Conditions: Breast Cancer Metastatic Triple Negative
Keywords: Pembrolizumab Radiotherapy 16-032
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out what effects, good and/or bad, pembrolizumab has on the patient and areas of cancer in their body that did not receive radiation therapy.

Detailed description:

Arms:
arm 1: Subjects will receive pembrolizumab 200 mg as an IV infusion. RT begins D1 prior to dose 1 of Pembrolizumab. Pembrolizumab will be administered as a 30 minute IV infusion. Radiotherapy will be performed using external beam ionizing radiation as standard therapy in accordance with institutional standard practice. The dose of radiation will be a standard regimen/fractionation used in palliation: 3000 cGy, delivered in five 600 cGy fractions within 5-7 days.

Interventions: intervention 1: Pembrolizumab intervention 2: Radiotherapy
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 1 of 78
 
 
 
 
 
 
A Multicenter Single Arm Phase II Study to Asse ss the Efficacy of Pembrolizumab Plus 
Radiotherapy in Metastatic Triple Negative Bre ast Cancer Patients 
 
PROTOCOL FACE PAGE FOR 
MS K THE RA P E UT IC /D IA GN OS T IC P RO T OC OL 
Principal Investigator/Department: 
Christopher Barker, MD 
Radiation Oncology 
Co-Principal 
Investigator(s)/Department: 
Ayca Gucalp, MD 
Lizza Lebron-Zapata, MD 
George Plitas, MD, PhD 
Medicine 
Radiology 
Surgery 
Investigator(s)/Department: 
Simon Powell, MD, PhD 
Beryl McCormick, MD 
Oren Cahlon, MD 
Timothy Chan, MD, PhD 
Nadeem Riaz, MD 
Robert Samstein, MD 
Jose Baselga, MD. 
Larry Norton, MD 
Nancy T. Sklarin, MD 
Mark E. Robson, MD 
Victoria S. Blinder, MD 
Jacqueline F. Bromberg, MD 
Sarat Chandarlapaty, MD, PhD 
Elizabeth Comen, MD 
Gabriella D‟Andrea-Carlino, MD 
Monica N. Fornier, MD 
Teresa A. Gilewski, MD 
Shanu Modi, MD 
Marry Ellen Moynahan, MD 
Andrew D. Seidman, MD 
Tiffany A. Traina, MD 
Neil Iyengar, MD 
Constantinos T. Sofocleous, MD, PhD 
Hannah Wen, MD 
Zhigang Zhang, PhD 
Karen Schupak, MD 
Annemarie F. Shepherd, MD 
John Cuaron, MD 
Jillian Tsai, MD 
Richard Gewanter, MD 
Pinaki Dutta, MD 
Boris Mueller, MD 
Borys Mychalczak, MD 
Daphna Gelblum, MD 
Lior Braunstein, MD 
Atif Khan, MD 
Nancy Lee, MD 
Paul Hamlin, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Graduate Medical Education 
Medicine 
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Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 2 of 78
 
 
 
 
 
Stuart Lichtman, MD 
Steven Sugarman, MD 
Jasmeet Chadha Singh, MD 
Sarah Schweber, MD 
Arlyn Apollo, MD 
Pamela Drullinsky,  MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Chau Dang, MD 
Diana Lake, MD 
Michael Mauro, MD 
Pedram Razavi, MD 
Shari Goldfarb, MD 
Louise Ligresti, MD 
Neha Korde, MD 
Rachel Grisham, MD 
Wanqing Iris Zhi, MD, PhD 
Colette Owens, MD 
Jason Konner, MD 
Azadeh Namakydoust, MD 
Marina Shcherba, DO 
Virginia Klimek, MD 
Loren Michel, MD 
Rachel Sanford, MD 
Serena Wong, MD 
Darragh Halpenny, MD, MBBCH 
Karen Dougherty, APN 
Janice Terlizzi, APN 
Karin Budrock, NP 
Roseann Caruso, NP 
Medicine 
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Radiology 
Nursing 
Nursing 
Nursing 
Nursing 
Consenting 
Professional(s)/Department: 
Simon Powell, MD, PhD 
Beryl McCormick, MD 
Oren Cahlon, MD 
Christopher Barker, MD 
Jose Baselga, MD. 
Larry Norton, MD 
Nancy T. Sklarin, MD 
Mark E. Robson, MD 
Victoria S. Blinder, MD 
Jacqueline F. Bromberg, MD 
Sarat Chandarlapaty, MD, PhD 
Elizabeth Comen, MD 
Gabriella D‟Andrea-Carlino, MD 
Monica N. Fornier, MD 
Teresa A. Gilewski, MD 
Ayca Gucalp, MD 
Shanu Modi, MD 
Marry Ellen Moynahan, MD 
Andrew D. Seidman, MD 
Radiation Oncology 
Radiation Oncology 
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Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 3 of 78
 
 
 
 
 
Tiffany A. Traina, MD 
Neil Iyengar, MD 
Karen Schupak, MD 
Annemarie F. Shepherd, MD 
Jillian Tsai, MD 
Richard Gewanter, MD 
Pinaki Dutta, MD 
Boris Mueller, MD 
Borys Mychalczak, MD 
Daphna Gelblum, MD 
John Cuaron, MD 
Lior Braunstein, MD 
Atif Khan, MD 
Nancy Lee, MD Paul 
Hamlin, MD Audrey 
Hamilton, MD Mila 
Gorsky, MD Stuart 
Lichtman, MD 
Steven Sugarman, MD 
Jasmeet Chadha Singh, MD 
Sarah Schweber, MD 
Arlyn Apollo, MD 
Pamela Drullinsky,  MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Chau Dang, MD 
Diana Lake, MD 
Michael Mauro, MD 
Pedram Razavi, MD 
Shari Goldfarb, MD 
Louise Ligresti, MD 
Neha Korde, MD 
Rachel Grisham, MD 
Wanqing Iris Zhi, MD, PhD 
Colette Owens, MD 
Jason Konner, MD 
Azadeh Namakydoust, MD 
Marina Shcherba, DO 
Virginia Klimek, MD 
Loren Michel, MD 
Rachel Sanford, MD 
Serena Wong, MD 
Medicine 
Medicine 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
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Ple ase Note: A Consenting Professional must have completed the mandatory Human 
Subje cts Education and Ce rtification Program. 
 
OneMSK Sites 
Manhattan 
Basking Ridge 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 4 of 78
 
 
 
 
 
Commack 
Rockville Centre 
Westchester 
Monmouth 
 
 
 
 
 
Participating Institution s 
PI's Name 
Site's Role 
Cedars-Sinai Medical Center 
Alice Ho, MD 
Data Collection 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 5 of 78
 
 
 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMM ARY AND/OR SCHEM A ...............................................................................9 
 
2.0 
OBJECTIV ES AND SCI ENTIFIC AIMS ......................................................................................10 
 
3.0 
BACKGROUND AND RATIONAL E...........................................................................................10 
 
4.0 
OVERVIEW OF ST UDY DESIGN/INT ERVENTION ....................................................................16 
 
4.1 
Design .................................................................................................................................16 
 
4.2 
Intervention ..........................................................................................................................16 
 
5.0 
THERAP EUTIC/DI AGNOSTIC AGENTS ...................................................................................16 
 
6.0 
CRIT ERIA FOR SUBJECT ELIGIBILIT Y ...................................................................................17 
 
6.1 
Subject Inclusion Criteri a .......................................................................................................17 
 
6.2 
Subject Exclusion Criteria ......................................................................................................17 
 
7.0 
RECRUITM ENT PLAN .............................................................................................................20 
 
8.0 
PRETREATM ENT EV AL UATION ..............................................................................................22 
 
9.0 
TREAT MENT/INT ERV ENTION PL AN .......................................................................................22 
 
10.0 
EVALUATION DURI NG T REATM ENT/INT ERV ENTION .............................................................36 
 
11.0 
TOXICITIES/SIDE EFF ECTS ....................................................................................................45 
 
12.0 
CRIT ERIA FOR THERAPEUTIC RESPONS E/OUT COM E ASS ESSM ENT ..................................45 
 
13.0 
CRIT ERIA FOR REM OVAL F ROM ST UDY ...............................................................................61 
 
14.0 
BIOSTATISTICS ......................................................................................................................62 
 
15.0 
RES EARCH PARTICIPANT REGISTRATION AND RANDOMI ZATION PROCEDURES .............64 
 
15.1 
Research Participant Registration ..........................................................................................64 
 
15.2 
Randomizati on ......................................................................................................................64 
 
16.0 
DAT A M ANAGEM ENT ISSUES ................................................................................................65 
 
16.1 
Quality Assurance .................................................................................................................65 
 
16.2 
Data and Safety Monitoring ...................................................................................................66 
 
16.3 Regulatory Documentation…………………………………………………………………..69 
 
17.0 
PROT ECTION OF HUMAN SUBJECTS ....................................................................................69 
 
17.1 
Pri vacy .................................................................................................................................70 
 
17.2 
Serious Adverse E vent (SAE) Reporting .................................................................................70 
 
18.0 
INFORM ED CONS ENT PROCEDURES ....................................................................................70 
 
19.0 
REF ERENCES .........................................................................................................................76 
 
20.0 
APPENDICES ..........................................................................................................................78 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 6 of 78
 
 
 
 
 
List of Abbreviations 
 
 
 
Abbreviation or 
Specialized Term 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BC 
breast cancer 
CBC 
complete blood count 
CEA 
carcinogenic embryonic antigen 
CMP 
complete metabolic panel 
CD 
cluster of differentiation 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte antigen 4 
ECI 
event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
EKG 
electrocardiogram 
ELISA 
enzyme-linked immunosorbent assays 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
HBV 
hepatitis B virus 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 7 of 78
 
 
 
 
 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IHC 
immunohistochemistry 
IMF 
Immune Monitoring Facility 
IRB 
Institutional Review Board 
irAE 
immune-related adverse event 
irRC 
immune-related response criteria 
IV 
intravenous(ly) 
LFT 
liver function test 
MAb 
monoclonal antibody 
MSK 
Memorial Sloan-Kettering Cancer Center 
MDSC 
Myeloid derived suppressor cell 
miRNA 
micro ribonucleic acid 
MR I 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NIH 
National Institute of Health 
NK 
natural killer 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 8 of 78
 
 
 
 
 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed death 1 
PD-L1 
programmed death ligand 1 
PET-CT 
positron emission tests- computed tomography 
PK 
pharmacokinetics 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RT 
Radiation therapy 
SAE 
serious adverse event 
SD 
stable disease 
TIL 
tumor infiltrating lymphocyte 
TNBC 
triple negative breast cancer 
TNF-α 
tumor necrosis factor alpha 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 9 of 78
 
 
  
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
The primary endpoint of the study is to determine the efficacy of pembroli zumab with RT 
in subjects with triple negati ve breast cancer ( TNBC), adopting a phase II, Simon two- 
stage, si ngle-arm design. In the first stage, 9 patients will be enrolled. Among them, if 
no objecti ve tumor responses are observed, then subject enrollment wi ll be terminated. 
If at least 1 response is observed, then the s tudy will be expanded to enroll another 8 
patients for a total of 17 treated subjects. Eligible patients will have metastatic TNBC 
that is resistant to conventional chemotherapy or have decli ned conventional therapy. 
 
The primary endpoint is overall response rate in the unirradiated lesion(s), as defi ned by 
RECIS T v. 1.1. Secondary endpoints are to assess the safety, overall survival and 
progression free survi val by RECIS T v 1.1 criteria after treatment with RT + 
pembrolizumab. A n additional secondary endpoi nt is to assess the overall response rate 
by immune -related response criteria (irRC). E xploratory endpoints are to characterize 
the immunologic response and to evaluate the radiologic changes by PET-CT 
associated with RT+ pembrolizumab. 
 
All subjects will undergo 3000 cGy i n 5 fractions of RT over approximately 1 week, to be 
started within 1-3 days prior to starting Cycle 1 of pembroli zumab. All patients will have 
at least one locally advanced or metastatic lesion for which palliative RT is considered 
appropriate standard therapy, and at least one other measurable index lesion that will 
not undergo RT. Pembrolizumab will be administered via IV i nfusion at 200 mg every 
three weeks (Q3W). 
 
PET-CT or MRI will be performed duri ng screeni ng, at wk 13 (+1 wk) and q9 weeks (+1 
wk) thereafter (as per standard care). Tumor measurements and determination of tumor 
responses will be performed according to REC IST 1.1. 
 
If wk 13 PET-CT or MR demonstrates progression of disease, then pembrolizumab will 
be discontinued. If wk 13 PET-CT or MR demonstrates complete response, partial 
response or stable disease, pembroli zumab will be conti nued q3 weeks until disease 
progression, up to 24 months . All subjects will be followed up to 2 years or until the 
study closes. 
 
Mandatory research biopsies will be obtai ned at baseline and then at week 7 (+1 wk). 
Peripheral research blood samples will be obtained at baseline, wks 1, 4, 7, 10 and 13 
(+1 wk). 
 
 
It is estimated that up to 17 patients will be enrolled over 2 years. 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 10 of 78
 
 
 
 
 
Schema: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1RT: 3000 cGy x 5 fractions. D1 represents the 1st day of RT (fraction #1). 
2The fi rst dose of pem brolizumab will be initiated D1-3 of RT. The date of the fi rst dose of 
pembrolizum ab= Wk 1. 
3Research bloods can be obtai ned aft er consent and up to D1 of RT. 
4Optional fecal sam ples will be collected from patients withi n 7 days of e ach cycle of pembrolizumab. 
5Baseline imaging m ust be obtai ned prior to D1 of RT. 
6Baseline bi opsy may be from archi ved tissue. If archi ved tissue is unavailabl e, it must be obtained prior 
to D1 of RT. A mandatory research biopsy will be performed at Wk 7 (+1 Wk) 
7A confirm atory PET-CT or M RI at Wk 19 is only planned for subset of patients in whom Wk 13 scan 
demonstrates new lesions. 
  
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
• 
The primary objective is Overall Response Rate i n unirradiated lesion(s) 
(Complete Response + Partial Response), as defi ned by REC IST v. 1.1. 
 
• 
Secondary objectives are: 
 
o To confirm the safety of pembrolizumab co-administered with RT. 
o To evaluate other disease specific parameters including overall survi val 
and progression free survival by REC IST v 1.1 criteria. 
o To determine overall response rate by immune-related response criteria 
(irRC). 
 
• 
Exploratory objecti ves are: 
 
o To explore immune-based correlati ves, as described in detail i n Section 
12.3. 
o To explore the radiologic changes by PET-CT with pembroli zumab+ RT. 
 
 
 
3.0 
BACKGROUND AND RATIONALE 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 11 of 78
 
 
 
 
 
Triple negative breast cancer (TNBC), defi ned as estrogen receptor and progestero ne 
receptor levels <1% and HER2 -negative (0-1+ by immunohistochemistry or 
HER2/CEP17 ratio <2 or HER2 signals/cell <4 by i n-situ hybridization [1]), comprises 
10-15% of breast cancers. TNBC is associated with rapid growth, early metastasis and 
unfavorable prognosis compared to other subtypes of breast cancer [2]. Since targeted 
treatment options such as endocrine therapy and HER2 -directed therapies are 
unavailable, chemotherapy is the mainstay of treatment. A lthough both chemotherapy 
and radiation therapy (RT) are common treatments for palliation and local control in 
metastatic or recurrent TNBC, there are few effecti ve therapeutic regimens available at 
this time. 
 
RT has been well described to have numerous immune-modula tory effects. RT-i nduced 
tumor cell death i ncreases the supply of tumor -specific antigens, leads to the release of 
signaling molecules that attract immune cells to the tumor microenvironment and leads 
to the upregulation of PD-L1 on tumor cells [3,4]. Whether RT combi ned with PD-L1 
blockade can increase the response rate in unirradiated metastases is the subject of 
this trial. 
 
3.1 
Rationale for Immune Augmentation in Trip le Negative Breast Cancer 
 
Triple negative breast cancer (TNBC) constitutes 10-15% of breast cancers, but is 
characterized by disproportionately poor clinical outcomes compared to other subtypes 
of breast cancer and relatively poor responses to palliative chemotherapy regimens [5]. 
There is a growi ng body of evidence indicating that women with TNBC patients are 
ideally suited for immunotherapy trials. Specifically, dense lymphocytic infiltration has 
been observed i n a significant proportion of TNBCs, i ndicating an i nherent interplay 
between the tumor and the immune system. F urthermore, numerous adjuvant and 
neoadjuvant studies have recently shown that the presence of these tumor i nfiltrati ng 
lymphocytes (TILs) confirmed both prognostic and predictive impact [6-9]. 
 
Recently published studies suggest that distant metastatic invasion of TNBC may be 
potentially induced by immune/inflammatory deregulation. Among a set of 45 -gene 
signature that was found to be statistically predictive in distant disease recurrence in 
TNBC, ten genes are found to be within TGF-β signaling pathway, associated with 
immune suppressed phenotype [10 ]. In BC patients, either decreased number of 
effector CD8(+) T cells, or i ncreased number of regulatory T-cells, was associated with 
adverse tumor characteristics such as lymph node metastasis, higher stage, and Ki -67 
immunopositivity [11]. Corroborating these findi ngs, across multiple large adjuvant and 
 
neoadjuvant datasets, the quantity of tumor i nfiltrating lymphocytes in early stage triple 
negati ve breast cancers has been associated with improved survi val, and i ncreased 
likelihood of response to chemotherapy [12 ]. Functional assays demons trate that 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 12 of 78
 
 
 
 
 
adequate activation of tumor i nfiltrating lymphocytes (TILs) deri ved from BC tissue could 
restore the appropriate antitumor immune responses. This emerging data underscores 
the potential of a therapeutic strategy that induces immune-mediated anti-tumor 
responses. 
 
In light of these data, an immunomodulatory agent, pembrolizumab 10mg/kg q2wk, was 
evaluated in a phase Ib cohort of metastatic TNBC patients [9]. Pembroli zumab is a 
therapeutic blocking antibody targeting programmed death 1 (PD-1), a surface receptor 
found on chronically antigen-exposed T-cells associated with downregulation of T-cell 
cytotoxic acti vity [13]. In this population (median prior treatments = 2.5), the overall 
response rate was 19% by RECIS T1.1, with an additional 25.9% with stable disease 
(figure 3.2.1A). Responses were durable, with the median duration of response not 
reached (median follow-up 9 mo). The treatment was safe (grade III/IV toxicity: 15.6%). 
In a similar phase Ib cohort of the anti-program death ligand 1 (PD-L1) antibody, 
MPDL3470A, an objective response rate of 33% was observed i n evaluable TNBC 
patients [14]. 
 
 
 
Figure 3.1.1A Waterfall p lot of objective responses to pembrolizumab in 
TNBC 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 13 of 78
 
 
 
 
 
 
 
 
3.2 
Rationale for Immunotherapy plus Radiation Therapy 
 
Radiation therapy (RT) is a standard palliati ve therapy uti lized i n patients with 
metastatic TNBC. RT results i n tumor destruction by ioni zing radiation i n the local region 
that is specifically targeted within the radiation fields. Therefore, RT is not exp ected to 
result in objecti ve systemic benefit. However, RT has been associated with induction of 
systemic immunity that can be augmented by co-stimulatory blockade with PD-1 leading 
to potential for tumor shri nkage[15-17 ]. 
 
The phenomenon of tumor destruction by RT leading to shri nking of tumors away from 
the site of initial treatment has been termed the abscopal effect. Albeit rare, when the 
abscopal effect occurs, the cli nical implications can be profound [4]. 
 
The rationale of the abscopal effect is that in situ tumor destruction releases a large 
amount of tumor antigens. A ntigen-presenti ng cells, such as dendritic cells, then take up 
these antigens in the periphery and migrate to lymph nodes where they acti vate CD4+ 
and CD8+ T-lymphocytes that recognize these tumor-antigens. Immune augmentation 
via immune co -stimulatory molecules then permits the ensuing immune response to 
strengthen and destroy cancer[18,19]. 
 
More recently, Dr. Postow from Memorial S loan-Ketteri ng Cancer Center reported this 
abscopal effect i n a patient who developed a systemic response to locali zed RT after 
having had disease progression while receivi ng CTLA -4 blockade (ipilimumab). 
Specifically, a right hilar lymph node and spleen metastases, which was not the target of 
RT, showed regression only after the patient received palliati ve RT after several months 
of CTLA-4 blockade. A delayed response to the ipilimumab was considered unlikely [4]. 
 
Multiple pre-clinical studies support the combination of RT with anti -PD-1. The 
combination of radiotherapy and anti-C TLA-4 antibody delayed growth of irradiated 
tumor, inhibited lung metastases, and improved survi val i n a 4T1 muri ne carci noma 
model [17 ]. These findi ngs were confirmed i n a 9H10 model, in which combination 
therapy enhanced primary tumor regression and produced abscopal regression of non- 
irradiated lesions [16]. A nother muri ne model demonstrated that the combi nation of 
radiotherapy and antibodies against CD137 + PD -1 was curative and associated with 
tumor-antigen specific CD8+ T-cell i nfiltration [20]. Finally, Deng and colleagues showed 
that RT enhanced the effect of anti-PDL-1 in the TUBO breast cancer cell line, with 
reduced TUBO tumor growth after mice were re -challenged i n the opposite flank, 
implyi ng systemic immunity. 
 
The preclinical models and the cli nical observation provide compelli ng rationale to 
further study RT i n combi nation with immune augmentation by co-stimulatory blockade. 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 14 of 78
 
 
 
 
 
Pembrolizumab is an optimal immunotherapy agent to study, as this agent has recently 
been FDA-approved for use in metastatic melanoma and is therefore ready to be tested 
for efficacy in other disease sites and in combination with other treatments. Metastatic 
TNBC is an ideal target for such a study because 1) there is a lack of effecti ve the rapies 
in heavily pre -treated TNBC and therefore this study represents an opportunity to 
improve their outcomes 2) TNBC is an immunogenic subtype of breast cancer and 3) 
RT is commonly i ndicated for palliation or enhancement of local disease control. 
 
The sequencing and dose/fraction of radiation to optimally harness the proimmunogenic 
effects of checkpoint i nhibitor therapy is unknown. Pre-clinical data suggests that when 
combined with CTLA-4 antibody antagonists, an oligofractionated regimen was more 
effecti ve at induci ng an abscopal response compared to a single large fraction [4,16,21]. 
Multiple studies have exami ned the role of radiation dose and fractionation i n generati ng 
anti-tumor immune responses[22]. In murine models of RT, several groups have 
demonstrated enhanced productio n of circulating IFN-gamma expressing, tumor- 
specific CD8+ T cells with higher doses of RT (7.5 -15 Gy) deli vered focally to 
tumors.[23] For example, using an MCA38 colorectal cancer model, Dewan et al found 
that 8 Gy x 3 was most effecti ve i n combi nation with anti -CTLA-4 therapy.[16]  However, 
the best synergy in a 4T1 mammary carcinoma model i n combi nation with CTLA -4 was 
found with fractionation of 12 Gy x 1 and 12 Gy x 2.[17] Although the preclinical data 
does not provide a consistent answer as to the best fractionation to use, it can be 
hypothesi zed from the preclinical data that higher doses per fraction generate great 
antigen-release leadi ng to improved anti-tumor immune responses. 
 
We selected 3000 cGy/5 fractions because it is a standard radiation dose/fractionation, 
which is commonly used in the palliati ve setti ng. This dose/fractionation is higher than 
traditional standard palliative doses, but is generally safe to deliver i n virtually all 
locations throughout the body. This is likely to produce better antigen release. The study 
permits the first dose of pembrolizumab to be deli vered followi ng the initiation of 
radiation. This would enable enrollment of patients who need to urgently begi n palliative 
radiation. 
 
3.3 
Rationale for Pembroliz umab Dose Selection/Regimen/Modification 
 
An open-label P hase I trial (Protocol 001) was conducted to evaluate the safety and 
clinical activity of single agent MK-3475 (pembroli zumab).  The dose escalation portion 
of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered 
every 2 weeks (Q2W) i n subjects with advanced solid tumors. All three dose levels 
were well tolerated and no dose-limiting toxicities were observed.  This first in-human 
study of MK-3475 showed evidence of target engagement and objective evidence of 
tumor si ze reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD 
has been identified to date.  Recent data from other clinical studies withi n the MK-3475 


Memorial Sloan Kettering Cancer Center
IRB Number: 16-032 A(8) 
Approval date: 11-Dec-2018 
Page 15 of 78
 
 
 
 
 
program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and cli nical activity. 
 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half -life (refer to IB). 
Pharmacodynamic data (IL -2 release assay) suggested that peripheral target 
engagement is durable (>21 days).  This early PK and pharmacodynamic data provides 
scientific rationale for tes ting a Q2W and Q3W dosing schedule. 
 
 
A population pharmacokinetic analysis has been performed usi ng serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
withi n the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to 
have a wide therapeutic range based on the melanoma i ndication.  The differences in 
exposure for a 200 mg fi xed dose regimen relati ve to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remai n well withi n the establishe d exposure margi ns 
of 0.5 – 5.0 for MK-3475 i n the melanoma indication. The exposure margi ns are based 
on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the 
proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden 
on exposure. In addition, exposure was similar between the NSCLC and melanoma 
indications. Therefore, there are no anticipated changes i n exposure between diffe rent 
indication settings. 
 
 
The rationale for further exploration of 2 mg/kg and comparable doses of 
pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of 
pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W i n melanoma patients , 
2) the flat exposure-response relationships of pembrolizumab for both efficacy and 
safety i n the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of 
tumor burden or i ndication on distribution behavior of pembroli zumab (as assessed by 
the population PK model) and 4) the assumption that the dynamics of pembrolizumab 
target engagement wi ll not vary meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fi xed dosing is 
based on simulations performed usi ng the population PK model of pembroli zumab 
showi ng that the fi xed dose of 200 mg every 3 weeks wi ll provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintai n indi vidual patient exposures in the exposure range established in melanoma 


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as associated with maximal efficacy response and 3) will mai ntain indi vidual patients 
exposure i n the exposure range established in melanoma that are well tolerated and 
safe. 
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors. A fi xed dosing scheme wi ll also 
reduce complexity i n the logistical chain at treatment facilities and reduce wastage. 
 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This will be a Simon two-stage design, phase II study. It will be conducted to determi ne 
the efficacy and safety of pembroli zumab plus RT in subjects with metastatic TNBC who 
are undergoing standard palliative radiation therapy. 
 
4.2 
Intervention 
 
All patients will have at least one locally advanced or metastatic lesion for which 
palliative RT is considered appropriate standard therapy, and at least one other 
measurable i ndex lesion that will not undergo RT. Only recurrent lesio ns that are 
symptomatic and/or requiri ng palliation will be irradiated.  All subjects wi ll begin RT 
duri ng C ycle 1, within 7 days prior to starting pembroli zumab. Subjects will receive 
pembrolizumab via IV i nfusion at 200 mg every three weeks (+ 3 days), and continue 
treatment until progression of disease, initiation of alternati ve cancer therapy, 
unacceptable toxicity, or other reasons to discontinue treatment occur, up to 24 months. 
Patients who had a prior response without another reason to disconti nue t herapy after 
24 months will conti nue cli nic visits, routine blood work and PET-C T or MRI every 9 
weeks, and may resume treatment for an additional 12 months upon disease 
progression. Repeat palliative RT will be permitted i n select cases for the treatment of 
isolated, non-target lesions. Patients will be evaluated by physical exam and routi ne 
blood tests every three weeks duri ng the study period. PET-C T or MRI will be 
performed during screeni ng, and then at week 13 (+1 wk) and every 9 weeks (+1 wk) 
thereafter. Tumor measurements and determi nation of tumor responses will be 
performed according to RECIS T 1.1. 
 
Subjects may continue to receive pembroli zumab beyond radiographic disease 
progression i n the absence of clinical deterioration, and after discussion with the 
Principal Investigator. 
 
All subjects will be followed up to 2 years for survival or until the study closes. 
Exploratory research studies to evaluate the effect of this therapy will be performed in 


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patients usi ng research blood draws, and tumor biopsy at baseli ne and week 7 (+1 wk) 
for research purposes. 
 
4.3 
Estimated Duration of Subject Participation 
 
Subjects may be treated for up to 24 months, with the option to resume treatment for an 
additional 12 months upon disease progression, unless there is another reason to 
discontinue treatment. All subjects will be followed for survival for up to 2 years unless 
the Principal Investigator or Merck decides to end the study. 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
Pembrolizumab 
 
Pembrolizumab will be provided by Merck. Please refer to investigator brochure and 
MK-3475 Drug Preparation Instructions‟ manual (Appendi x D). 
 
 
Table 5.1A Product De scriptions 
 
Product Name & Pote ncy 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and 
usage of investigational product in accordance with the protocol and any applicable 
laws and regulations. Clinical supplies will be affixed with a cli nical label in accordance 
with regulatory requirements. 
 
5.2 
Radiotherapy 
 
Radiotherapy will be performed using external beam ioni zing radiation as standard 
therapy in accordance with institutional standard practice. The dose of radiation wi ll be a 
standard regimen/fractionation used in palliation: 3000 cGy, delivered in fi ve 600 cGy 
fractions withi n 5 -7 days. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
In order to be eligible for participation in this trial, the subject must: 


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1.  Be willi ng and able to provide written i nformed consent/assent for the trial. 
2.  Be female  18 years of age on day of signi ng informed consent. 
 
3.  Histologically or cytologically-confirmed TNBC (defined as ER <1%, PR <1%, 
her-2-neu 0-1+ by IHC or F ISH-negative or as per MD discretion) at each 
enrolli ng institution. 
 
4.  Metastatic or locally recurrent TNBC. 
 
5.  Subjects who are resistant to conventional chemotherapy or have decli ned 
conventional therapy for TNBC. Patients having received any prior line of 
systemic therapy for inoperable/recurrent or metastatic disease are eligible. 
 
6.  At least one tumor for which palliative RT is considered appropriate standard 
therapy. 
 
7.  At least one index lesion that will not undergo RT and which is measurable 
based on REC IST 1.1. 
 
8.  If an archived tumor tissue is unavailable, be willing to provide tissue from a 
newly obtained core or excisional biopsy of a tumor lesion.  Newly-obtained is 
defined as a specimen obtained up to 6 weeks (42 days) prior to i nitiation of 
treatment on Day 1 of RT 
 
9.  Repeat palliative RT will be permitted for the treatment of isolated, non-target 
lesions. 
 
10. Consent for blood draws for research purposes. 
 
11. Consent for use of available archi ved tissue for research purposes. 
12. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
13. Demonstrate adequate organ function as defined in Table 6.1A; all screeni ng 
labs should be performed within 28 days (+7 days) of treatment i nitiation, 
unless otherwise indicated. 


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Table 6.1A  Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count 
(ANC) 
≥1.5 K/mcL 
Platelets 
≥100 K /mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion 
or EPO dependency (withi n 7 days of 
assessment) 
Renal 
Serum creati nine  OR 
Measured or calculateda 
creatini ne clearance 
(GFR can also be used i n 
place of creati nine or CrCl) 
≤1.5 X upper limit of normal (ULN) 
OR 
≥60 mL/mi n for subject with creatini ne 
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 
≤ 5 X ULN for subjects with li ver 
metastases 
Albumi n 
>2.5 mg/dL 
Coagulation 
International Normali zed 
Ratio (INR) or Prothrombin 
Time (P T) 
≤1.5 X ULN unless subject is recei ving 
anticoagulant therapy 
as long as P T or aPTT is withi n therapeutic 
range of i ntended use of anticoagulants 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is recei ving 
anticoagulant therapy 
as long as P T or aPTT is withi n therapeutic 
range of i ntended use of anticoagulants 
aCreatinine clearance should be calculated per i nstitutional standard. 


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14. Female subject of chi ldbearing potential should have a negati ve pregnancy 
test or documentation of absence of pregnancy by a gynecologist within 2 
weeks of initiating radiation therapy. 
 
15. Female subjects of chi ldbearing potential should be willi ng to use 2 methods 
of birth control or be surgically sterile, or abstain from heterosexual acti vity for 
the course of the study through 120 days after the last dose of study 
medication. Subjects of childbeari ng potential are those who have not been 
surgically sterili zed or have not been free from menses for > 1 year. 
 
 
 
6.2 
Subject Exclusion Criteria 
 
The subject must be excluded from participating i n the trial if the subject: 
 
1.  Is currently participating and receivi ng study therapy or has participated in a 
study of an investigational agent and received study therapy or used an 
investigational device withi n 4 weeks of the first dose of treatment. 
 
2.  Has a diagnosis of immunodeficiency or is receivi ng systemic steroid therapy 
or any other form of immunosuppressi ve therapy withi n 7 days prior to the 
first dose of trial treatment. 
 
3.  Has a known history of active TB (Bacillus Tuberculosis) 
 
4.  Hypersensitivity to pembroli zumab or any of its excipients. 
 
5.  Has had a prior anti-cancer monoclonal antibody (mAb) withi n 4 weeks prior 
to study Day 1 or who has not recovered (i.e ., > Grade 1 or at baseli ne) from 
adverse events due to agents administered more than 4 weeks earlier. 
 
6.  Has had prior chemotherapy or targeted small molecule therapy within 2 
weeks prior to study Day 1 or who has not recovered (i.e., > Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
 
7.  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the i ntervention prior to starti ng therapy. 
 
8.  Has a known additional malignancy that progressed or required treatment in 
the last 5 years. E xceptions include basal cell carci noma of the skin or 
squamous cell carcinoma of the skin that has undergone potentially curati ve 
therapy or in situ cervical cancer. 
 
9.  Has known acti ve central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Subjects with previously treated brai n parenc hymal 
metastases may participate provided they are stable (without evidence of 
progression by imagi ng for at least four weeks prior to the first dose of trial 
treatment and any neurologic symptoms have returned to baseli ne), have no 
evidence of new or enlargi ng brai n metastases, and are not usi ng steroids for 


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at least 7 days prior to trial treatment. This exception does not i nclude 
carcinomatous meningitis, which is excluded regardless of clinical stability. 
 
10. Has acti ve autoimmune disease that has required systemic treatment in the 
past 2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
 
11. Has known history of/acti ve, non-infectious pneumonitis requiring treatment 
with steroids or has history of/acti ve interstitial lung disease. 
 
12. Has an active i nfection requiring systemic therapy. 
 
13. 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 i n the best 
interest of the subject to participate, i n the opinion of the treati ng i nvestigator. 
 
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
15. Is pregnant or breastfeeding, or expecting to concei ve or father children withi n 
the projected duration of the trial, starting with the pre -screening or screeni ng 
visit through 120 days after the last dose of trial treatment. 
 
16. Has recei ved prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent 
or has participated in another Merck pembrolizumab cli nical trial. 
 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
 
18. Has known acti ve Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitati ve] is detected). 
 
19. Has recei ved a live vaccine within 30 days of planned start of study therapy. 
 
Note: Seasonal i nfluenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal i nfluenza vaccines (e.g., 
Flu-Mist®) are live attenuated vaccines, and are not allowed. 


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7.0 
RECRUITMENT PLAN 
 
This study will be available to all patients seen at Memorial Sloan Ketteri ng Cancer 
Center and Cedars Sinai, who meet the eligibility criteria outlined in section 6.0. 
 
MSK is a large referral center for metastatic TNBC. Drs. C hristopher Barker and A yca 
Gucalp will facilitate accrual across the Radiation Oncology and Medical Oncology 
(Breast Medicine) departments, respecti vely. MSK is equipped with the necessary 
laboratory infrastructure (i.e. the MSK Immune Monitori ng Facility) to conduct the 
immune monitoring exploratory studies described in section 12.0. 
 
Participants will also be enrolled by Cedars Sinai, a large referral center for breast 
cancer i n southern California. 
 
The investigators take due notice of the NIH policy concerni ng inclusion of women and 
minorities in cli nical research populations.  There will be no limitation to access with 
regard to race or gender. Patients will be required to read, agree to, and sign an IRB- 
approved i nformed consent form prior to registration on this trial. The registration 
procedure will be conducted as described in section 15.0. Patients will not receive 
payment for their participation on this study. 
 
Participating site recruitment will be conducted as outlined within the protocol. The 
participating site that requires a limited wai ver must obtain it from its own site 
IRB/Provacy Board (PB) via a separate protocol addendum or request. It is the 
responsibility of the MSK staff to confirm that participating data collection site has a 
limited wai ver approval by its local IRB /PB. 
 
 
8.0 
PRETREATMENT EVALUATION 
 
• 
To be completed withi n 28 + 7 days of starting radiation therapy (unless otherwise 
indicated): 
 
• 
PET-CT scan with contrast (diagnostic CT of chest, abdomen and pelvis). If 
patient is unable to recei ve CT contrast, or the abdominal/pelvic target lesion is 
indetermi nate on CT scan, then MRI with contrast (abdomen and pelvis) plus CT 
chest without contrast may be performed. Non-co ntrast CT CAP may be used if 
the target lesion(s) do not require contrast for accurate measurements 
• 
12-lead Electrocardiogram (EKG) 
• 
Signed informed consent for study participation 
• 
History and physical examination i ncludi ng height, weight, vital signs 
(temperature, pulse rate, respiratory rate, blood pressure , pulse oximetry), 
performance status (ECOG), and review of pathology and medications. 
• 
Urine or serum pregnancy test for all women of childbeari ng potential or 
documentation of absence of pregnancy by a gynecologist (withi n two weeks of 


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starti ng RT). If the test result is positi ve related to pregnancy, the patient will not 
be allowed to participate i n this study. 
 
 
• 
CBC with differential and platelet count 
• 
Complete metabolic panel (sodium, potassium, chloride, bicarbonate, BUN, 
creatini ne, glucose, total protein, albumin, bilirubin, alkaline phosphatase, AST, 
ALT, corrected calcium) 
• 
Magnesium 
• 
Amylase 
• 
Lipase 
• 
LDH 
• 
Phosphorus 
• 
Thyroid function panel (TSH, free & total T3, free T4) 
• 
PT/INR & aPTT 
• 
Serology for HepBsAg, HepBcAb and hepatitis C antibody (negati ve test prior to 
screeni ng period is acceptable) 
• 
Tumor markers (CEA, CA 15-3, CA 19-9) 
• 
Research blood samples 
• 
Perform baseline tumor biopsy for diagnostic purposes. Achival biopsy tissue will 
be used if sufficient tissue is available (at least 1 FFPE-preserved core 
contai ning viable tumor), as confirmed by the respecti ve site pathologist. Archi val 
tissue must be obtained within 6 weeks of starting pembrolizumab, with no anti - 
neoplastic therapies administered between the biopsy and start of 
pembrolizumab. Archi val tissue biopsy specimens can be either from the 
radiation target or the non-target radiation lesions 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Subjects wi ll receive pembroli zumab 200 mg as an IV i nfusion accordi ng to the dosi ng 
and route described in Table 5.1A. RT begins on D1, prior to dose 1 of Pembroli zumab. 
 
Pembrolizumab will be administered as a 30 minute IV infusion (every effort should be 
made to target infusion timing to be as close to 30 mi nutes as possible. However, given 
the variability of infusion pumps from site to site, a wi ndow of -5 mi nutes and +10 
minutes is permitted (i.e., i nfusion time is 30 mi nutes: -5 min/+10 min). 
 
9.1 
Monitoring of Dose Admin istration 
 
Subjects wi ll be monitored during and after infusion with assessment of vital signs per 
institutional practice. 
 
In the event of an i nfusion-related reaction, refer to Appendi x C for guidance. 


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As with any antibody, allergic reactions to dose admi nistration are possible. Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study perso nnel must be trained to recogni ze and treat anaphylaxis. The 
study site must have immediate access to emergency resusci tation teams and 
equipment i n addition to the ability to admit subjects to an i ntensive care u nit if 
necessary. 
 
9.2 
Concomitant Medications 
 
9.2.1  Permitted Concomitant Medication 
 
Investigators may prescribe concomitant medications or treatments (e.g., 
acetaminophen, diphenhydramine) deemed necessary to provide adequate prophylactic 
or supporti ve care except for those medications identified as “excluded” as listed in 
Section 9.3.2. 
 
9.2.2  Excluded Concomitant Medications 
 
Subjects must be i nstructed not to take any medications, including over-the -counter 
products, without first consulti ng with the investigator. 
 
The following medications are considered exclusionary during the study. The Pri ncipal 
Investigator must be notified if a subject receives any of these duri ng the study. 
 
 
• 
Any investigational anticancer therapy. 
 
• 
Any concurrent chemotherapy (except as per study), immunotherapy, or biologic 
therapy. 
 
Note: Concurrent use of bone-directed therapies, such as 
bisphosphonates or denosumab, are permitted. 
 
• 
Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for 
diabetes and hormone replacement therapy) is acceptable. 
 
• 
Immunosuppressive medications includi ng, but not limited to systemic 
corticosteroids (>10 mg/day prednisone or equivalent), methotrexate, 
azathioprine, and tumor necrosis factor alpha (TNF -α) blockers. Use of 
immunosuppressive medications for the management of i nvestigational product - 
related AEs, in subjects with contrast allergies is acceptable. In addition, use of 
inhaled and i ntranasal corticosteroids is permitted. 
 
 
 
 
9.3 
Dose Modifications or Scheduling Delays 


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9.3.1  Pembrolizumab Dose Modifications 
 
Adverse  events  (both  non-serious  and  serious)  associated  with  pembrolizumab 
exposure may represent an immunologic etiology.   These adverse events may occur 
shortly after the first dose or several months after the last dose of treatment. 
 
Pembrolizumab dose modifications will not be allowed. However, pembroli zumab must 
be withheld for drug-related toxicities and severe or life-threatening AEs as per Table 
9.3.1A below. See Appendix C ( E vents of Clinical Interest Guidance Document) for 
supporti ve care guidelines, including use of corticosteroids to treat immune related AEs. 


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Table 9.3.1A: Dose Modification and Toxicity Management Guidelines for Immune - 
re lated AEs Associated with Pe mbrolizumab 
 
Ge neral ins truc tions : 
1. Corticos teroid taper s hould be initiated upon AE imp roving to Grade 1 or les s and continue to taper over at 
leas t 4 wee ks . 
2. For s ituations where pembro lizu mab has been withheld, pe mbro lizu mab can be res umed after A E has been 
reduced to Grade 1 or 0 and corticos teroid has been tapered. Pembro lizu mab s hould be permanently 
dis continued if A E does not resolve with in 12 weeks of las t dos e or corticosteroids cannot be reduced to 
≤10 mg prednis one or equivalent per day within 12 wee ks . 
3. For s evere and life-threatening irAEs , IV corticos teroid s hould be initiated firs t followed by oral s teroid. 
Other immunos uppress ive treatment s hould be initiated if irA Es cannot be controlled by corticos teroids . 
Immune -relate d 
AEs 
Toxicity 
grade or 
condi tions 
(CTCAEv4 .0) 
Action taken to 
pe mbrolizuma 
b 
irAE manage ment with 
corticos teroi d and/ or 
other therapies 
Monitor and follow-up 
Pneumonit is 
Grade 2 
Withhold 
•   Admin is ter 
corticos teroids (initial 
dose of 1-2 mg/ kg 
prednis one or 
equivalent) followed by 
taper 
• 
Monitor participants for 
s igns and symptoms of 
pneumonitis 
• 
Evaluate partic ipants 
with s us pected 
pneumonitis with 
radiographic imaging 
and initiate 
corticos teroid treatment 
• 
Add prophylactic 
antibiotics for 
opportunis tic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
dis continue 
Dia rrhea / Colitis 
Grade 2 or 3 
Withhold 
•   Admin is ter 
corticos teroids (initial 
dose of 1-2 mg/ kg 
prednis one or 
equivalent) followed by 
taper 
• 
Monitor participants for 
s igns and symptoms of 
enterocolitis (ie , 
diarrhea, abdo mina l 
pain, blood or mucus in 
s tool with or without 
fever) and of bowe l 
perforation 
(ie, peritoneal s igns and 
ileus ). 
• 
Partic ipants with ≥ 
Grade 2 dia rrhea 
s us pecting colitis 
s hould cons ider GI 
cons ultation and 
performing endos copy 
to rule out colit is . 
• 
Partic ipants with 
diarrhea/colit is s hould 
be advis ed to drink 
libera l quantities of 
clear flu ids . If 
Grade 4 
Permanently 
dis continue 


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s ufficient oral fluid 
intake is not feas ible, 
flu id and electrolytes 
s hould be s ubstituted 
via IV infus ion. 
AST / ALT 
elevation or 
Increas ed 
bilirubin 
Grade 2 
Withhold 
•   Admin is ter 
corticos teroids (initial 
dose of 0.5- 1 mg/kg 
prednis one or 
equivalent) followed by 
taper 
• 
Monitor with liver 
function tests (cons ider 
weekly or mo re 
frequently until liver 
enzy me value returned 
to bas eline or is s table 
Grade 3 or 4 
Permanently 
dis continue 
•   Admin is ter 
corticos teroids (initial 
dose of 1-2 mg/ kg 
prednis one or 
equivalent) followed by 
taper 
Type 1 diabetes 
me llitus (T 1DM ) 
or 
Hyperglyce mia 
Newly ons et 
T1DM or 
Grade 3 or 4 
hyperglycemia 
ass ociated 
with evidence 
of -ce ll 
failure 
Withhold 
•   Initiate ins ulin 
replace ment therapy for 
participants with T1DM 
•   Admin is ter anti- 
hyperglycemic in 
participants with 
hyperglycemia 
• 
Monitor participants for 
hyperglycemia or other 
s igns and symptoms of 
diabetes . 
Hypophys itis 
Grade 2 
Withhold 
•    Admin is ter 
corticos teroids and 
initiate hormona l 
replace ments as 
clin ically indicated. 
• 
Monitor for s igns and 
s ymptoms of 
hypophys itis (including 
hypopituitaris m and 
adrenal ins uffic iency) 
Grade 3 or 4 
Withhold or 
permanently 
dis continue1 
Hyperthyroidis m 
Grade 2 
Continue 
•   Treat with non-s elective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
• 
Monitor for s igns and 
s ymptoms of thyroid 
dis orders . 
Grade 3 or 4 
Withhold or 
permanently 
dis continue1 
Hypothyroidis m 
Grade 2-4 
Continue 
•    Initiate thyroid 
replace ment hormones 
(eg, levothyroxine or 
liothyroinine) per 
s tandard of care 
• 
Monitor for s igns and 
s ymptoms of thyroid 
dis orders . 
Nephritis and 
Renal 
dys function 
Grade 2 
Withhold 
•    Admin is ter 
corticos teroids 
(prednis one 1-2 mg/ kg 
or equivalent) fo llo wed 
by taper. 
• 
Monitor changes of 
renal function 
Grade 3 or 4 
Permanently 
dis continue 
Myocarditis 
Grade 1 or 2 
Withhold 
•    Bas ed on s everity of 
AE ad minis ter 
• 
Ens ure adequate 
evaluation to confirm 


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Grade 3 or 4 
Permanently 
dis continue 
corticos teroids 
etiology and/or exc lude 
other caus es 
All other 
immune-related 
AEs 
Intolerable/ 
pers is tent 
Grade 2 
Withhold 
•    Bas ed on type and 
s everity of AE 
adminis ter 
corticos teroids 
• 
Ens ure adequate 
evaluation to confirm 
etiology and/or exc lude 
other caus es 
Grade 3 
Withhold or 
dis continue 
bas ed on the 
type of event. 
Events that 
require 
dis continuation 
include and not 
limited to: 
Gu llain-Ba rre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
dis continue 
1. 
Withhold or permanently dis continue pembrolizu mab is at the dis cretion of the inves tigator or treating 
phys ician. 
NO TE: 
For partic ipants with Grade 3 o r 4 immune -re lated endocrinopathy where withhold of pe mbro lizu mab is 
required, pe mbro lizu mab may be res umed when AE res olves to ≤ Grade 2 and is controlled with hormonal 
replace ment therapy or achieved metabolic control (in cas e of T 1DM ). 
 
 
9.3.2  Discontinuation of Study Therapy after CR 
 
Discontinuation of treatment may be considered for subjects who have attained a 
confirmed CR that have been treated for at least 24 weeks with pembroli zumab and had 
at least two treatments with pembroli zumab beyond the date when the initial CR was 
declared. Subjects who then experience radiographic disease progression may be 
eligible for up to one year of additional treatment with pembrolizumab via the Second 
Course P hase at the discretion of the investigator if no cancer treatment was 
administered si nce the last dose of pembrolizumab, the subject meets the safety 
parameters listed i n the Inclusion/E xclusion criteria, and the trial is open. S ubjects will 
resume therapy at the same dose and schedule at the time of initial disconti nuation. 
Additional details are provided in section 9.5 . 
 
9.3.3 D iscontinuation of Study Therapy after PD 
 
Discontinuation of treatment may be considered for subjects who have initial evidence 
of PD at first re-staging (week 13 , +1 wk) and is not cli nically stable, or is clinically 
stable and PD is confirmed 4-6 weeks after the date of first re -staging (weeks 17-19). 


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9.4 
Second Course Phase (Retreatment Period) 
 
Subjects who stop pembroli zumab with SD or better may be eligible for up to one year 
of additional pembrolizumab therapy if they progress after stopping study treatment. 
This retreatment is termed the Second Course Phase of this study and is only available 
if the study remai ns open and the subject meets the following conditions: 
 
Either: 
 
• 
Stopped initial treatment with pembrolizumab after attai ning an investigator - 
determined confirmed CR according to REC IST 1.1, and 
 
• 
Was treated for at least 24 weeks with pembrolizumab before disconti nuing 
therapy, and 
 
• 
Received at least two treatments with pembroli zumab beyond the date when the 
initial CR was declared 
 
Or: 
 
• 
Had SD, PR or CR and stopped pembroli zumab treatment after 24 months of 
study therapy for reasons other than disease progression or lack of safety, and 
 
• 
Experienced an investigator-determined confirmed radiographic disease 
progression after stopping their i nitial treatment with pembrolizumab, and 
 
 
 
• 
Did not recei ve any anti-cancer treatment si nce the last dose of pembrolizumab 
aside from the assigned chemotherapy backbone, and 
 
• 
Has a performance status of 0 or 1 on the ECOG Performance Scale, and 
 
• 
Demonstrates adequate organ function as detailed i n inclusion criteria, and 
 
• 
Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might interfere with the subject‟s participation for the 
full duration of the trial or is not i n the best interest of the subject to participate, in 
the opinion of the treati ng i nvestigator, and 
 
• 
Meets the following criteria regardi ng childbearing potential/contraception: 
 
o Female subject of childbearing potential should have a negative serum or 
uri ne pregnancy test within 72 hours prior to recei ving retreatment with 
study medication or have been declared not pregnant by a gynecologist, 
and 
 
o Female subject of childbearing potential should be willing to use 2 methods 
of birth control or be surgically sterile, or abstain from heterosexual acti vity 
for the course of the study through 120 days after the last dose of study 
medication (Reference Section 9.5.7). S ubjects of child beari ng potential 
are those who have not been surgically sterilized or have been free from 
menses for > 1 year. 


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Subjects who restart treatment will be retreated at the same dose and dose interval as 
when they last received pembrolizumab. Treatment will be administered for up to one 
additional year. Visit requirements are outlined in the trial flow chart. 
 
9.5     Supportive Care Guidelines 
 
Subjects should recei ve appropriate supporti ve care measures as deemed necessary 
by the treating investigator.  Suggested supporti ve care measures for the management 
of adverse events wi th potential immunologic etiology are outlined below and in greater 
detail in the ECI guidance document. Where appropriate, these guidelines i nclude the 
use of oral or intravenous treatment with corticosteroids as well as additional anti - 
inflammatory agents if symptoms do not improve with admi nistration 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 i nfection, 
which might require additional supporti ve care. The treatment guideli nes are intended to 
be applied when the investigator determines the events to be related to pembroli zumab. 
 
Note: if after the evaluation the event is determined not to be related, the 
investigator is instructed to follow the EC I reporti ng guidance (Appendi x C) but 
does not need to follow the treatment guidance (as outli ned in the EC I guidance 
document). Refer to Section 9.4 for dose modification. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event. Suggested 
conditional procedures, as appropriate, can be found i n the EC I g uidance document 
(Appendix C). 
 
Management of Pneumonitis 
 
• 
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
•    For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-i nflammatory measures, as needed. 
 
• 
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid admi nistration. 
 
Management of Diarrhea/Colitis 
 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 


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• 
All subjects who experience diarrhea/colitis should be advised to dri nk 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 confi rm or rule out colitis. 
 
• 
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer 
oral corticosteroids. 
 
• 
For Grade 3 or 4 d iarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids. 
 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and conti nued over no less than 4 weeks. 
 
Management of Type 1 diabetes mellitus (if new onset, including diabetic 
ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketos is 
(ketonuria) or metabolic acidosis (DKA) 
 
• 
For T1DM or Grade 3-4 Hyperglycemia 
o Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 
o Evaluate patients with serum glucose and a metabolic panel, uri ne 
ketones, glycosylated hemoglobin, and C-peptide. 
 
 
Management of Hypophysitis 
 
• 
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and conti nued over no less 
than 4 weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
• 
For Grade 3-4 events, treat with an i nitial 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. 
 
Management of Hyperthyroidism o r Hypothyroidism: 
 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically duri ng treatment, and as 
indicated based on cli nical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
 
• 
Grade 2 hyperthyroidism events (and Grade 3 -4 hypothyroidism): 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 


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o In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroi nine, is indicated per standard of care. 
• 
Grade 3-4 hyperthyroidism 
o 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. 
 
Management of Hepatic toxicities 
 
• 
For Grade 2 events, monitor li ver function tests more frequently until returned 
to baseli ne values (consider weekly). 
o Treat with IV or ora l corticosteroids 
• 
For Grade 3-4 events, treat with i ntravenous corticosteroids for 24 to 48 
hours. 
• 
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and conti nued over no less than 4 weeks. 
 
 
Management of Renal Failure or Nephrit is 
 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
 
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
 
Management of Infusion Reactions 
 
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely withi n 24 hours of completion of infusion. 
 
Table 9.5.3A shows treatment guidelines for subjects who experience an infusion 
reaction associated with admi nistration of pembroli zumab (MK -3475). 
 
Table 9.5.3A: Pembrolizumab Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Tre atment 
Premedication at subsequent 
dos ing 
Grade 1 
Mi ld reaction; inf usion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed med ically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires inf usion interruption but 
responds promptly to symptomatic 
Stop Infus ion and monitor s ymptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
inf usion of pembrolizumab (MK- 


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NCI CTCAE Grade 
Tre atment 
Premedication at subsequent 
dos ing 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV f luids); 
prophylactic medications indicated 
f or < =24 hrs. 
IV f luids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed med ically stable in the opinion of the 
investigator. 
If symptoms resolve w ithin one hour of 
stopping drug inf usion, the inf usion may be 
restarted at 50% of the original inf usion rate 
(e.g., f rom 100 mL/hr to 50 mL/hr). 
Otherw ise dosing w ill be held until symptoms 
resolve and the subject should be 
premedicated f or the next scheduled dose. 
Subje cts who de ve lop Grade 2 toxicity 
des pite adequate premedication s hould 
be permanently dis continued from further 
trial tre atment administration. 
3475) w ith: 
 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of inf usion); recurrence of 
symptoms follow ing initial 
improvement; hospitalization 
indicated f or other clinical sequelae 
(e.g., renal impairment, pul monary 
inf iltrates) 
Grade 4: 
Lif e-threatening; pressor or 
ventilatory support indicated 
Stop Infus ion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV f luids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed med ically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subje ct is permanently dis continued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 
 
 
9.5.4  Management of Nausea/vomiting 
 
Nausea and vomiting should be treated aggressively, and consideration should be given 
in subsequent cycles to the administration of prophylactic antiemetic therapy according 
to standard institutional practice. S ubjects should be strongly encouraged to maintain 
liberal oral fluid i ntake. 


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9.5.5  Use of anti-infectives 
 
Subjects with a documented infectious complication should receive oral or IV antibiotics 
or other anti-infecti ve agents as considered appropriate by the treati ng investigator for a 
given infectious condition, according to standard i nstitutional practice. 
 
9.5.6  Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea or vomiting. 
 
9.5.7  Contraception 
 
Pembrolizumab may have adverse effects on a fetus i n utero. F urthermore, it is not 
known if pembroli zumab has transient adverse effects on the composition of sperm. 
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 
methods of birth control or are considered highly unlikely to concei ve. Highly unlikely to 
conceive is defined as 1) surgically steri lized, or 2) postmenopausal (a woman who is 
≥45 years of age and has not had menses for greater than 1 year will be considered 
postmenopausal), or 3) not heterosexually active for the duration of the study.  The two 
birth control methods can be either two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. S ubjects should start usi ng birth control from 
study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy. 
 
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper i ntrauterine device, sponge, or spermicide. 
Appropriate hormonal contracepti ves will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (i ncludi ng 
oral, subcutaneous, i ntrauterine, or intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur duri ng the study.  In order to 
participate in the study they must adhere to the contraception requirement (described 
above) for the duration of the study and during the follow-up period defi ned in section 
11.4 - Pregnancies.  If there is any question that a subject wi ll not reliably comply wit h 
the requirements for contraception, that subject should not be entered i nto the study. 
 
9.5.8  Use in Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment with pembroli zumab, the 
subject will immediately be removed from the study. The site wi ll contact the subject at 
least monthly and document the subject‟s status unti l the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the 
Sponsor and to Merck without delay and within 24 hours if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabli ng or life - 
threatening complication to the mother or newborn). The study i nvestigator will make 
every effort to obtain permission to follow the outcome of the p regnancy and report the 


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condition of the fetus or newborn to the Sponsor. It is unknown whether pembrolizumab 
is excreted in human mi lk. Since many drugs are excreted in human milk, and because 
of the potential for serious adverse reactions i n the nursi ng infant, subjects who are 
breast-feeding are not eligible for enrollment and should be removed from study 
immediately. 
 
 
9.6 
Subject replacement strategy 
 
Subjects wi ll be treated on p rotocol on a modified intention-to-treat analysis, whereby 
the following s ubjects will be excluded from analysis and replaced with a newly-enrolled 
subject: 
 
• 
Subjects who fail to receive at least part of 1 dose of therapy; 
 
• Subjects who withdraw consent prior to week 13 and/or are lost to follow-up, 
precluding assessment of safety and efficacy at week 13. 
 
Subjects who cli nically progress prior to week 13 and discontinue therapy, but who 
tolerate therapy up until the poi nt of disconti nuation, will not be included in the 
determination of safety, but will be i ncluded as treatment failures in the determi nation of 
ORR. 
 
9.7 
Clinical Criteria for Early Trial Termination 
 
Early trial termi nation will be the result of the criteria specified below: 
 
1.  Quality or quantity of data recordi ng is i naccurate or incomplete 
 
2.  Poor adherence to protocol and regulatory requirements 
 
3.  Incidence or severity of adverse drug reaction i n this or other studies 
indicates a potential health hazard to subjects 
 
4.  Plans to modify or disconti nue the development of the study drug 
 
In the event of a Merck decision to no longer supply study drug, ample notification wi ll 
be provided so that appropriate adjustments to subject treatment can be made. 


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Screening 
<28+7 days 
3 Week 1 
(C1D1) 
Week 4 
(C2D1) 
Week 7 
(C3D1) 
Week 10
(C4D1) 
Week 1313 
(C5D1) 
End of 
stud y 
vi sit 14 
Pembrolizumab 1 
x 
x 
x 
x 
x 
Radi ation Treatm ent 
2 
x 
Informed consent 
x 
Pathology 
x 
Medical history 
x 
EKG 
x 
PET-CT and/or MRI 4 
x 
x 
Height and wei ght 
x 
Physical examination 
x 
x 
x 
x 
x 
x 
x 
Vital signs 5 
x 
x 
x 
x 
x 
x 
x 
Perform ance status 
x 
x 
x 
x 
x 
x 
x 
Report medications 
x 
x 
x 
x 
x 
x 
x 
Report side effects 
x 
x 
x 
x 
x 
CBC 
6,7 
x 
x 
x 
x 
x 
x 
x 
CMP 
6,8 
x 
x 
x 
x 
x 
x 
x 
Thyroid function panel 
6 
(TSH, free & total T3 and 
free T4) 
x 
x 
x 
x 
x 
x 
x 
CEA, CA 15-3 & CA 19 -9 6 
x 
x 
x 
x 
x 
x 
Amylase, Lipase, Mg, LDH 6 
x 
x 
x 
x 
x 
x 
x 
Phosphorus 6 
x 
PT/INR & aP TT 6 
x 
Hepatitis B and C 6,9 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
Table 10A 


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Pregnancy test 6,10 
x 
x 
x 
x 
x 
x 
Research bl oods 6,11 
x 
x 
x 
x 
x 
x 
Research tumor biopsy
12
 
x 
x 
Optional fecal samples for 
microbiome analysis 15 
x 
x 
x 
x 
x 
x 
 
1. 
Each c ycle is approxim ately 3 w eeks in duration, co rres ponds to 1 com pleted pembrolizum ab treatm ent. 
Pembrolizum ab w il begin approxim ately 1 -3 days after s tart of RT. Subs equent cycles of pembrolizum ab will 
be given q 3 w eeks +/- 3 days . 
2. 
RT w ill begin on D1 and consis t of 3000 cGy in 5 fractions . RT w ill be adm inis tered prior to dose 1 of 
pem brolizumab and w il be com pleted w ithin 5-7 days . 
3. 
Procedures m us t be perform ed w ithin 28 days (+7 days ) prior to D1 of RT, unless other indicated. 
4. 
PE T-CT or MRI w ill be perform ed during s creening, then at w eek 13 (±1 w k), then q9 weeks (±1 w k) 
thereafter. PET-CT includes a s eparate diagnos tic CT of the ches t, abdom en and pelvis (CAP) w ith contras t. If 
patient is unable to receive CT CAP w ith contras t or the abdom inal/ pelvic target lesion is indeterm inate on CT 
then MRI w ith contras t (abdom en and pelvis ) plus CT w ithout contras t (ches t) may be performed. Im aging m ay 
be delayed up to 2 w eeks if patient is receiving additional RT. Patients w ho have received prior treatment for 
brain m etas tases w il receive brain MRIs at w eek 13 (±1 w k), then q9 weeks (±1 w k) thereafter. 
5. 
Vital s igns to include tem perature, pulse rate, respiratory rate, blood press ure and puls e oxim etry. 
6. 
E xcept for s creening/bas eline blood work, all s ubsequent blood w ork will be obtained prior to each dose of 
pem brolizumab. 
7. 
Hem atology to include s tandard com plete blood cel (CBC) panel. 
8. 
Com prehens ive metabolic panel includes: s odium , potassium , chloride, bicarbonate, BUN, creatinine, glucos e, 
total protein, album in, bilirubin, alkaline phos phatas e, AST, ALT, corrected calcium . 
9. 
Serology for HepBs Ag, HepBcAb and hepatitis C antibody (unless previous ly tes ted negative). 
10.  Urine or s erum pregnancy tes t or docum entation of absence of pregnancy by a gynecologis t is required w ithin 
2 w eeks of s tarting radiation. Serum is preferred to urine tes t. 
11.  Blood draws for res earch purposes perform ed after obtaining cons ent but prior to s tarting RT, then w eeks 1, 4, 
7,10 and 13 (±3d) for al patients . A m inimum of 4 CPT tubes of blood w ill be required at all tim epoints . 
12.  Res earch tumor biops y w ill be perform ed at bas eline (only if archived tiss ue is unavailable) and at w k 7(±1w k) 
for all patients . Additionally, up to 20 x 5 m slides (uns tained) w ill be reques ted on al patients for res earch 
purposes . 
13.  Pembrolizum ab w il continue q3w  after the w eek 13 evaluable tim epoint for up to 24 m onths or until 
progression of diseas e, w hichever comes firs t. PET-CT and/or MRI w ill be obtained q9w  (+ 1 w k) after w eek 
13 until 24 months or POD. No research bloods or fecal s am ples w ill be collected after Week 13. How ever, 
patients w ho meet s tudy criteria m ay rem ain on -s tudy after Week 13. All clinical and lab ass essm ents w ill be 
completed as outlined in table 10A w ith the exception of the res earch bloods . 
14.  End of Study vis it w ill occur 2-4 w eeks after las t dose of pem brolizumab for patients who dis continue the s tudy 
due to progress ion of dis eas e or toxicities . PET-CT or MRI to be done only if las t im aging w as conducted 
greater than four weeks prior to the date of the End of Study Vis it. 
15.  All fecal s am ples for microbiom e analys is are optional and w ill be directly m ailed by the patient in a pre -labeled 
box address ed to the laboratory for analys is . 
 
 
10.1 
Detailed explanation of required evaluations and interventions 
 
Indi vidual trial procedures are described in detail in the Table 10A above. In addition to 
evaluations/i nterventions illustrated above , it may be necessary to perform these 
procedures at unscheduled time poi nts if deemed clinically necessary by the 
investigator. 
 
Furthermore, additional evaluations/testi ng may be deemed necessary by the Sponsor 
and/or Merck for reasons related to subject safety. In some cases, such 
evaluation/testi ng may be potentially sensiti ve i n nat ure (e.g., HIV, Hepatitis C, etc.), 


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and thus local regulations may require that additional i nformed consent be obtained 
from the subject. In these cases, such evaluations/testi ng will be performed in 
accordance with those regulations. 
 
10.1.1 Informed Consent 
 
Consenting professionals must obtain documented consent from each potential subject 
prior to participating in a clinical trial. 
 
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 i nformed consent form 
and any written i nformation provided to the subject must receive the IRB‟s 
approval/favorable opinion i n advance of use.  The subject or his/her legally acceptable 
representati ve should be informed i n a timely manner if new information becomes 
available that may be relevant to the subject‟s willingness to conti nue participation in the 
trial.  The communication of this i nformation 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 requirements, applicable laws and regulations 
and Sponsor requirements. 
 
10.1.2 Inclusion/Exclusion Criteria 
 
All i nclusion and exclusion criteria will be reviewed to ensure that the subject qualifies 
for the trial. 
 
10.1.3 Medical History 
 
A medical history must be obtained and documented. Medical history will include all 
active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be cli nically significant by the Investigator. Details regardi ng the disease 
for which the subject has enrolled in this study will be recorded separately and not listed 
as medical history. 


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10.1.4 Prior and Concomitant Medications Review 
 
Prior Medications 
 
Prior medication use will be reviewed and documented, 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 i n 
this study will be recorded separately and not listed as a prior medication. 
 
Concomitant Medications 
 
Medications will be recorded, i f any, taken by the subject during the trial. All 
medications related to reportable SAEs and EC Is should be recorded as defi ned i n 
Section 11.0. 
 
10.1.5 Disease Details and Treatments 
 
Disease Details 
 
Prior and current details regarding disease status must be obtained and documented. 
 
Prior Treatment Details 
 
All prior cancer treatments i ncludi ng systemic treatments, radiation and surgeries must 
be reviewed and documented. 
 
10.1.6 Subsequent Anti-Cancer Therapy Status 
 
All new anti-neoplastic therapy initiated after the last dose of trial treatment must be 
reviewed and documented.  If a subject initiates a new anti-cancer therapy, it is advised 
that the 30 day Safety Follow-up visit occur before the first dose of the new therapy. 
Once new anti-cancer therapy has been i nitiated the subject will move i nto survival 
follow-up. 
 
10.1.7 Adverse Event (AE) Monitoring 
 
Each subject will be evaluated for potential new or worseni ng AEs as specified in the 
Trial Flow Chart and more frequently if cli nically indicated. Adverse experiences will be 
graded and recorded throughout the study and during the follow -up period according to 
NC I CTCAE Version 4.0 (see Section 11.2). Toxicities will be characteri zed in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. 
 
For subjects receivi ng treatment with pembroli zumab all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determi ne if it is 
possibly an event of cli nical i nterest (ECI) of a potentially immunologic etiology (termed 


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immune-related adverse events, or irAEs); see the separate EC I guidance document i n 
Appendix C regarding the identification, evaluation and management of potential irAEs. 
 
Please refer to section 11.2 for detailed information regarding the assessment and 
recording of AEs. 
 
10.1.8 Full Physical Exam 
 
A complete physical exam will be performed during the screeni ng period and 
documented . C linically significant abnormal fi ndings should be recorded as medical 
history. A full physical exam should be performed during screening, 
 
10.1.9 Directed Physical Exam 
 
For cycles that do not require a full physical exam per the Trial Flow Charta directed 
physical exam wi ll be performed and documented as clinically i ndicated prior to trial 
treatment admi nistration. 
 
10.1.10 Vital Signs 
 
Vital signs will be taken at screening, prior to the admi nistration of each dose of trial 
treatment and at treatment discontinuation as specified in the Trial F low Chart. Vital 
signs should i nclude temperature, pulse, respiratory rate and blood pressure. 
 
10.1.11 Eastern Cooperative Oncology Group (ECOG) Performance 
 
ECOG status (see Section 10.0 ) will be assessed at screening, prior to the 
administration of each dose of trial treatment and disconti nuation of trial treatment as 
specified in the Trial Flow C hart. 
 
10.1.12 Laboratory Procedures/Assessments 
 
After C ycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to 
dosing. Blood work must be drawn but not resulted prior to treatment. 


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10.1.13 RESEARCH BLOOD AND BIOPSY SPECIMENS 
 
10.1.13.1 Research blood 
 
For all patients, blood specimens will be obtained for research purposes during 
screeni ng, then at weeks 1, 4, 7, 10, and 13 (± 3 days). Specimens should be collected 
prior to drug administration. Four (4) CPT tubes of blood are to be collected i n BD 
Vacutainer® CPT™ Cell Preparation Tubes with Sodium Heparin. Each tube should 
contai n approximately 10 cc of blood. 
 
For MSK participants, peripheral blood mononuclear cells and plasma will then be 
isolated per i nstitutional practice i n the MSK Immune Monitoring Facility (IMF). 
 
For Cedars-Sinai participants, peripheral blood mononuclear cells and plasma will be 
isolated and prepared at Cedars-Sinai as per MSK standard operati ng procedure 
guidelines (Appendi x C). CPT tubes for research blood specimens will be provided by 
MSK. All specimens will be anonymized, contai n the subject‟s i nitials, date of birth and 
date of collection). Participants‟ full name, date of birth, date of procedure will be shared 
with MSK. A ll specimens will be stored in the laboratory of Dr. S tephen S hiao. The 
blood specimens will be batch-shipped overnight on dry ice to: 
 
 
Dr. Phillip Wong 
Memorial S loan Ketteri ng Cancer Center 
409 E. 69th St, Z-1513 
New York, NY 10065 
 
 
Shipments must occur on a Monday, Tuesday or Wednesday in order to be received by 
the MSK IMF on a Tuesday, Wednesday or Thursday. A requisition for Blood 
Specimens (Appendi x A) must accompany all specimens. Specimens will be tracked by 
the Medidata Rave database. Dr. P hilip Wong, the MSK P I and the Cedars-Sinai 
Medical Center P I will be notified by email ( wongp@mskcc.o rg; barke rc@mskcc .org; 
alice.ho@cshs.org) when shipments go out and to confirm receipt of shipments. The 
preferred courier is Federal Express overnight. 
 
Analysis of all participant’s immune markers (described in Section 12.3) will be 
performed by the MSK IMF (Dr. Philip Wong). Data will be shared throughout the 
study and at the end of study. MSK secure email or Secure File Transfer System 
will be utilized to share data across institutions. 
 
10.1.13.2 Research biopsy 
 
Pre-treatment tumor tissue wi ll be obtained during screening from archi ved tumor 
biopsy tissue performed prior to study enrollment. If archi ved tissue is unavailable, then 
a standard of care biopsy of a metastatic lesion will be obtai ned. A n on-treatment 
research biopsy will be obtained at week 7 (± 1 wk), preferably from the same site as 


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the baseline biopsy and from a non-irradiated lesion. For MSK participants, the lesion(s) 
that will be biopsied will be at the discretion of the institutional Interventional Radiologist, 
after discussion with the MSK P I. For Cedars-Sinai Medical Center participants, the 
lesion(s) that will be biopsied will be at the discretion of the institutional Interventional 
Radiologist, after discussion with the Cedars-Sinai P I. 
 
Patients will be permitted to conti nue enrollment and treatment on protocol i n the event 
that i nsufficient material was obtained from the biopsy. The on-treatment research 
biopsy will not be required if this is no longer considered appropriate at the time of the 
planned procedure, for example, if the tumor is no longer accessible or the procedure is 
deemed to be unsafe. Tumor lesions planned for on-treatment biopsy may be an index 
lesion if  2 cm i n at least one diameter. 
 
If technically feasible, subjects will undergo up to 5 core biopsies. The first three core 
biopsies will be placed in formali n and processed for FFPE ; an additional 2 core 
biopsies will be immediately frozen in liquid nitrogen and then stored at -80°C (Appendix 
B). The mi nimum core length is 6mm. 
 
 
For MSK participants, a ll tissue obtai ned duri ng biopsy procedures will be sent to Dr. 
Hannah Wen at MSK Pathology for analysis. 
 
For Cedars-Sinai participants, biopsy specimens wi ll be obtained according to the same 
instructions as detailed above for MSK participants. A ll specimens will be anonymi zed, 
contai n the subject‟s i nitials, date of birth and date of collection. Participants‟ full name, 
date of birth, date of procedure will be shared with MSK. All specimens will be stored i n 
the laboratory of Dr. Stephen S hiao. For every 5 specimens collected, tissue will then 
be batch-shipped every overnight at ambient room temperature to: 
 
 
Dr. Hannah Wen 
Department of Pathology 
MSK 
New York, NY 10065 
 
 
Shipments must occur on a Monday, Tuesday or Wednesday in order to be received by 
the MSK IMF on a Tuesday, Wednesday or Thursday. A requisition for Biopsy 
Specimens (Appendi x B) must accompany all submitted specimens. Specimens will be 
tracked by the Medidata Rave database. Dr. Hannah Wen, the MSK P I and the Cedars- 
Sinai PI will be notified by email (weny@mskcc.o rg; 
barkerc@mskcc.org;alice.ho@cs hs .org) when shipments go out and to confirm receipt 
of shipments. The preferred courier is Federal E xpress overnight. 


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For all participants, analysis of the biopsy specimens will be performed at MSK by Dr. 
Hannah Wen. Treatment response (treatment effects, tumor cellularity) i n on-treatment 
biopsy and TILs count i n the pre- and post- treatment biopsies will be evaluated on the 
H&E stained sections. Immunohistochemical stains for PD -1, PD-L1, and T-cell markers 
(CD3, CD4, CD8, FOXP3, CD25) will be performed at the MSK Pathology Core Facility 
using established protocols with appropriate controls. The immunohistochemical stained 
sections will be reviewed by Dr. Hannah Wen. PD-1 and PD-L1 expression in tumor 
cells and in TILs will be scored separately. The expression of T-cell markers will be 
analyzed in TILs and any changes of expression between baseli ne and on-treatment 
biopsies will be noted. 
 
 
IHC staini ng for ER, P R and HER2 testi ng will be performed at the enrolling institution. 
Data will be shared throughout the study and at the end of study. MSK secure emai l or 
Secure File Transfer S ystem will be utilized to share data across institutions. 
 
10.1.14 Tumor Imaging Assessments 
 
The preferred imaging modality is PET-C T, which will be obtained as per the flow chart 
schedule. The CT portion of the PET-CT will be a separate dedicated CT scan of the 
chest, abdomen, and pelvis (CAP) with intravenous (IV ) and oral contrast, from which 
measurements will be made for the primary endpoi nt of objective response rate using 
RECIS T v. 1.1. If patient is unable to recei ve IV contrast for the CT, or if the lesion is 
indetermi nate on C T, then MRI with IV contrast (of abdomen and pelvis)  could be 
performed. The CT component of the PET-CT will remain a diagnostic CAP with oral 
contrast, but no IV contrast. 
 
Patients who have received prior treatment for brain metastases will receive additional 
brain MRIs at week 13 (±1 wk), then q9 weeks (±1 wk) thereafter, in order to evaluate 
response   in   the   brai n.   These   assessments   will   be   included   in  the   REC IST 
measurements. 
 
 
 
For Cedars-Sinai participants, all study imagi ng wi ll be performed at Cedars-Sinaiand 
follow the above guidelines. RECIS T reads for the primary endpoint will be performed at 
Cedars-Sinai. For analysis of the secondary endpoints of immune-related response 
criteria and PET response criteria, all PET-C T scan imagi ng wi ll be submitted 
electronically to MSK co-P I Dr. Lizza Lebron-Zapata for irRC and PRC analyses. Patient 
name, date of birth, date of procedure and relevant medical history will be shared with 
MSK. Data wi ll be shared throughout the study and at the end of study. The imagi ng 
studies will be sent by Secure File Transfer system to Dr. Li zza Lebron-Zapata at 
lebronzl@mskcc.org or by CD-rom mailed to: 
 
Dr. Lizza Lebron-Zapata 
Memorial S loan-Ketteri ng Cancer Center 
Radiology Department 
500 Westchester Avenue 


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West Harrison, NY 10604 
  
 
10.1.15 Withdrawal/Discontinuation 
 
When a subject discontinues/withdraws prior to trial completion, all applicable acti vities 
scheduled for the final trial visit should be performed at the time of disconti nuation. Any 
adverse events, which are present at the time of discontinuation/withdra wal, should be 
followed i n accordance with the safety requirements outlined i n Section 11.2 - 
Assessing and Recordi ng Adverse E vents. S ubjects who a) attain a CR or b) complete 
24 months of treatment with pembrolizumab may disconti nue treatment with the o ption 
of restarti ng treatment if they meet the criteria specified in Section 9.5. A fter 
discontinui ng treatment following assessment of CR, these subjects should return to the 
site for a Safety Follow-up Visit (described in Section 10.1.16.1) and then proceed to the 
Follow-Up Period of the study (described in Section 10.1.16.2). 
 
 
 
 
10.1.16 Visit Requirements 
 
Visit requirements are described below. 
 
10.1.16.1 Safety Follow-Up Visit 
 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after 
the last dose of trial treatment or before the initiation of a new anti -cancer treatment, 
whichever comes first. All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded. Subjects with an AE of Grade > 1 will be followed until the resolution of the 
AE to Grade 0-1 or until the beginni ng of a new anti-neoplastic therapy, whichever 
occurs first. SAEs that occur withi n 90 days of the end of treatment or before initiation 
of a new anti-cancer treatment should also be followed and recorded. S ubjects who are 
eligible for retreatment with pembroli zumab may have up to two safety follow-up visits, 
one after the Treatment Period and one after the Second Course Phase. 
 
10.1.16.2 Follow-up Visits 
 
Subjects who disconti nue trial treatment for a reason other than disease progression will 
move into the Follow-Up P hase and should be assessed every 12 weeks (84 ± 7 days) 
by radiologic imaging to monitor disease status. Every effort should be made to collect 
information regarding disease status until the start of new anti -neoplastic therapy, 
disease progression, death, end of the study or if the subject begi ns retreatment with 
pembrolizumab as detai led in Section 9.5. Information regarding post-study anti- 
neoplastic treatment will be collected if new treatment is i nitiated. 


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Subjects who are eligible to receive retreatment with pembroli zumab according to the 
criteria in Section 9.5 wi ll move from the follow-up phase to the Second Course P hase 
when they experience disease progression. Details are provided i n Section 9.6 . 
 
10.1.16.3 Survival Follow-up 
 
Once a subject experiences confirmed disease progression or starts a new anti -cancer 
therapy, the subject moves into the survi val follow -up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 
Summary of toxicities of agents 
 
11.1.1 Pembrolizumab 
 
Pembrolizumab is an FDA-approved agent on formulary for the treatment of metastatic 
melanoma. It is investigational for use i n metastatic TNBC. A comprehensi ve list of 
toxicities may be found i n Lexicomp and i n the investigator‟s brochure. Principal side 
effects of pembroli zumab are listed in table 11.1.1A. 
 
Table 11.1.1A: Principal side effects of pembrolizumab 
 
Cardiovascular 
Peripheral edema 
Central Nervous 
System 
Fatigue, headache, chills, insomnia, dizziness, optic neuritis (rare), uveitis 
(rare) 
Endocrine 
Hyperglycemia, hyponatremia, hypoalbuminemia, hypertriglyceridemia, 
hypocalcemia, adrenal insufficiency (rare), hypophysitis (rare) 
GI 
Nausea, decreased appetite, constipation, diarrhea, vomiting, abdominal 
pain, pancreatitis (rare), increased serum AST, hepatitis (rare) 
Heme 
Anemia, hemolytic anemia (rare) 
Neurological/Muscular
Arthralgias, limb pain, myalgia, back pain, arthritis (rare), Lambert-Eaton 
syndrome (rare), myositis (rare), partial epilepsy (rare), rhabdomyolysis 
(rare), 
Respiratory 
Cough, dyspnea, upper respiratory tract infection 
Miscellaneous 
Fever 
Dermatologic 
Exfoliative dermatitis (rare) 
Renal 
Interstitial nephritis (rare), nephritis (rare), 
 
11.1.2 Toxicities of Radiation Therapy 
 
Toxicities may occur from radiation treatment. The type and risk of toxicity will depend 
on the presence of normal tissue structures i n close proximity to the target. These 
normal tissue doses will be constrai ned by the treatment plan to deliver doses no more 


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than those recommended in the MSK Department of Radiation Onco logy guidelines: 
(http://teams hare/dep t/medp hys/eb tp/P ublic%20Docume nts/Forms /Pub lic%20View.asp 
x). These guidelines will be shared with and followed by Cedars-Sinai. 
 
The estimated risks of each type of toxicity are noted below, and include: 
 
1. Grade 2-3 ski n (erythema, dry or moist desquamation, patchy ulceration) - 10% 
2. Grade 1-2 non-debilitating fatigue- 30% 
 
3. Any grade brachial plexopathy- 5-7% 
4. Grade 3 bowel (bowel perforation, obstruction or hemorrhage) - 2-5% 
5. Grade 2-4 peripheral nerve (neuropathy or severe neuropathic pain unresponsi ve 
to medications)-2-5% 
6. Grade 2-4 b ladder (hemorrhagic cystitis, chronic cystitis mani festing in frequency 
and urgency) - 2-5% 
7. Grade 2-4 rectum (injury including ulceration or perforation)-2-5% 
8. Grade 2-4 osteonecrosis or bone fracture- 5-10% 
 
 
11.2 
Assessing and Recording Adverse Events 
 
An adverse event is defi ned as any untoward medical occurrence i n a patient or cli nical 
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 uni ntended sign (i ncludi ng an abnormal 
laboratory fi nding, for example), symptom, or disease temporally associated with the 
use of a medicinal product or protocol-specified procedure, whether or not considered 
related to the medicinal product or protocol-specified procedure. Any worseni ng (i.e., 
any clinically significant adverse change i n frequency and/or intensity) of a preexisti ng 
condition that is temporally associated with the use of the Merck‟s product, is also an 
adverse event. 
 
Merck product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (i ncludi ng 
placebo or active comparator medication) or marketed, manufactured by, licens ed by, 
provided by or distributed by Merck for human use. 
 
Adverse events may occur duri ng the course of the use of Merck product in cli nical trials 
or withi n the follow-up period specified by the protocol, or prescribed in cli nical practice, 
from overdose (whether accidental or intentional), from abuse and from withdrawal. 


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Adverse events may also occur in screened subjects duri ng any pre-allocation baseli ne 
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 followi ng cessation of treatment and at each exami nation on the Adverse E vent 
case report forms/worksheets. The reporting timeframe for adverse events meeting any 
serious criteria is described in section 11.2. 
 
11.3 Definition of an Overdose for This Protocol and Reporting of Overdose 
to the Sponsor and to Merck 
 
For purposes of this trial, an overdose of pembrolizumab wi ll 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 i ndicated. In the event of overdose, the subject should be 
observed closely for signs of toxicity. Appropriate supporti ve treatment should be 
provided if clinically i ndicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck 
product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
 
If a dose of Merck‟s product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious E vent of Cli nical Interest (EC I), usi ng the terminology 
“accidental or intentional overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 
hours to the Sponsor and within 2 working days hours to Merck Global Safety. (A ttn: 
Worldwide Product Safety; FAX 215 993-1220) 
 
11.4 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation i n a 
subject (spontaneously reported to them)or 30 days followi ng cessation of treatment if 
the subject initiates new anticancer therapy, whichever is earlier. A ll 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 


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reported as serious events (Important Medical E vents).  If the pregnancy conti nues to 
term, the outcome (health of infant) must also be reported. 
 
Such events must be reported withi n 24 hours to the Sponsor and withi n 2 worki ng days 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993 -1220) 
 
11.5 
Immediate Reporting of Adverse Events to the Sponsor and to Merck 
 
11.5.1 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 existi ng i npatient hospitali zation; 
• 
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 11.6-1 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it 
results in hospitalization or death. 
 
Any serious adverse event, or follow up to a serious adverse event, i ncludi ng death due 
to any cause other than progression of the cancer under study that occurs to any 
subject from the time the consent is signed through 90 days followi ng cessation of 
treatment, or the initiation of new anti-cancer therapy, whichever is earlier, whether or 
not related to Merck product, must be reported withi n 24 hours to the Sponso r and 
withi n 2 working days to Merck Global Safety. 
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs. 
 
Additionally, any serious adverse event, considered by an 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 the Sponsor and to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number: +1-215-993-1220 


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A copy of all 15 Day Reports and A nnual Progress Reports is submitted as required by 
FDA, European Union (E U), 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 i nvestigators will submit a copy of these reports to 
Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of 
submission to FDA. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
11.5.2 Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (EC I) and must be recorded as such on the Adverse Event case report 
forms/worksheets and reported within 24 hours to the Sponsor and withi n 2 worki ng 
days to Merck Global Safety. (A ttn: Worldwide Product Safety; FAX 215 993- 
1220)Events of clinical interest for this trial i nclude: 
 
1. An overdose of Merck product, as defined in Section 7.2.1 - Defi nition of an Overdose 
for This Protocol and Reporti ng of Overdose to t he Sponsor, that is not associated 
with cli nical 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 bilirubi n lab value that is greater than or e qual to 2X the 
upper limit of normal and, at the same time, an alkali ne phosphatase lab value that is 
less than 2X the upper limit of normal, as determi ned by way of protocol-specified 
laboratory testi ng or unscheduled laboratory testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equi valent). 
 
11.5.3 Additional adverse events 
 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “E vent of Clinical Interest and Immune - 
Related Adverse Event Guidance Document”).  This document can be found in 
Appendix C and pro vides guidance regarding identification, evaluation and 
management of ECIs and irAEs. 
 
ECIs (both non-serious and serious adverse events) identified i n this guidance 
document from the date of first dose through 90 days following cessation of treatment, 


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or 30 days after the i nitiation of a new anticancer therapy, whichever is earlier, need to 
be reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220), regardless of attribution to 
study treatment, consistent with standard SAE reporting guideli nes. 
 
Subjects should be assessed for possible EC Is prior to each dose. Lab results should 
be evaluated and subjects should be asked for signs and symptoms suggesti ve of an 
immune-related event. S ubjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes.  If lab results or 
symptoms i ndicate a possible immune-related EC I, then additional testi ng should be 
performed to rule out other etiologic causes.  If no other cause is found, then it is 
assumed to be immune -related. 
 
11.6 Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events according to 
the NC I Common Termi nology for Adverse E vents (CTCAE), version 4.0. A ny 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 C TCAE grade must a lso be evaluated for seriousness. 


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Table 11.6A:  Instructions of how an investigator should evaluate all adverse events 
 
V4.0 CTCA E 
Grading 
Grade 1 
M ild; as ym ptom atic or m id s ym ptom s ; clinical or diagnos tic obs ervations only; inte rvention not indicate d. 
Grade 2 
M oderate ; m inim al, local or noninvas ive interve ntion indicated; lim iting age -appropriate ins trum ental ADL. 
Grade 3 
Se ve re or me dically s ignificant but not imm e diate ly life -thre ate ning; hos pitalization or prolongation or hos pitalization 
indicate d; dis abling; lim iting se lf-care ADL. 
Grade 4 
Life thre ate ning conse que nces ; urge nt inte rvention indicate d. 
Grade 5 
De ath re late d to AE 
Se rious ness 
A serious adverse even t is a ny adverse eve nt occurrin g at any dose or dur ing any use of Merck pro duct th at: 
†Re s ults in de ath; or 
†Is life thre ate ning; or places the su bj ect, in the view of the investig ator, a t imme diate r isk of de ath f ro m th e even t as i t occurred ( Not e: Th is do e s not 
inclu de a n adverse event t hat, had it occurred in a more severe f or m, mig ht h ave caused dea th.); or 
†Re s ults in a pe rs iste nt or s ignificant dis ability/incapacit y (substant ia l d isruption of on e‟s a bility t o cond uct nor mal lif e f unctio ns); or 
†Re s ults in or prolongs an e xis ting inpatie nt hos pitalization (hospitaliza tio n is def ined as an in pat ient ad missio n, reg ardless of le ng th of stay, 
even if the hosp ita lizat ion is a precaut ion ary measure f or cont inu ed o bservatio n. ( Not e: Hospita lizatio n [ inclu ding h ospit ali zation f or an e l ective 
procedure] f or a preexisti ng con dit io n w hich has not w orsened does not const itut e a ser ious a dve rse event.); or 
†Is a conge nital anom aly/birth de fe ct (in of fspring of subject t akin g th e prod uct regard less of ti me to di agn osis);or 
Is a new cance r; (that is not a con dit ion of the stu dy) or 
Is an ove rdose (w hether accidenta l or int ent iona l).  Any adverse event associated w ith an overdose is consi dered a serio us adverse ev ent. An 
overdose th at is not associ ated w ith an adverse eve nt is co nsidere d a non-seri ous event of clin ical int erest an d must be re porte d w ithin 24 ho urs. 
Othe r im portant me dical e ve nts that may n ot resul t i n de ath, not be lif e thre aten ing , or n ot req uire hospi talizat ion may be consid ered a serious 
adverse event w hen, base d up on appro priat e me dica l judg men t, th e even t may jeo pard ize the s ubj ect an d may requ ire medica l or surg i cal 
intervent io n to prevent one of the o utco mes liste d previ ously (des ign ated above by a †). 
Duration 
Recor d the start an d stop dat es of the adverse event. If l ess than 1 day, in dicat e the appr opria te len gth of time and un its 
Action tak e n 
Did t he a dverse event ca use th e Merck prod uct to be d iscont inue d? 
Re lations hip 
to tes t drug 
Did t he Merck pro duct cause the adverse even t? Th e de ter minat ion of the like lih ood that the Merck prod uct caused t he a dverse event w il l be provid ed 
by an i nvestig ator w ho is a qu alif ied p hysician . The invest igat or‟s sig ned/ date d i nit ia ls on t he source docu ment or w orksheet that su ppor ts the 
causality note d on the A E f orm, ensures t hat a me dica lly q ua lif ied assessment of causa lity w as done. Th is in itialed d ocu me nt must be r e tain ed f or the 
require d regu lat ory ti me f ra me. Th e criter ia b elow are int end ed as ref erence g uidelin es to assist t he investi gator  in assessi n g th e l ikeliho od of a 
relat ionsh ip b etw een the t est drug and the adverse even t base d up on t he ava ilable inf ormation. 
The follow ing compone nts are to be us e d to as sess the re lations hip be twe e n the M erck product and the AE ; the great er the correlat ion w ith 
the co mpon ents an d th eir respect ive e le ments (i n nu mb er and /or i ntens ity), the more like ly the Merck prod uct caused t he adverse event (AE): 
Expos ure 
Is th ere evi dence that the su bj ect w as actually exposed to t he Merck pro duct such as: re li ab le h istory, accepta ble co mp liance 
assessment (pi ll co unt, diary, etc.), expecte d ph ar maco log ic ef f ect, or measure ment of drug/ metab olite in bod ily spec i me n? 
Time Cours e 
Did t he A E f ollow in a reaso nab le t e mp oral se que nce f rom ad min istrat ion of the Merck pro duct? 
Is th e t i me of onset of the A E co mp atible w ith a drug-i nduce d ef f ect (applies to tr ials w ith invest igat io nal me dicinal prod uct)? 
Lik e ly Cause 
Is th e A E n ot reaso nab ly explained by ano ther e tio lo gy such as und erlyi ng d isease, oth er drug(s)/vaccine(s), or oth er host or 
environ ment al f actors 
Re lations hip 
The follow ing compone nts are to be us e d to as sess the re lations hip be twe e n the tes t drug and the AE: (continue d) 


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De challe nge 
Was th e Merc k prod uct d iscontin ued or dose /exposure/f reque ncy reduced ? 
If yes, di d the A E resolve or i mprove? 
If yes, this is a p ositive decha l leng e. If no, this is a n egat ive d echalle nge. 
(Not e: Th is criteri on is not app lica ble if : (1) the A E result ed in d eat h or p er man ent disab ility; (2) t he A E reso lved/ improved d espit e 
contin uat ion of the Merck pro duct; or (3) t he tr ial is a s ing le-dose drug tr ia l); or (4) Merck pro duct(s) is/are o nly use d on e ti me.) 
Re challe nge 
Was th e sub ject re-expose d to t he Merck product in t his study? 
If yes, di d the A E recur or w orsen? 
If yes, this is a p ositive rechal le nge. If no, th is is a neg ative r echallen ge. 
(Not e: Th is criteri on is not app lica ble if : (1) the in itial A E result ed in d eat h or p er man ent disab ility, or (2) t he t r ial is a s ing le-dose 
drug tri al); or ( 3) Merck product(s) is/are used only one t i me). 
NOTE: IF A RECHA LL ENGE IS PLA NNED FOR A N A DV ERSE EV ENT WHICH WA S SERIOUS A ND WHICH MAY HAV E BEEN 
CA USED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT  POSES ADDITIONA L POTENTIA L 
SIGNIFICA NT RISK TO THE SUBJECT, THEN THE RECHALL ENG E MUST BE A PPROV ED IN A DVANCE BY THE U. S. 
CL INICAL MONITOR AS PER DOSE MODIFICA TION GUIDEL IN ES IN THE PROTOCOL . 
Cons is te ncy 
w ith Trial 
Tre atme nt 
Profile 
Is th e cl inica l/p atho lo gica l presen tat ion of the A E cons istent w ith previo us know ledge reg arding th e Merck pro duct or dr ug cl ass 
phar maco lo gy or toxico logy? 
Th e assessment of relat ionsh ip w ill b e report ed o n th e case rep ort f orms /w orksheets by a n i nvestiga tor w ho is a qu al if ied p hysician accordin g to his/h er best cl in ical 
judg men t, inclu din g consi derat ion of the a bove e le ments. 
Re cord one of the follow ing 
Us e the follow ing s cale of crite ria as guidance (not all crite ria m ust be prese nt to be indicative of a M e rck product 
re lations hip). 
Ye s , the re is a re as onable 
poss ibility of M erck product 
re lations hip. 
Th ere is ev ide nce of exposure t o the Merck prod uct.  The te mpora l sequ ence of th e A E o nset relative to t he a d ministrat io n of the 
Merck pro duct is reasona ble .  The A E is more li ke ly explain ed by the Merck product t han by an other cause . 
No, the re is not a re as onable 
poss ibility M erck product 
re lations hip 
Sub ject d id not rece ive th e Merck prod uct OR te mpor al seq uence of the A E onset re lat ive to ad min istration of the Merck prod uct is 
not reaso nab le OR t here is an other obvio us cause of the A E.  (Also e ntered f or a subj ect w ith overdose w ithout an associate d A E.) 
 
 
 
to M erck 
product 
(continue d) 


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11.7 Sponsor Responsibility for Reporting Adverse Events 
 
All Adverse E vents will be reported to regulatory authorities, IRB/IECs and 
investigators i n accordance with all applicable global laws and regulations. 
 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1. Evaluation o f Primary Endpoint 
The primary endpoint of the pilot phase is to Overall Response Rate in unirradiated lesion(s) 
(Complete Response + Partial Response), as defi ned by REC IST v. 1.1. The definitions of 
CR and PR are specifically described in Section 12.1.1. 
 
12.1.1 Response Assessments 
 
For the purposes of this study, patients will be evaluated for response at Week 13 (+1 wk), 
then every 3 cycles (approximately 9 weeks, +1  wk), or as clinically indicated if interim 
toxicity occurs  mandati ng cancer staging  re-assessment. RECIS T v. 1.1 criteria will be 
used. 
 
CT sca n with co ntrast o f the c hest, abdome n, and pelvis 
 
• CT scans should be performed with contiguous cuts in slice thickness of 5 mm or 
less. Spiral CT should be performed using a 5-mm contiguous reconstruction 
algorithm. 
 
MRI sca ns 
 
• 
MRI of the abdomen and pelvis is acceptable for measurement of lesions provided 
that the same anatomical plane is used for serial assessments. If possible, the same 
imaging device should be used for serial evaluations. In case of MRI, measurements 
will be preferably performed in the axial (transverse) plane on contrast-enhanced 
T1-weighted images. However, there are no specific sequence recommendations. 
 
• 
Patients who have recei ved prior treatment for brain metastases  will also rece i ve 
brain MRIs at week 13 (±1 wk), then q9 weeks (+1 wk) thereafter, in order to evaluate 
response  in  the  brai n.  These  assessments  will  be  included  in  the  REC IST 
measurements. 
 
 
Measurability of Tumor Lesions 
 
Tumor lesions will be categori zed as follows: 
 
• 
Measurable Lesions -   Must be accurately measured i n at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum 
size of: 


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• 
10 mm by CT scan (irrespecti ve  of scanner type) and  MRI (no  less  than 
double the slice thickness and a minimum of 10 mm) 
 
• 
10 mm caliper measurement by cli nical exam (when superficial) 
 
• 
Malignant   lymph   nodes   are   considered   pathologically   enlarged   and 
measurable, a lymph node must be ≥ 15 mm i n short axis when assessed by 
CT scan (C T scan slice thickness recommended to be no greater than 5 mm). 
 
• 
Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions 
(or  sites  of  disease),  i ncludi ng  small  lesions  (longest  diameter  <  10  mm  or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis). Lesions considered truly 
nonmeasurable    i nclude     the    following:     leptomeni ngeal    disease,    ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
• 
Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 2 
lesions per organ) representati ve of all i nvolved organs should be identified as target 
lesions. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement i n which circumstance the next largest lesion which can 
be measured reproducibly should be selected. 
 
• 
Non-target Lesions - It is possible to record multiple nontarget lesions i nvolvi ng the 
same organ as a single item on the case record form (e.g., “multiple enlarged pelvic 
lymph nodes” or “multiple liver metastases”) 
 
 
Response Criteria 
 
Evaluation of Target Lesions 
 
• 
Complete Response - Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm 
(the sum may not be “0” if there are target nodes). 
 
• 
Partial Response - At least a 30% decrease i n the sum of the diameters of targe t 
lesions, taki ng as reference the baseli ne sum diameters. 
 
• 
Progressive Disease - At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study). In addition to the relative i ncrease of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered progression.) 
 
• 
Stable Disease - Neither sufficient shrinkage to qualif y for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum of diameters while on study. 


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Evaluation of Non-target Lesions 
 
• 
Complete Response - Disappearance of all non-target lesions and normali zation of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
 
• 
Non-complete  response/Non-progressive  disease   (Partial  Response/Stable 
Disease) - Persistence of 1  or  more  non-target lesion(s) and/or maintenance  of 
tumor marker level above the normal limits. 
 
• 
Progressive Disease - Unequi vocal progression of existing non-target lesions will be 
defined as the overall level of substantial worseni ng in non-target disease suc h that, 
even in presence of SD or PR in target disease, the overall tumor burden has 
increased  sufficiently  to  merit  discontinuation  of  therapy.  In  the  absence  of 
measurable disease, change in non-measurable disease comparable in magnitude to 
the increase that would be required to declare PD for measurable disease. Examples 
include an increase in a pleural effusion from „trace‟ to „large,‟ an increase in 
lymphangitic disease from locali zed to widespread. 
 
 
 
Appearance of New Lesions 
 
The appearance of new lesions is considered PD according to RECIST v 1.1 guidelines. 
Considering the unique response kinetics that have been observed with immunotherapy, 
new  lesions  may  not  represent  true  disease  progression  (Wolchok,  Hoos  et  al.2009) 
Subjects i nitially assessed as PD by modified RECIST v 1.1 criteria, in the absence of 
significant clinical deterioration warranti ng disconti nuation of study treatment wi ll conti nue 
treatment and receive a confirmatory scan at least 4 weeks later. The followi ng criteria will 
be used to determine if study treatment will be conti nued: 
 
• If the tumor burden at the confirmatory scan is >20% larger than the tumor burden at 
the i nitial PD scan, the subject will be considered to have confirmed PD and will be 
discontinued from study treatment. 
 
• If the tumor burde n at the confirmatory scan is withi n 20% of the tumor burden at the 
initial PD scan, the subject wi ll be considered to have SD and will continue treatment 
until  the  next  scheduled  scan  3  months  after  the  initial  PD .  Any  subsequent 
scheduled tumor assessment visit showing that the tumor burden is >20% larger than 
the tumor burden at the initial PD scan will be considered as confirmed PD, and the 
subject will be discontinued from study treatment. 
 
• In subjects  with  new  lesions  i n the  setti ng  of overall  response, the  decision  to 
conti nue treatment will be discussed on a case by case basis between the P I and 
study monitor. 


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• 
It is important to maintain the schedule of assessments every 3 months and subjects 
having  confirmatory  scans  for  PD  must  return  for  the  next  scheduled  visit  per 
protocol. 
  
 
Evaluation of Overall Response 
 
Table 12.0 provides overall responses for all possible combi nations of tumor responses in 
target and non-target lesions with or without the appearance of new lesions. 
 
 
Table 12.0 
Evaluation of Overall Response 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete 
response 
Complete response 
No 
Complete response 
Complete 
response 
Not evaluable 
No 
Partial response 
Complete 
response 
Non-complete response / 
non-progressi ve disease 
No 
Partial response 
Partial response 
Non-progressi ve disease 
and 
not evaluable a 
No 
Partial response 
Stable disease 
Non-progressi ve disease 
and 
not evaluable a 
No 
Stable disease 
Not all evaluated 
Non-progressi ve disease 
No 
Not evaluable 
Progressive 
disease 
Any 
Yes/No 
Progressive 
disease 
Any 
Progressive disease 
Yes/No 
Progressive 
disease 
Any 
Any 
Yes 
Progressive 
disease 
a Not evaluable is defined as either when no or only a subset of lesion 
measurements are made at an assessment. 
 
 
 
12.2 
Evaluation of Secondary and Exploratory Endpoints 
 
 
12.2.1 Secondary Endpoint:  Evaluation by immune-related response 
criteria (irRC) 


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Because irREC IST not yet been validated in breast cancer, we propose assessing disease 
control with irRC as a secondary objective. We will assess disease control at 13 weeks 
using immune-related response criteria (irRC) (Wolchok, Hoos et al. 2009). irRC involves 
assessment of non-targeted, non-irradiated lesions. Response is defined as irCR, irPR or 
irSD over a period of at least 4 weeks. Imaging before the week 13 time point will not be 
specified, to account for the possibility that a subset of patients will experience an immune- 
relate response, by which response are preceded by radiographic progression, related to 
delayed response kinetics and/or T-cell tumoral infiltration. 
 
 
 
12.2.2 Exploratory Endpoint:  Evaluation by PET Response Criteria (PRC) 
 
In subjects recei ving PE T-CT, radiographic response by PE T will be compared to standard 
assessment with CT CAP. This comparison will help evaluate whether metabolic uptake 
might be useful in distinguishing clinical response to immunotherapy in breast cancer 
patients, who are frequently evaluated off-protocol with PE T/CT. 
 
PET-CT is commonly used as a standard-of-care modality for evaluati ng response to 
palliative therapy in metastatic breast cancer. However, on study, response to treatments is 
often measured anatomically using the REC IST v 1.1 guidelines. However, there are 
limitations in usi ng anatomic response criteria alone, particularly when evaluating bone 
metastases without an extraosseous component, which is common in breast cancer 
patients. F urthermore, while REC IS T criteria may be appropriate for evaluating response to 
conventional cytotoxic therapies, they may not be ideal for evaluati ng response i n the 
setting of dynamic i nfiltration with immunotherapy. 
 
“PERC IST” (PET Response Criteria in Solid Tumors), is a commonly proposed method for 
measuri ng treatment response based on metabolic response criteria with PET [69]. A 
limitation of PERC IS T is that it only takes i nto account the single hottest lesion and it relies 
upon SUV peak measurements, which are not easily reproducible in lesions with low FDG - 
avidity, as are often found in breast cancer. Since there are no standardi zed methods for 
quantifyi ng FDG-tracer avidity i n i ndividual tumor lesions, we will use a modification of 
PERCIST criteria called “PET Response Criteria” (PRC) that is currently bei ng utili zed i n 
other cancer protocols at MSK requiring metabolic assessment. In brief, the S UVmax of 
tumor(s) will be measured and recorded. In order to be consistent with the definition of 
overall response as defined i n the primary endpoi nt, only non-targeted, non-irradiated 
tumor(s) will be assessed by P RC. On subsequent studies, the same target lesion will be 
measured and recorded. Lesions where SUVmax is no greater than background will be 
recorded as zero. 
 
According to PRC, response or progression will be graded as follows: 
 
CR: All lesions no greater than background SUVmax 
 
PR: SUVmax decreased by >30% greater than background 


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SD: Lesions that do not fit criteria for response or progression 
 
PD: SUM SUVmax increased by >30% or development of a new lesion within the 
radiated field 
 
 
 
We anticipate that the most common discrepancy between PRC and REC IST v 1.1 will be 
whe n there is a CR on PRC, but PR on RECIS T v 1.1. In these cases, RECIS T v 1.1 (and 
not PRC) will be utilized for response assessment. RECIS T measurements will be done on 
the dedicated CT portion of the PET/CT. 
 
12.3 Correlative Studies 
 
Changes in immunologic biomarkers may be evaluated for associations with overall 
response rate and safety (adverse event) data. Core biopsies may be used for correlati ve 
studies such as IHC, tumor mutation analysis, proteomic analysis, and immunodiversity. 
PDL-1 immunohistochemistry will be done by a Merck designated laboratory. Other 
correlati ve s tudy assessments wi ll be done at MSK. 
 
12.3.1 Whole Blood 
 
Flow cytometry will be performed on baseline and on-treatment to assess baseli ne and 
changes in composition/acti vation status of lymphocyte subsets present in peripheral blood 
mononuclear cell preparations (PBMCs). Assays may include evaluation of frequencies of 
CD8+ and CD4+ T-cell subsets (activated/ effector/ regulatory) and their expression of 
activation, exhaustion, and proliferati ve markers such as IC OS, Ki-67, PD-1, CTLA-4, LAG-3 
and TIM-3. Additional analysis of T cell function i n select samples via analysis of production 
of intracellular cytokines such as IF N-gamma upon acti vation may be included.  NK cell 
populations may be monitored in a similar fashion with a focus on characterizi ng subsets 
defined by the expression of acti vation markers (e.g. NKG2D; IL-21R) and/or by markers 
that are associated with the potential of NK cells to lyse target cells (e.g., CD107a, 
granzyme, perforin). Additional flow cytometry-based assays will focus on defi ning and 
monitori ng the abundance of myeloid-deri ved suppressor cells (MDSCs), a cell type which 
appears to negati vely impact anti-tumor acti vity and which has been shown to promote 
immune escape by limiti ng acti vated CD8 T-cell infiltration into the tumor microenvironment 
[25]. Immune cells may be evaluated usi ng HLA-A2-restricted tetramer assays to detect and 
quantify the presence of T cells directed agai nst specific antigens that are anticipated to be 
presented to the immune system during study treatment. Detecti ng on-treatment i ncreases 
in these T cell populations may be considered evidence of adaptive immune responses i n 
TNBC 
 
12.3.2 Plasma 
 
To understand the prevalence of circulating proteins and the impact they may have on the 
clinical activity and/or safety of pembroli zumab treatment, the protei n concentrations of a 
panel of cytokines, chemoki nes, and other relevant immunomodulatory, soluble factors may 


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be investigated by ELISA and/or other relevant multiplex-based protein assay methods. 
Examples of analyses to be assessed may include but are not limited to factors i nduced by 
IF Nγ signali ng (e.g., T cell chemoattractants CXCL9; CXCL10) and ot her factors generally 
involved i n i nflammatory processes. Plasma may be used also to assess the presence 
and/or concentration of anti-tumor antibodies using a multiplex platform such as Invitrogen‟s 
Protoarray platform(c). Levels of sPD-L1 in peripheral blood may also be assessed. 
 
12.3.3 Tumor Tissue 
 
The presence of TILs withi n tumors i n response to pembroli zumab treatment will be 
evaluated baseli ne and on-treatment biopsies. Archived tissue (up to 20 x 5 m unstained 
slides) and biopsy tissue may be analyzed usi ng immunohistochemistry for PD-L1 
expression and other immune-related genes, and gene expression (Nanostring and/or RT- 
QPCR) research platforms. Laser Capture Microdissection may be uti lized to enrich specific 
regions of tumor material for use in similar or additional downstream applications, which 
may include in-situ hybridization, flow cytometry, ELISA, targeted sequencing using MSK- 
IMPACT platform, and/or assessment of mi RNA. MSK IMPACT testing will be done on 
tumor tissue from Cedars-Sinai patients, if possible. At MSK, patients will sign MSK IRB#12- 
245 to have MSK IMPACT testing. At Cedars-Sinai, patients either sign similar genetic 
profiling institutional protocols or i nformation about the genetic profiling will be placed i n the 
study consent form. 
 
In all cases, the goal may be to determine the abundance of a battery of immunoregulatory 
genes or protei ns associated with cancer cells and/or cancer-i nteracting lymphocytes 
derived from biopsied material. Other biomarkers may be evaluated as de termi ned by 
additional data. Remaini ng specimens may be stored for future studies related to TNBC 
immunity. 
 
 
 
12.3.3.1 MSK IMPACT Testing 
 
The consent indicates that samples and genetic information collected may be shared with 
other qualified researchers and placed in online databases. An example of an online 
database is the NIH dbGAP database, which is monitored by the National Institutes of 
Health, and may be made accessible to investigators approved by the U.S. government. 
Such information will not include identifying information such as name. It is also stated i n 
the Research Authorization that research data (e.g. genomic sequence) may be shared 
with regulators. The requirements for submission of genotype/phenotype data i nto the NIH 
dbGAP or any other public database will be followed as per the IRB S OP for Genomic Data 
Sharing. 
 
In the course of this research it is possible that some patients whose tumors are analyzed 
through investigational “next-generation” profiling i n a research (non-CLIA) environment will 
be found to have somatic or germline mutations in genes that are known to be associated 
with an i ncreased risk of cancer or other diseases. It will be stated in the consent that the 
participants will not receive any specific results from research tests. The consent wi ll tell 


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participants that if they wish to have genetic testing done for personal reasons than they 
should make an appoi ntment with the MSK Clinical Genetics Service or Cli nical Genetics 
Service at their site. 
 
If i n the course of this research a research findi ng is obtai ned that, i n the opinion of the 
investigator, may be critical to the preventi ve care of the participant o r their family, the 
investigator can communicate that findi ng to the MSK IRB Genomic Advisory Panel (GAP). 
The fi nding will be reviewed by the GAP to determine whether the incidental fi nding should 
be discussed with the participant. For MSK patients, in the event that the GAP determines 
that the fi nding should be discussed with the participant, and the participant has consented 
to be re -contacted, then the treati ng/consenti ng physician shall be contacted by the panel 
and asked to refer the participant to the Cli nical Genetics Service for further discussion of 
the research findi ng. 
 
The following information must be provided to GAP for review: 
• Participant Name/MRN # 
• Type of Biospecimen (tissue, blood, sali va) 
• Incidental Findi ng 
• Collection Protocol # 
• Contact: ocrgapirb@mskcc .org 
 
For non-MSK patients being treated at one of the participating i nstitutions, in the event the 
GAP determi nes that the fi nding should be discussed with the participant, and the 
participant has consented to be re-contacted, the findi ngs will be returned to the Site 
Principal Investigator. Site policies on returning these research fi ndings to the patient 
should be followed. 
 
 
We anticipate that other research assays may be i ncorporated into this pro tocol as 
technology evolves. 
 
12.3.4 Optional Fecal Samples for Microbiome Analysis 
 
Many factors have been shown to regulate the anti -tumor immune response and, in 
particular, the immune set point as determined by the basal immune responses.  Recent 
evidence has found that most, if not all, immune response are shaped by the i nteraction of 
the immune system with the microbiome[26]. Several experimental models revealed that the 
efficacy of immune therapies i ncluding CpG and checkpoint i nhi bitors can be i nfluenced by 
the microbiome.[27 ] F urthermore, studies in patients on checkpoint i nhibitors have shown 
that the microbiome can predict immune-related toxicity. [28] Thus, for this trial we plan to 
collect optional fecal samples for microbiome sequenci ng as a potential biological correlate 
for efficacy and/or toxicity at baseli ne, Wk 1, 4, 7, 10 and 13 (up to 1 wk after 
pembrolizumab). Kits for sample collection will be provided to all particip ants who opt to 
participate in this optional part of the trial, upon registration to the trial. Each kit will be 
provided with a pre -labeled box to be shipped back by the patient for analysis to the 
laboratory of the Cedars-Sinai Medical Center P I who will be conducting this analysis: 


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Page 61 of 78 
 
 
 
 
 
 
 
Dr. Stephen Shiao 
Cedars-Sinai Medical Center 
110 N. George B urns Rd #D4094D 
Los Angeles, CA 90048 
 
 
All specimens will contain the subject‟s name and date of collection. The shipping and 
receipt of specimens will be tracked i n the Medidata Rave database and by emails sent to 
the MSK P I and Cedars-Sinai Medical Center P I (barkerc@mskcc.org ; 
stephe n.s hiao@cs hs.o rg). 
 
 
 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the i nvestigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrati ve and/or other safety reasons. 
 
A subject must be disconti nued from the trial for any of the followi ng reasons: 
 
• The subject or legal representati ve (such as a parent or legal guardian) withdraws 
consent. 
 
• Confirmed radiographic disease progression 
 
Note: A subject may continue on treatment with confirmed radiographic progression if 
clinically stable or cli nically improved. 
 
• Unacceptable adverse experiences 
 
• Intercurrent illness that prevents further admi nistration of treatment 
 
• Investigator‟s decision to withdraw the subject 
 
• Subject death 
 
• The subject has a confirmed positive serum pregnancy test 
 
• Noncompliance with trial treatment or procedure requirements 
 
• The subject is lost to follow-up 
 
• Completed 24 months of treatment with pembrolizumab 
 
Note: 24 months of study medication is calculated from the date of first dose. 
Subjects who stop pembrolizumab after 24 months may be eligible for up to one year 
of additional study treatment at the discretion of the PI if they responded during the 
initial 24 months and then progressed after stopping study treatment. 
 
• Administrati ve reasons 


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After the end of treatment, each subject will be followed for 30 days for adverse event 
monitori ng (serious adverse events will be collected for 90 days after the end of treatment). 
Subjects who disconti nue for reasons other than progressive disease will have post- 
treatment follow-up for disease status until disease progression, i nitiating a non-study 
cancer treatment, withdrawi ng consent or becomi ng lost to follow-up, for up to 2 years. After 
documented disease progression each subject will be followed by telephone for overall 
survi val until death, withdrawal of consent, the end of the study, or 2 years, whichever 
occurs first. 
 
If consent is withdrawn, the subject will not recei ve any further i nvestigational product or 
further study observation. 
 
 
14.0 BIOSTATISTICS 
 
The primary endpoint of this trial is the overal l response rate of non-irradiated lesions i n 
metastatic TNBC treated with RT plus pembroli zumab, as measured by REC IS T v 1.1 at 
Week 13 of the study. A two -stage Simon‟s optimal design will be employed to the test the 
null hypothesis that the true response rate is <5% versus the alternati ve hypothesis that the 
true response rate is at least 25%, with type I error rate of 0.05 and type II error rates of 
0.20. 
 
In the first stage, we will accrue 9 patients. If no objecti ve tumor responses are observed 
among these 9 patients, then subject enrollment will be termi nated and the study wi ll be 
declared non-promising. If at least 1 response is observed among these 9 subjects, then the 
study will be expanded to enroll another 8 patients for a total of 17 treated subjects. At the 
end of the study, if 2 or fewer objective tumor responses are observed i n a cohort, then the 
study will be considered a failure. If a patient dies before the 13 week assessment, then the 
death will be considered as a non-response. If at the end of the study ≥3 tumor responses 
are observed, then pembrolizumab plus RT will be considered worthwhile. The accrual time 
is estimated to be 2 years. 
 
 
 
14.1 Rationale of Null Hypothesis for Primary Endpoint 
 
As per section 3.1.1, the objecti ve response rates in a single-arm study of pembrolizumab 
alone in metastatic TNBC patients was 19% by RECIS T 1.1, with an additional 25.9% with 
stable disease (Nanda et al, presented at San Antonio Breast Cancer Symposium 2014). 
The patients included i n this study were all PD -L1 positive, which has been hypothesized to 
result in higher overall response rates. In our study, we will include both PD-1 positive and 
PD-1 negative TNBC patients, which may result in lower response rates to pembroli zumab. 
Furthermore, we anticipate accrui ng a population of later-line metastatic TNBC patients than 
were treated in the above study, and that response rates will decli ne in patients with further 
lines of therapy. Finally, it is well known that there is currently no “targeted therapy” for 
TNBC and these patients lack effective therapeutic options. Therefore, we have selected a 
null hypothesis of 5% as an unacceptable response rate. 


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14.2 Secondary endpoints 
 
For the 1st secondary objecti ve of safety, we will defi ne adverse events as grade 3 toxicities 
secondary to radiation or grade 4 toxicities of any ki nd. We will use a sequential stopping 
rule to assess safety i n the following way. If, among the first cohort of 9 patients, we have 
more than 2 adverse events, then we wi ll stop and declare it unsafe. Or if among the total 
17 patients, we have more than 4 adverse events, then we also declare unsafe.  The time 
window for defi ning an ad verse event from treatment will be up to 8 weeks after the 
completion of RT. This sequential stoppi ng rule for safety has a stoppi ng probability of 0.06 
if the true toxicity rate is 10% or lower, and a stopping probability of 0.82 if the true toxicity 
rate is 35% or higher. Attribution of adverse event due to radiation will be determi ned by a 
panel of 3 MSK radiation oncologists. 
 
The secondary objecti ve of overall survival rate will be evaluated by the Kaplan-Meier 
method. The secondary objecti ve of progression free survi val wi ll be evaluated according to 
RECIS T v 1.1 criteria and the Kaplan-Meier method. 
 
The secondary objecti ve of o verall response as defi ned by usi ng the immune-related 
response criteria (irCR+irP R+irSD) wi ll be evaluated at 13 weeks . This rate will be 
calculated with a 95% confidence i nterval. Considering the unique response ki netics that 
have been observed with immunotherapy, not all new lesions at week 13 may not represent 
true disease progression. Therefore, for a select proportion of patients who appear to have 
new lesions on the week 13 scan, a confirmatory scan at week 19 is planned and will be 
evaluated using the response criteria outline in Section 12.1.1. 
 
14.3 Exploratory analyses 
 
Exploratory research studies will be done to eval uate the effect of this therapy on 
biomarkers using research blood draws , microbiome (fecal) analysis and tumor biopsies at 
baseline and at week 7(+1 wk). Research blood tests will be obtained at baseli ne and at 
wks 1, 4, 7, 10 and 13 of pembrolizumab concurrent with routi ne blood work prior to 
administration of pembrolizumab. Optional fecal samples will be at baseline and up to 7 
days followi ng each cycle of pembro lizumab. C hanges from the baseli ne to post-treatment 
measures of will be computed as relative proportions. Correlations between these changes 
and the overall response (as measured by REC IST v. 1.1 or safety will be exami ned by 
Wilcoxon rank sum tests. 
 
Association between PDL1 expression with both PFS and ORR wi ll be analyzed usi ng Cox 
regression and Fisher‟s exact tests, respectively. 
 
Association between LDH levels at baseli ne, week 7, and week 13 with both PFS and ORR 
will be analyzed usi ng Cox regression and Wilcoxon rank sum tests, respecti vely. 


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An additional exploratory endpoi nt will be usi ng PET-Response Criteria (PRC) to assess 
overall response (CR+PR, for non-targeted, unirradiated lesions ) followi ng pembrolizumab + 
RT. This endpoint will be analyzed descripti vely. 
 
 
 
15.0  P ARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 MSK Research Participant Registration 
 
 
Confirm eligibility as defined in the section entitled Inclusion/E xclusion Criteria. Obtai n 
informed consent, by following procedures defined i n section entitled Informed Consen t 
Procedures. During the registration process registering i ndividuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signi ng the Eligibility 
Checklist is confirming whether or not the participant is eligible to enrol l i n the study. Study 
staff are responsible for ensuring that all i nstitutional requirements necessary to enroll a 
participant to the study have been completed. See related Clinical Research Policy and 
Procedure #401 (Protocol Participant Registration). 
 
15.1.1 Registration for Participating Sites 
 
Central registration for this study wi ll take place through MSK‟s Clinical Trials Management 
System (CTMS). 
 
To complete registration and enroll a participant from another institution, the site must first 
contact the MSK study coordinator to notify him/her of the participant registration. 
 
Once the MSK study coordi nator is notified, the site will document the participant‟s consent 
by associati ng the participant to the protocol in CTMS. This will genera te a study ID number 
that is unique and must be written on all data and correspondence for the participant. 
 
After associating the participant to the protocol, the site will enter the consent status i n real- 
time, but no later than 2 busi ness da ys , from when the informed consent was signed. 
 
The following documents must be saved to CTMS withi n 2 b usi ness da ys of documenti ng 
consent status: 
 
• The completed or partially completed MSK eligibility checklist 
• The signed informed consent and HIPAA Authoriza tion form 
 
 
Supporti ng source documentation for eligibility questions (e.g. laboratory results, pathology 
report, radiology reports, MD notes, physical exam sheets, medical history, prior treatment 
records, and EKG report) will be sent to the MSK study coordi nator withi n 30 days of 
consent so eligibility can be verified. Once the MSK study coordi nator verifies eligibility the 
site will be notified to enter eligibility and on study status i n C TMS, which wi ll complete 
participant registration. 
 
15.2 Randomization 


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There is no randomization. 
 
16.0 DATA MANAGEMENT ISSUES 
 
A MSK Research Study Assistant (RSA) from the Department of Radiation Oncology 
(Breast Service) will be assigned to the study. The responsibilities of the RSA include 
project compliance, data collection, abstraction and entry, data reporti ng, regulatory 
monitori ng, problem resolution and prioriti zation, and coordi nati ng the acti vities of the 
protocol study team. 
 
The data collected for this study will be entered i nto a secure database (Medidata). Source 
documentation will be available to support the computeri zed patient record . 
 
16.01 Data and Source Documentation for Participating Sites 
 
Data 
The participating sites will enter data remotely i nto electronic Case Report Forms (eCRFs) 
withi n the Medidata Rave system. Data entry guidelines have been generated for this study 
and participating site staff will receive database traini ng prior to enrolli ng the first participant. 
The participating site P I is responsible for ensuri ng these forms are completed accurately 
and i n a timely manner. A Data and Source Documentation Submission Timeline is shown 
in Table 1 below. 
 
 
Source Documentation 
Source documentation refers to original records of observations, clinical fi ndings and 
evaluations that are subsequently recorded as data. Source documentation should be 
consistent with data entered into eCRFs. Relevant source documentation to be submitted to 
the MSK study coordinator throughout the study i ncludes: 
• 
Baseline measures to assess pre-protocol disease status (ex. C T, PSA, bone 
marrow) 
• 
Treatment records 
• 
Toxicities/adverse events that meet study reporting requirements not previously 
submitted with SAE Reports 
• 
Response designation 
• 
Any other forms of source documentation required per protocol 
 
 
Source documentation must include a minimum of two identifiers to allow for data 
verification. MSK will maintai n the confidentiality of any subject-identifiable i nformation it 
may encounter. 
 
Table 1: Data and Source Documentation Submission Time lines 
 
 
Time point 
Data 
Source Documentation 
Baseline 
Within 24 hours of consent 
(see section15.1.1) 
Within 24 hours of consent 
(see section 15.1.1) 


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Study Visits 
Within 14 days of the study visit 
Within 14 days of the study visit 
Serious Adverse 
E vents 
Within 3 days of event(see section 17.2.1); 
Updates to be submitted as availabl e 
Within 3 days of event (see section 
17.2.1) 
 
16.1 Quality Assurance 
 
Regular registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routi ne data quality reports will be generated to assess missing data 
and i nconsistencies. Accrual rates and extent and accuracy of evaluations and fo llow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random -sample data quality 
and protocol compliance audits may be conducted by the study team, at a mi nimum of once 
per year, more frequently if indicated. 
 
16.1.1 Quality Assurance for Participating Sites 
 
Monitoring 
 
Each data collection site i ncluding MSK wi ll be monitored periodically by MSK. Monitoring 
visits will be conducted every 4-8 weeks, dependent upon the protocol and patient accrual 
and activity. The monitor and the participating site will identify a mutually agreeable time for 
each monitoring visit. At least 10 busi ness days ahead of the visit, the monitor will send the 
site a notification letter that details the date and expectations of the visit. Monitori ng may be 
conducted remotely or in-person.  The monitor must be allowed access to all protocol 
regulatory and source documents to assess compliance with the protocol, federal 
regulations and GCPs. The monitor will assess all data for completeness of source 
documents and to confirm data being recorded i n the eCRFs is accurate. If monitori ng will 
be done remotely, sites must agree i n advance to provide source documents as required. 
During onsite visits, the monitor will also i nspect and review the facilities and investigational 
product storage area.  The participating site will mai ntain accurate records of dispensi ng of 
study drugs for drug accountability. Drug accountability will be reviewed at monitoring visits. 
Study drug and bottles must be retained until the monitor performs drug accountability of the 
study drug(s). 
 
 
The site Investigator(s) and/or an authori zed member of the Investigator‟s staff should allow 
sufficient  time  during  monitori ng  visits  to  discuss  fi ndings.  The  Investigator(s)  or  an 
authori zed member of the Investigator‟s  staff will make any necessary corrections during 
and between monitoring visits 
 
Auditing 
Each participating site accrui ng participants to this protocol may be audited by MSK for 
protocol and regulatory compliance, data verification and source documentation.  Audits of 
selected participant records may be conducted on-site or remotely. 


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Audits wi ll be summarized and a fi nal report will be sent to the P I at the audited participating 
site within 30 days of the audit. The report will i nclude a summary of fi ndings, participant- 
specific case review, recommendations on any performance and/or shortcomi ngs and 
request fo r corrective action, when necessary. When correcti ve action is required, the 
participating site must reply within 45 days of receipt of the audit report with their corrective 
action plan. 
 
 
 
16.2 Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute i n September 2001.  The plans address the 
new policies set forth by the NC I in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitori ng of Clinical Trials”, which can be found at 
http://ca ncertrials.nci.ni h.go v/researc hers/ds m/inde x.html.  The DSM P lans at MSK were 
established and are monitored by the Office of Clinical Research.  The MSK DSM Plans can 
be found on the MSK Intranet at: 
http://msk web5.mskcc .org/i ntra net/_assets /_tab les/co nte nt/35968 9/Data_safety%20 Monito ri 
ng07.pdf 
 
16.3 Regulatory Documentation 
 
Prior to implementing this protocol at MSK, the protocol, i nformed consent form, HIPAA 
authori zation and any other i nformation pertaining to participants must be approved by the 
MSK Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol 
document and each participating site will utili ze that document. 
 
The following documents must be provided to MSK before the participating site can be 
initiated and begin enrolling participants: 
• Participating Site IRB approval(s) for the protocol, appendices, informed consent 
form and HIPAA authori zation 
• Participating Site IRB approved informed consent form 
• Participating Site 1572 
• Conflict of Interest forms for Participating Site Investigators on the 1572 
• Participating Site IRB membership list 
• Participating Site IRB‟s Federal Wide Assurance number and OHRP Registration 
number 
• Curriculum vitae and medical license for each i nvestigator and consenting 
professional 
Documentation of Human S ubject Research Certification training for investigators 
and key staff members at the participating site 
• Documentation of Good Clinical Practice (GCP) trai ning for the P I and co -P I at the 
participating site 
• Participating site labora tory certifications and laboratory normal reference ranges 
 
Upon receipt of the required documents, MSK will formally contact the site and grant 
permission to proceed wi th enrollment. 


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16.3.1 
Amendments 
 
Each change to the protocol document must be organized and documented by MSK and 
approved first by the MSK IRB/PB. Protocol amendments that affect MSK only (e.g. change 
in MSK Co-Investigator, MSK translation, etc.) do not require IRB review at the participating 
site(s). A ll other protocol amendments will be immediately distributed to each participating 
site upon receipt of MSK IRB/PB approval. 
 
 
Each participating site must obtai n IRB approval for all amendments withi n 45 ca le ndar da ys 
of MSK IRB/PB approval. If the amendment is the result of a safety issue or make s eligibility 
criteria more restricti ve, participating sites wi ll not be permitted to continui ng enrolli ng new 
participants until site IRB approval of the revised protocol documents is granted and 
submitted to MSK. 
 
Site-Initiated Amendments/Modifications 
 
Each participating site must provide all site IRB approvals for 
amendments/modifications and the most current approved version of the site 
informed consent form and HIPAA authorization at the time of approval. Documents 
must be submitted to MSK on a continui ng basis. 
 
16.3.2 Additional IRB Correspondence 
 
Continui ng Review Appro val 
The Continui ng Review Approval letter from each participating site‟s IRB and the most 
current approved version of the informed consent form must be submitted to MSK withi n 7 
days of expiration. Failure to submit the re-approval i n the stated timeline will result in 
suspension of new participant enrollment. 
 
Deviations 
A protocol deviation on this study is defined as any incident involvi ng non-adherence to an 
IRB approved protocol. Deviations typically do not have a significant effect on the rights, 
safety, or welfare of research participants or on the integrity of the resultant data. Deviations 
that represent unanticipated problems i nvolvi ng risks to participants or others, or serious 
adverse events should be reported according to sections 17.3 and 17.5. 
 
Deviations that do not adversely affect the rights and/or welfare of the participant or the 
scientific validity of the study and are related to protocol scheduling changes outside of the 
allowed wi ndow due to a holiday (e.g., New Year‟s, Thanksgi ving, etc.) and/or i nclement 
weather or other natural event do not require reporti ng to the MSK IRB/PB. However, they 
must be clearly documented in the patient‟s medical record. 
 
 
 
Prospective Deviations 


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Deviations to the research protocol that involve an i nformed consent procedure change 
and/or treatment/pharmacy alterations that are not allowed by the protocol require 
prospective approval from the MSK IRB /PB prior to the change bei ng carried out. 
Participating sites should contact the MSK P I who will i n turn seek approval from the MSK 
IRB/PB. Deviations to the research protocol that i nvolve patient eligibility will not be 
permitted. 
 
Retrospective Deviations 
 
Deviations that i nclude a change or departure from the research protocol without prior 
approval from the MSK IRB/PB are considered retrospective deviations. Retrospective 
deviations should be reported to the MSK P I as soon as possible, who will in turn report the 
deviation to the MSK IRB/PB as per MSK guidelines. 
 
 
Participating Site IRB Reporting 
Participating sites should report all deviations to their i nstitution‟s IRB pe r local guidelines. 
Approvals/acknowledgments from the participating site IRB for protocol deviations should be 
submitted to MSK upon receipt. 
 
 
Other co rrespo ndence 
Participating sites should submit all other correspondence to their i nstitution‟s IRB acco rding 
to local guidelines, and submit copies of official site IRB correspondence, i ncludi ng 
approvals and acknowledgements, to MSK. 
 
 
16.3.3 
Document maintenance 
The MSK P I and participating site P I will maintai n adequate and accurate records to fully 
document protocol implementation and allow data to be subsequently verified. 
 
The participating sites will ensure that all regulatory documents and participating site IRB 
correspondence are mai ntained in an on-site regulatory binder and sent to MSK as outlined 
withi n the protocol. The on-site regulatory binder will be reviewed by the designated study 
monitor at monitoring visits. A regulatory binder for each participating site will also be 
maintai ned at MSK withi n the institution‟s Protocol Information Mana gement S ystem (P IMS). 
 
After study closure, the participating sites will mai ntain all source documents, study related 
documents and eCRFs for 7 years. 
 
 
 
16.4 Noncompliance 
 
If a participating site is noncompliant with the protocol document, accrual pri vileg es may be 
suspended and/or contract payments may be withheld, until the outstandi ng issues have 
been resolved. 
 
 
 
17.0 PROTECTION OF HUMAN SUBJECTS 


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Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to IRB guideli nes. 
 
Inclusion of Women and Minorities: Memorial S loan-Ketteri ng Cancer Center has filed 
forms HHS 441 (ci vil rights), HHS (handicapped individual), 639 -A (sex discrimination), and 
680 (age discrimination); we also take due notice of the NIH policy concerni ng i nclusion of 
women and minorities i n clinical research populations. Patients of all raceswill be accepted 
into the protocol. The proposed study population is as described in section 7.0. 
 
Exclusion of Lactati ng or Pregnant Women: Children have been excluded from this study. 
Triple negative breast cancer is an adult cancer. Thus, the relevance of this drug to the 
pediatric population has not been established. Lactating and pregnant women are also 
excluded because of potential anti-proliferative effects of chemotherapy that may be harmful 
to the developing fetus or nursi ng i nfant. 
 
Benefits: It is possible that this treatment wi ll result i n shri nkage of triple negative breast 
cancer or i n a stabilization of an otherwise progressing disease. It is not known, of course, 
whether these or any other favorable events will occur. It is not known whether this 
treatment will affect the overall survival of the patients. 
 
Costs: The patient will be responsible for the costs of standard medical care, i ncludi ng, CT 
scans, all drug administration fees and all hospitali zations, even for complications of 
treatment. Pembrolizumab will be supplied to patients by Merck at no cost. Patients will not 
be responsible for the costs of blood procurement obtai ned for research purposes or the 
cost for obtai ning the tumor biopsy for research purposes. 
Incentives: No i ncenti ves will be offered to patients/subjects for participation in the study. 
Alternati ves: Patients may be eligible for other investigational studies, or focus on palliative 
care options. 
 
Confidentiality: E very effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential. Patient‟s name or any other personally identifyi ng 
information will not be used i n reports or publications resulti ng from this study. The Food 
and Drug Admi nistration or other authori zed agencies (e.g., qualified monitors) may review 
patients‟ records and pathology slides, as required. 
 
17.1 Privacy 
 
MSK‟s Privacy Office may allow the use and disclosure of protected health i nformation 
pursuant to a completed and signed Research A uthori zation form. The use and disclosure 
of protected health i nformation will be limited to the indi viduals described in the Research 
Authori zation form. A Research Authori zation form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 Serious Adverse Event (SAE) Reporting 


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An adverse event is considered serious if it results i n ANY of the followi ng outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitali zation 
• 
A persistent or significant i ncapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitali zation may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or s ubject and may require medical or surgical 
intervention to prevent one of the outcomes listed i n this definition 
  
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant‟s last i nvestigational treatment or intervention. A ny 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported . 
  
If an SAE requires submission to the IRB office per IRB SOP RR -408 „Reporti ng of Serious 
Adverse E vents‟, the SAE report must be sent to the IRB withi n 5 calendar days of the 
event. The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to  saemski nd@mskcc .org. 
 
 
For all other trials: Reports that i nclude a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to  sae@mskcc .org. 
 
 
The report should contai n the following i nformation: 
Fields populated from C RDB: 
• 
Subject‟s i nitials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and ti tle 
 
Data needing to be entered: 


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• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the followi ng 
o A explanation of how the AE was handled 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The P I‟s signature and the date it was signed are required on the completed report. 
 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office. 
 
17.2.1 Sponsor Serious Adverse Event (S AE) Reporting 
 
Any serious adverse event, or follow up to a serious adverse event, i ncludi ng death due to 
any cause other than progression of the cancer under study that occurs to any subject from 
the time the consent is signed through 90 days followi ng cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck 
product, must be reported withi n 5 calendar days to the MSK Safety Office and within 2 
working days to Merck Global Safety. 
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the i nvestigator at 
any time outside of the time period specified in the previous paragraph also must be 
reported immediately to the Sponsor and to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number: +1-215-993-1220 
 
A copy of all 15 Day Reports and A nnual Progress Reports is submitted as required by 
FDA, European Union (E U), Pharmaceutical and Medical Devices agency (PMDA) or other 
local regulators. Investigators will cross reference this submission according to local 
regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of 
submission. Additionally investigators will submit a copy of these reports to Merck & Co., 
Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 


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All subjects with serious adverse events must be followed up for outcome. 
 
Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (EC I) (see Appendix C) and must be recorded as such on the Adverse Event case 
report forms/worksheets and reported within 2 working days to Merck Global Safety. If they 
are serious adverse events , they must be reported to MSK Safety Office within 5 calendar 
days. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
Events of clinical interest for this trial i nclude: 
 
1. A n overdose of Merck product, as defi ned in Section 11.1.3 - Defi nition of an Overdose 
for This Protocol and Reporti ng of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
 
2. A n elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubi n lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkali ne phosphatase lab value that is less 
than 2X the upper limit of normal, as determi ned 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 underlyi ng etiology. The trial site guidance for assessment and 
follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent). 
 
3. In the event a subject develops any of the followi ng non-serious AEs that do not result i n 
hospitali zation, a detailed narrati ve of the event should be reported as an ECI withi n 2 
working days to Merck Global Safety: 
 
a. Grade ≥ 3 diarrhea 
b. Grade ≥  3 colitis 
c. Grade ≥ 2 pneumonitis 
d. Grade ≥ 3 hypo- or  hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Cli nical Interest and 
Immune-Related Adverse E vent Guidance Doc ument.”  This document provides guidance 
regarding identification, evaluation and management of EC Is and irAEs. Additional EC Is 
are identified i n this guidance document and also need to be reported to the Sponsor within 
5 calendar days to the MSK Safety Office (only if the EC I is a serious adverse event) and 
withi n 2 working days to Merck Global Safety. 
 
Subjects should be assessed for possible EC Is prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune- 
related event. Subjects who develop an EC I thought to be immune -related should have 


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additional testing to rule out other etiologic causes. If lab results or symptoms i ndicate a 
possible immune-related EC I, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then i t is assumed to be immune -related. 
 
ECIs that occur in any subject from the date of first dose through 90 days followi ng 
cessation of treatment, or the initiation of a new anticancer therapy, whichever is earlier, 
whether or not related to the Merck‟s product, must be reported withi n 5 calendar days to 
the MSK Safety Office (only if the EC I is a serious adverse event) and within 2 working days 
to Merck Global Safety. 
 
17.3 SAE Reporting for Participating Sites 
 
 
Responsibilities of Participating Sites 
 
• Participating sites are responsible for reporting all SAEs to their local IRB per local 
guidelines. Local IRB SAE approvals/acknowledgments must be sent to MSK upon 
receipt. 
• Participating sites are responsible for submitting the SAE Report Form to MSK withi n 
3 cale ndar da y of learning of the event. 
• When a death is unforeseen and indicates participants or others are at increased risk 
of harm, participating sites should notify the MSK P I as soon as possible but withi n 
24 ho urs of the time the site becomes aware of the event. 
 
SAE contact information: 
Email: ReidyM@mskcc.org to the attention of 16-032 Research Staff (C linical Research 
Coordinator Megan Reidy) 
 
AND 
 
MSK PI Dr. C hristopher Barker at: barkerc@mskcc.org 
 
Responsibilities of MSK 
 
• MSK Research Staff are responsible for submitti ng all SAEs to the MSK IRB /PB as 
specified in 17.2 and Merck. 
• The MSK P I is responsible for i nforming all participating sites about all unexpected 
SAEs that are either possibly, probably, or definitely related to the study intervention 
withi n 15 days of receivi ng the stamped SAE report from the MSK IRB/PB. 
• The MSK P I is responsible for i nforming all participating sites within 24 hours or on 
the next busi ness day about a death that is unforeseen and indicates pa rticipants or 
others are at i ncreased risk of harm. 
 
17.4 Safety Reports 
MSK must submit outside safety reports to the MSK IRB/PB according to institutional 
guidelines. All outside safety reports will be made available to the participating sites. 
Outside safety reports that are reportable to the MSK IRB/PB wi ll be distributed to the 
participating sites immediately upon recei ving a stamped copy from the MSK IRB/PB. 


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Participating sites wi ll receive a special alert for any outside safety reports that warrant a 
significant change to the conduct of the study. Outside safety reports t hat are not reportable 
to the MSK IRB/PB, will be sent to the participating sites monthly. 
 
 
Participating sites are responsible for submitting safety reports to their site IRB per their 
local guideli nes. A ll site IRB approvals/acknowledgments of safety re ports must be sent to 
MSK upon receipt. 
 
17.5 Unanticipated Problems 
 
Unanticipated problems involving risks to participants or others (UPs) are defined as any 
incident, experience or outcome that meets all of the followi ng criteria: 
• Unanticipated (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described i n the protocol-related documents, such as the IRB- 
approved research protocol and i nformed consent document; and (b) the 
characteristics of the subject population being studied; and 
• Related or possibly related to participating in the research (possibly related means 
there is a reasonable probability that the i ncident, experience or outcome may have 
been caused by procedures involved i n the research); and 
• Suggests that the research place participants or others at a greater risk of harm 
(includi ng physical, psychological, economic, or social harm) than was previously 
known or recogni zed. 
 
 
Participating sites are responsible for reporting all UPs to MSK as soon as possible but 
withi n 3 cale ndar days  of learni ng of the event. UPs that are SAEs should be reported to 
MSK via SAE Report form as per section 17.3. All other UPs should be reported to MSK 
in a memo signed by the site P I. 
 
 
MSK is responsible for submitti ng UPs to the MSK IRB/PB accordi ng to institutional 
guidelines. In addition, MSK is responsible for notifying participating sites of all non-SAE 
UPs that may affect the sites. 
 
 
 
18.0  INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenti ng professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be i nformed that they are free to 
withdraw from the study at any time. All participants must sign an IRB /PB -approved consent 
form i ndicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this 
Center. The consent form will include the followi ng: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 


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IRB Number: 16-032 A(8) 
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Page 76 of 78 
 
 
 
 
 
2. The length of study and the likely follow-up required. 
3. Alternati ves to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients wi ll be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study i nterventions/i nteractions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenti ng professional wi ll 
fully explai n the aspects of patient pri vacy concerning research specific i nformation.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authori zation component of the informed consent form. 
 
Each participant and consenti ng professional will sign the consent form. The participant 
must recei ve a copy of the signed informed consent form. 
 
18.1 INFORMED CONSENT PROCEDURES FOR PARTICIPATING SITES 
 
The investigators listed on the Consenting Professionals Lists at each participating site may 
obtain i nformed consent and ca re for the participants accordi ng to good cli nical practice and 
protocol guideli nes. 
 
A note will be placed i n the medical record documenting that informed consent was 
obtained for this study, and that the participant acknowledges the risk of participation. 
 
 
 
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20.0  APPENDICES 
 
APPENDIX B: Requisition for Research Biopsy Specimens 
 
APPENDIX C: PEMBROLIZUMAB PROGRAM (MK-3475) Event of Clinical Interest 
Guidance Document, Version 5.0 
 
APPENDIX D: MK-3475 Drug Preparation Instructions‟ manual