatory review will occur on a biennially basis by the 
DSMC for regulatory compliance. 
The participating site’s source documents are audited remotely via either review of redacted source 
documents downloaded by the site into the CRA console of OnCore and/or via access to the site’s 

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electronic medical records.  The DSMC Monitor/Auditor will audit no more than three participant 
charts at each participating site during the course of auditing this trial. 
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.   
Multicenter communication 
The UCSF Coordinating Center includes the UCSF PI (Study Chair) and the UCSF study team. 
The UCSF Coordinating Center and HCRN provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter clinical 
trial.  HCRN and the UCSF Coordinating Center will also coordinate monthly conference calls 
with the participating sites.  The following issues will be discussed as appropriate: 
•Enrollment information.  
•Adverse events (i.e., new adverse events and updates on unresolved adverse events and new 
safety information). 
•Protocol Violations. 
•Other issues affecting the conduct of the study. 
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center and HCRN, as well as the participating sites.  The data (i.e., copies of source documents) 
from the participating sites will be downloaded into the PC console of OnCore prior to the 
remote monitoring visits in order for the DSMC to monitor the participating site’s compliance 
with the protocol and applicable FDA regulations. 
3Review and Oversight Requirements 
3.1Adverse Event Monitoring  
All Grade 3-5 adverse events (AEs), regardless of being unexpected or considered to be 
associated with the use of the study drug will be entered into OnCore®, UCSF’s Clinical Trial 
Management System. 
All clinically significant adverse events must be reported to HCRN by the participating sites who 
will then report the clinically significant AEs to Merck and the Study Chair within 10 business 
days of becoming aware of the event or during the next scheduled quarterly conference call, 
whichever is sooner.   

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Adverse events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute.  Adverse events are further given an assignment of attribution or 
relationship to the investigational agent(s) or study procedure.  Attribution categories are: 
•  Definite – The adverse event is clearly related to the investigational agent(s) or study 
procedure. 
•  Probable – The adverse event is likely related to the investigational agent(s) or study 
procedure. 
• Possible – The adverse event may be related to the investigational agent(s) or study 
procedure. 
• Unrelated – the adverse event is clearly not related to the investigational agent(s) or 
study procedure. 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings.  All adverse events entered into OnCore® will be reviewed on 
a monthly basis at the UCSF Coordinating Center Site Committee meetings.  All grade 3-5 
adverse events must be reported to the UCSF Coordinating Center by the participating sites 
within 10 business days of becoming aware of the event or during the next scheduled monthly 
conference call, whichever is sooner.  The UCSF Site Committee will review and discuss the 
selected toxicity, the toxicity grade, and attribution assignment from the UCSF Coordinating 
Center and the participating sites.  
3.2Serious Adverse Event Reporting  
By definition, an adverse event is defined as a serious adverse event (SAE) according to the 
following criteria: 
•Death. 
•Life-threatening (i.e., results in an immediate risk of death). 
•    Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Permanent or significant disability/incapacity. 
•  Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that suggests a 
significant hazard, contraindication, side effect, or precaution that may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
•  Event occurring in a gene therapy study. 
•   Event that changes the risk/benefit ratio of a study. 

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•  Any other event the Principal Investigator judges to be serious or which would suggest a 
significant hazard, contraindication, side effect, or precaution. 
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported in 
accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a Med 
Watch form.   
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event 
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm 
All Serious adverse events are entered into OnCore®, as well as submitted to the IRB (per IRB 
guidelines) via iRIS®.  All SAEs, whether expected or unexpected, must be reported to the 
UCSF Coordinating Center within one business days of becoming aware of the event.  The SAEs 
are reviewed and audited by the UCSF Data and Safety Monitoring Committee on an ongoing 
basis and discussed at DSMC meetings, which take place every six weeks.  The date the SAE 
was sent to all required reporting agencies will be documented in OnCore®.  
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be possibly, probably, or definitely 
related either to the investigational drug or any research related procedure, HCRN will report this 
information to the Study Chair at the UCSF Coordinating Center or the assigned designee within 
1 business day. The Study Chair must then notify the DSMC Chair or qualified alternate within 1 
business day of this notification. The contact may be by phone or e-mail.
3.3Review of Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Study Chair at the UCSF 
Coordinating Center is responsible for notifying HCRN and the DSMC at the time the increased 
rate is identified. The report will indicate if the incidence of adverse events observed in the study 
is above the range stated in the Investigator Brochure or package insert. 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, HCRN, 
the DSMC Chair (or Vice Chair) and the DSMC Director must be notified within one business 
day and the IRB must be notified within their reporting guidelines. 
HCRN
In addition, all suspected adverse reactions considered “serious” must be sent electronically to 
 HCRN within 1 business day of becoming aware of the event and 

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HCRN will report this information within 1 business day to the Study Chair and Merck. The 
suspected adverse reactions considered “serious” will be reviewed and monitored by the Data 
and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC meeting, 
which take place every six (6) weeks. 
Data and Safety Monitoring Committee Contacts: 
 
  Katie Kelley, MD (DSMC Chair) 
  
 
  
 
  
 
  UCSF HDFCCC 
  San Francisco, CA 94158  
 
 John McAdams (DSMC Director)  
 
 
 
UCSF HDFCCC 
San Francisco, CA 94143 
 
(Version 12Oct2020)

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Appendix 4 TBCRC (Translational Breast Cancer Research Consortium)
Collection of Microbiome Samples in Immuno-Oncology Studies
Patient Survey
Study Patient ID# _________
Age: _____    Sex:        Male        Female       Zip Code of primary residence: 
__________
Race: 
 White
 American Indian/Alaskan Native 
 Black or African American 
 African American    African 
 American-born African    Caribbean Black 
 Native Hawaiian/Pacific Islander 
 Guamanian or Chamorro    Samoan 
 Native Hawaiian    Other Pacific Islander 
 Asian 
 Chinese    Indian    Laotian    Thai 
 Cambodian    Japanese    Pakistani    Vietnamese 
 Filipino    Korean    Taiwanese    Other 
 Some other race 
 Choose not to disclose
 
Proton Pump Inhibitor (PPI) use within 30 days:       Yes          No 
   If yes – medication name 
____________________________________________________
Antibiotic use within 30 days:        Yes          No
   If yes – antibiotic name, dose, duration 
__________________________________________
Probiotic use within 30 days:        Yes          No       
   If yes – frequency (daily, weekly) 
_______________________________________________
Steroid use (other than inhaled or topical) within 30 days:      Yes          No

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   If yes – medication name, dose, duration 
_________________________________________
Primary diet (select one):
Vegetarian (vegetables and some animal products such as eggs and milk)
Vegan (no animal products)
Omnivore (both animal and plant products)
High fiber (>20 g fiber/day) diet:        Yes          No
Please scan and e-mail to Pam Skaran (skaran.pamela@mayo.edu)

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APPENDIX 5 TBCRC Stool Collection Kit
Instruction
KIT CONTENTS
1. Fecal collection tube (with pre-affixed barcode)
2. Coring brush
3. Plastic bulb pipette (for collection of loose stool)
4. 2 Feces Catchers (1 is a spare)
5. Plastic Ziploc bag
6. "Biohazard" bag
7. Extra Barcode label (for lab/physician use only)
8. Return padded envelope with return label and barcode

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STOOL COLLECTION WITH FECES CATCHER
1. Open the Feces Catcher in the direction of the arrows.
Feces Catcher
2. Paste the Feces Catcher on the back of the toilet seat, as shown in the second 
image on the Feces Catcher.
3. Avoid water coming in contact with the Feces Catcher.
4. After defecating, take the sample as indicated in the subsequent instructions for the Fecal 
Collection Tube.
5. After taking the sample, loosen the Feces Catcher on both ends and press the ends 
together.
6. Drop the Feces Catcher in the toilet, wait until the paper is soft and can easily be flushed 
down the toilet
FECAL COLLECTION TUBE INSTRUCTIONS
1. Remove the pre-sterilized coring brush from its package.
2. Use the coring brush to poke stool repeatedly (10-12 consecutive pokes) in multiple different 
locations to get a representative sample of the entire stool.
3. Once the sample is collected on the coring brush (after all pokes of the stool have been 

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completed), Pickup the fecal collection tube and hold steady in one hand. Slowly twist 
the coring brush into the vial with a corkscrew motion. There will be resistance but 
push the coring brush all the way to the bottom of tube.
4. Hold vial steady and move coring brush up and down rapidly inside the tube 10-15 times 
without moving the swab out of the liquid.
5. At this point remove and discard the coring brush: Hold vial firmly and remove swab by 
slowly twisting out with a corkscrew motion.
6. Discard brush in the trash. DO NOT PLACE SWABS IN THE BIOHAZARD BAG.
SAMPLE RETURN SHIPMENT
1. Place the Fecal Collection Tube into the plastic Ziploc bag and seal the bag.
2. Place the bagged tube into the "biohazard" bag and seal the bag.
3. Place the "biohazard" bag into the provided pre-addressed FedEx mailer, seal the 
mailer, call for FedEx pick-up or drop off at FedEx location convenient for you 
 
NSTRUCTIONAL VIDEO: